Mast Cell Response to Parasites: from Recognition and Activation to Host Defense Modulation

Keywords

Parasite Protozoa Helminth Mast Cell Host Defense Immunity

Abstract

Parasites represent a diverse and widely distributed group of pathogens that cause diseases with significant global health implications. The interaction between parasite and host is characterized by a high degree of complexity, with both parties continuously adapting to changes in the other. The successful host invasion is largely attributable to the evasion strategies employed by parasites to ensure their survival in immunocompetent individuals. In turn, the host’s defense mechanisms utilize a variety of structures and processes, ranging from primary barriers to the most sophisticated ones, to counter the parasite attack. Acting as an early line of defense, the immune system includes a variety of cell types that are capable of recognizing, destroying, and eliminating infectious agents. Undoubtedly, the orchestration of first-line innate immune responses but also adaptive immunity processes during infection depends to a large extent on the involvement of tissue-resident mast cells (MCs). MCs are capable of supporting immune reactions to parasites through a broad spectrum of processes, including degranulation, synthesis and release of cytokines/chemokines and other mediators, and the generation of reactive oxygen species (ROS). They may also be involved in immune cell recruitment, phagocytosis, and the provision of extracellular DNA traps. Despite the well-documented association of MCs with antibacterial and antiviral defense, their role in host protection against parasites remains incompletely identified. This article provides an overview of the engagement of MCs in host defense mechanisms developed during parasitic infections. Furthermore, it considers the impact of parasites or parasite-derived molecules on the various aspects of MC activity.

Introduction

Parasitic infections caused by protozoa or helminths are distributed virtually worldwide, but predominantly they constitute a significant health problem in tropical developing countries where they are often neglected. Among the parasitic diseases with important mortality or morbidity rates, are malaria, leishmaniasis, amoebiasis, trypanosomiasis, and schistosomiasis. Furthermore, toxoplasmosis, ascariasis, and taeniasis represent common human parasitic illnesses. The widespread prevalence of parasites is due to their diverse anatomical, physiological, and behavioral adaptations, which allow them to survive even in extreme conditions [1]. Despite the global influence of parasites, effective antiparasitic therapeutics are limited, and malaria is currently the only parasitic disease for which two vaccines are available for humans and recommended by the World Health Organization (WHO) [2]. Depending on the species, parasites may be transmitted to their suitable hosts in several ways, both vertically and horizontally. For example, protozoa and helminths can be spread orally by ingesting water or food contaminated with invasive forms. A defining characteristic of certain parasitic nematodes is their capacity to autoinfect and, as a consequence, self-replicate within their host. Other modes of parasitic infection include active penetration through the skin or mucous membranes or direct contact between hosts. Finally, many blood parasites are transmitted by arthropod representatives that serve as disease vectors [3]. Infection with parasites may result in a spectrum of symptoms, ranging from mild discomfort to severe illness. In some individuals, infection progresses to a chronic phase, which, depending on the type and quantity of parasites, can lead to weakness, severe anemia, and malnutrition with weight loss. It is important to note that asymptomatic carriers of parasites constitute a great challenge for public health, meaning they have a silent infection. Nevertheless, they contribute to the transmission of the infection to the others.

Despite the large number and diversity of antigens presented by the parasite to the host immune system and the response initiated against them, parasites try to survive within the body host by using multiple evasion strategies that have been acquired over millions of years of evolution [4]. In turn, the host's defense mechanisms range from primary barriers to more complex responses involving diverse immune cells and mediators capable of identifying and eliminating infectious agents [5]. Undoubtedly, the orchestration of first-line innate immune responses and adaptive immunity during infection relies on the coordinated activity of various immune cells, including macrophages, granulocytes, dendritic cells, natural killer (NK) cells, B lymphocytes, and T lymphocytes [6]. Among these, tissue-resident mast cells (MCs) occupy a strategic position at the host-environment interface, especially in barrier tissues such as skin, and the gastrointestinal and genitourinary mucosa, which are common entry sites for parasites. Due to their location and rapid response capacity, MCs are well positioned to act as important responders during parasitic infections. These cells recognize pathogen-associated molecular patterns (PAMPs)/microbe‐associated molecular patterns (MAMPs), release preformed and newly synthesized bioactive mediators, recruit and activate other immune cells, and participate in processes such as phagocytosis and extracellular DNA trap (MCETs) formation [7, 8]. Although numerous studies have addressed the role of MCs in anti-parasitic defense, their involvement remains incompletely characterized. Therefore, the aim of the present article is to provide an overview of MC engagement in host defense mechanisms developed during parasitic infections. Furthermore, the article considers the impact of parasites or parasite-derived molecules on the various aspects of MC activity.

Hallmarks of the host immune response to parasites

To survive until parasites reach maturity and complete their life cycle, these organisms have evolved a variety of complex strategies. Frequently, these strategies are stage-specific, allowing parasites to use, avoid, or modulate the host's immune response and metabolism [9, 10]. Conversely, physical and chemical barriers, as well as numerous innate and adaptive components of the host immune system, have been identified as either less or more crucial during a parasite attack. However, the direction of the host immune response, reflecting differences in infection strategies, tissue localization, and interactions with the immune system, is primarily determined by the type of parasitic invader.

The primary line of host defense against parasites, as in the case of bacteria, viruses, or fungi, consists of anatomical and structural barriers, particularly the skin and mucosal surfaces, which are further supported by chemical defenses. Nevertheless, as the common site of infection or route of access for the parasites, mucosal barriers are frequently unable to repel the attack. This phenomenon has been well-described in the context of gut protozoa, such as Entamoeba histolytica [11] and Giardia duodenalis [12] or Toxoplasma gondii [13], which may lead to the opening of intercellular tight junctions and the subsequent breakdown of the intestinal mucosal barrier. Mucins, as integral components of the mucus layer, can either block parasite colonization or facilitate their expulsion. Conversely, data indicate that G. duodenalis [14], E. histolytica [15], and Trichuris muris [16] can proteolytically cleave the major structural component of the mucus gel, i.e., mucin 2 (MUC2), and disrupt the host colonic mucus by breaking down the macromolecular structure and invading the underlying epithelium. Another crucial element of mucosal defense is secretory immunoglobulin A (sIgA), which neutralizes pathogens and prevents their adhesion to the epithelium. sIgA antibodies are important for the clearance of E. histolytica [17], Giardia sp [18, 19], and Clonorchis sinensis [20]. In addition, some authors have proposed that IgA could function as a biomarker for worm infections [21, 22].

Recently there has been renewed interest in the interaction between the host gut microbiota and invading parasites. It is well established that intestinal parasites have a profound impact on the composition and diversity of the host microbiota, which in turn has significant implications for the efficacy of host defense mechanisms [23, 24]. Conversely, an increasing body of evidence suggests that the intestinal microbiota may be firmly involved in the defense against parasites [25, 26]. Nevertheless, the precise function of the gut microbiota in this process is still not well understood. Some reports indicate that the expulsion of parasites may be strongly dependent on the composition of the microbiota. For example, Li and colleagues [27] demonstrated that early Trichinella spiralis infection reduces gut microbiota diversity and alters its composition, leading to a predominance of bacteria that produce pro-inflammatory metabolites, such as ceramides. In the subsequent phase of the infection, the same authors observed an increase in the number of representatives belonging to the Lactobacillaceae family that have anti-inflammatory properties through the production of short-chain fatty acids (SCFAs). The presence of G. duodenalis was found to be reduced by Lactobacillus sp., while the bacteriocins produced prevented parasite adhesion [28–30]. It has been demonstrated that SCFAs, the principal microbiota-derived metabolites, exhibit inhibitory activities against protozoa [31, 32]. Microbiota-derived SCFAs are well-known anti-inflammatory mediators and regulatory T cell (Treg) inducers for host intestinal immunity, as was documented in the case of Echinococcus multilocularis-infected mice [33].

Following the breach of anatomical and chemical barriers by invaders, the host immune system must first recognize the threat, after which most, if not all, immune cell types are mobilized in antiparasitic defense. The identification of pathogens is achieved by expressing a set of pattern-recognition receptors (PRRs) by host immune cells. PRRs are able to recognize PAMPs/ MAMPs derived from microbes or parasites, including proteins, lipoproteins, lipids, and nucleic acids. PRRs also detect endogenous danger-associated molecular patterns (DAMPs) released upon cellular stress or tissue injury. These receptors include Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and C-type lectin receptors (CLRs) [34]. Some of these have been documented to detect components derived from parasites (Fig. 1). For instance, TLR1/2 and TLR2/6 heterodimers are capable of recognizing glycosylphosphatidylinositol (GPI) anchors of Plasmodium sp. [35] and/or Trypanosoma sp. [36]. Lipopeptidophosphoglycan (LPPG) of E. histolytica and Taenia crassiceps carbohydrates are the most common ligands for TLR4 [37, 38]. TLR11 and TLR12 are localized to endosomes to recognize T. gondii-derived profilin [39]. Other significant TLRs include TLR3, TLR7, and TLR9, which may collaborate with TLR11 and TLR12 in the host response to T. gondii [40, 41]. In turn, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), a known CLR, has been demonstrated to bind to Leishmania sp. or Schistosoma mansoni egg antigens [42, 43].

Each type of innate immune cell occupies a specific role within the host's defense system, collaborating with others to form interconnected networks regulated by cytokines and other molecules. Macrophages and neutrophils are among the most crucial players in the immune response due to their multifaceted functions. Concerning their capacity to phagocytose parasites, these cells can do so with some protozoa, smaller helminth larvae, and eggs. However, the adult forms are typically too large to be engulfed. Instead, macrophages and neutrophils contribute to the immune response against helminths by migrating to the infection site, secreting effector molecules such as reactive oxygen species (ROS), and recruiting other immune cells to attack the parasite. Of note is the observation that macrophages and neutrophils release extracellular DNA traps in response to protozoa and helminths [44–46]. Regarding antiparasitic properties of eosinophils, they are primarily based on their increase in the circulation and affected tissues during helminth infection. Eosinophils bind to the worm larvae through antibodies or complement, after which they release intracellular granules containing toxic substances for parasites, such as major basic protein (MBP), eosinophil cationic protein (ECP), and many others. Also, NK cells control parasitic infections by contributing to parasite lysis and producing significant amounts of interferon (IFN)-γ, a cytokine that is vital in the context of infection with intracellular protozoan parasites [47]. Nevertheless, the most characteristic feature of the immune response to parasite attack is the binding of immunoglobulin E (IgE) to the high-affinity IgE Fc receptor (FcεRI) on basophil and MC surfaces, which triggers degranulation and the release of numerous mediators, including interleukin (IL)-4 and IL-13. These, in turn, trigger a T-helper type 2 (Th2) response [48].

The innate immune defense system is supported by its specific soluble components. Among these, the complement system plays a pivotal role in the elimination of pathogens by forming the membrane attack complex (MAC) and promoting an inflammatory reaction on the surface of invaders. The available data regarding the effectiveness of the complement system in host defense against parasites appears to be largely ambiguous. Although the host complement system has been demonstrated to play a beneficial role during malaria infection [49], an increasing number of studies point to the effective evasion of this mechanism by many other parasites, such as Leishmania sp. [50], Trypanosoma sp. [51], and Fasciola hepatica [52]. Parasites avoid complement attacks using strategies including the expression of proteins that are homologous to host regulators to inhibit complement activation or the expression of proteins that target different complement components, to inhibit complement function and final formation of the MAC [53].

The role of numerous other effector molecules produced by the host organism for the elimination of parasites has been documented. Substances with a recognized role in anti-parasitic defense are antimicrobial peptides (AMPs). Among the AMPs, the defensins are the most extensively researched family, with several members demonstrating antiparasitic activities. The direct parasiticidal activity of β-defensin 130 (DEFB130) against Plasmodium falciparum [54], defensin α-1 against Trypanosoma cruzi [55], α-defensin-5 against T. gondii [56], and β-defensin-1 and -2 against Cryptosporidium parvum [57] has been observed. Furthermore, the potential of cathelicidins to damage E. histolytica or Leishmania sp. has also been revealed [58, 59].

The ability of parasites to evade innate immune mechanisms highlights the importance of adaptive immunity, which exhibits certain general patterns in its response. Typically, extracellular parasites (mainly helminths) induce a Th2-type response. The main drivers of this response are CD4⁺ Th2 cells, which release type-2 cytokines such as IL-4, IL-5, and IL-13, with contributions from group 2 innate lymphoid cells (ILC2s) that serve as an additional source of these cytokines [60]. Type 2 immune responses can be accompanied by IL-10, produced by Th2 cells as well as other T cell subsets and innate immune cells, which primarily exerts regulatory and immunosuppressive functions [61]. In turn, IL-4, mainly produced by Th2 cells, is important for Th2 cell differentiation, as well as for the activation of the class switching mechanism in B cells that enables IgE synthesis [62]. Conversely, intracellular protozoan infections rely on a Th1-type response to resolve infection and results in a significant increase of Th1 cytokines, including IL-1β, IL-12, tumor necrosis factor (TNF), and most importantly, IFN-γ. Some data suggests that IFN-γ-producing CD4⁺ Th1 cells are important for the infection caused by Leishmania sp. [63] and Plasmodium sp. [64]. However, it should be stressed that many intracellular protozoa have evolved sophisticated egress mechanisms that allow them to evade immune detection and destruction [65].

Although the aforementioned mechanisms and components each contribute in a parasite-specific manner, one of the central characteristics of anti-parasitic immunity is the activation of IgE-mediated type 2 responses. In this context, MCs emerge as pivotal effector cells acting at barrier sites, capable of bridging innate and adaptive immunity, and shaping the outcome of parasitic infections.

MCs and their role in host defense
The presence of MCs at surfaces in contact with the external environment, a common site of microbe attack, indicates that these cells constitute a potent arm of the immune response against external invaders. MCs are typically located in the subepithelial layers of the skin, the respiratory system, or the gastrointestinal and genitourinary tracts, but they are also found in the adipose tissue or around the blood vessels or nerves [66]. Furthermore, a number of additional factors contribute to the crucial role of MCs in host defense. MCs represent a dominant source of bioactive compounds that may affect all stages of microbial-induced inflammation, from its initiation, maintenance, and modulation, to resolution [67]. They include pre-formed mediators present within cytoplasmic granules (for example, histamine and proteases), lipid-derived molecules synthesized from arachidonic acids (for example, prostaglandins (PGs) and leukotrienes (LTs)), and a wide array of cytokines and chemokines [68]. The direct antimicrobial activity of MCs may be mediated through the release of antimicrobial peptides (AMPs) with multidirectional mechanisms of action [69]. Also, the formation of ROS or reactive nitrogen species (RNS), such as nitric oxide (NO), represents an important approach of MCs that contributes to pathogen eradication [70]. Crucial to the MC involvement in the host defense is their capacity to efficiently destroy microorganisms through phagocytosis and kill them through oxidative and non-oxidative pathways. Following phagocytosis, MCs can process pathogen-derived antigens for presentation mediated by class I and II major histocompatibility complex (MHC) molecules, thereby initiating adaptive antimicrobial immunity [71]. Also, MCs are able to release their nuclear DNA to become MCETs, which consequently trap and eliminate a variety of pathogens [72, 73]. Additionally, MCs may indirectly regulate host defense mechanisms through the activation of other immune cells and the release of chemoattractants, which recruit, for example, other phagocytic cells to the site of infection [74].
As mediators of host defense, MCs express multiple classes of PRRs that detect various MAMPs/PAMPs or endogenous DAMPs. Expression of TLRs, RLRs, NLRs, and CLRs has been confirmed in a wide range of MC types and MC cell lines [75, 76]. The selective activation of PRRs represents an essential mechanism in regulating the type of MC antimicrobial response. For example, PAMPs associated with bacteria are mainly recognized by TLR or NLR representatives. RLRs and some TLRs can detect viral double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), or envelope proteins. In turn, MCs express CLRs, which are essential for the sensing of fungal antigens [75]. However, limited data are available concerning the detection of parasite components by MCs. In a study conducted by Furuta and colleagues [77], it was demonstrated that MCs can produce TNF in response to the binding of TLR4 or FcεRI/IgE to malaria parasite-derived peroxiredoxin. A recent report indicates that 5ʹ-methylthioinosine, a P. falciparum-specific intermediate of the purine salvage pathway, is an agonist for TLR8, which has been documented to be expressed in MCs [78]. Besides, some studies suggest that parasites or parasite-derived constituents may influence the expression of certain PRRs in MCs. For example, stimulation of a hybrid rat mast cell line (HRMC) with either F2 or the total soluble extract of G. duodenalis resulted in an increase (but non-significant) in TLR2 and TLR4 expression in these cells [79]. Further, lipophosphoglycan (LPG) from Leishmania mexicana was observed to enhance the expression of TLR2 in bone marrow-derived MCs (BMMCs) [80].

Parasites affect MC activity

Modes of MC response to Protozoa
Evidence indicates that various species of parasitic protozoa may directly affect MC activity in vitro. Many available data concern their impact on the generation and/or release of bioactive molecules from MCs. Firstly, it has been documented that protozoa have different effects on the MC degranulation and the secretion of preformed mediators, including those known for their potent proinflammatory properties. The trophozoites of G. duodenalis and their total soluble extract have been observed to increase the expression of tryptase and the secretion of histamine from rat peritoneal MCs (PMCs) [79, 81]. Conversely, it has been demonstrated that the stimulation of BMMCs with an extract containing soluble proteins of Giardia activates those cells, resulting in the release of tryptase, but not degranulation [82]. A more pronounced stimulatory effect observed with whole Giardia trophozoites compared to the extract alone indicates the presence of additional factors that enhance MC degranulation and preformed mediator release. In turn, unambiguous data indicate that another common flagellated protozoan parasite, i.e., Trichomonas vaginalis, is capable of triggering MC degranulation. It has been reported that T. vaginalis-derived excretory-secretory product (ESP) or live trichomonads activate rat PMCs and human MC (HMC-1) line to degranulate [83–85]. It is worthy of note that when HMC-1 cells were exposed to live trichomonads, there was a notable increase in β-hexosaminidase release in proportion to the number of trichomonads present. Moreover, the addition of supernatants derived from human vaginal epithelial cells incubated with live T. vaginalis to HMC-1 cell cultures led to an increase in β-hexosaminidase secretion [86]. Also, parasites belonging to the Trypanosoma genus, i.e., Leishmania donovani and Leishmania tropica as well as Leishmania major and Leishmania infantum have been observed to activate the rat-derived basophilic leukemia cell (RBL-2H3) line or murine BMMCs, thus resulting in degranulation and β-hexosaminidase release [87, 88]. More detailed studies have confirmed that LPG, a surface protein derived from L. mexicana stimulates BMMCs from BALB/c but not C57BL/6 mice to degranulate, suggesting that susceptibility to LPG-induced MC activation is strain-dependent and may be attributed to the genetic background of the experimental model [80]. In addition, the exposure of primary MC types, such as BMMCs or rat PMCs to tachyzoites of the Apicomplexa protozoan T. gondii has been demonstrated to stimulate the secretion of histamine and serotonin by these cells [89, 90]. On the other hand, Smith and co-workers [91] documented that T. gondii inhibits RBL-2H3 cell degranulation and β-hexosaminidase release by suppressing the mobilization of intracellular Ca²⁺ by phospholipase C (PLC), a pivotal and well-known aspect of IgE/FcεRI-mediated signal transduction in MCs.
Same as central indicators of MC degranulation (histamine, β-hexosaminidase), other MC-derived mediators are synthesized in response to protozoa in vitro. Mounting evidence indicates that these organisms promote the production of a variety of factors, cytokines, and chemokines, including those with potent pro-inflammatory and antiparasitic properties. It was observed that the RH strain of T. gondii activates rat PMCs to release LTs, an important group of robust pro-inflammatory mediators known for their antiparasitic activities [90, 92]. Also, T. gondii lysates trigger the release of certain cytokines (TNF and IL-4) and chemokines (CCL2 and CXCL8) from HMC-1 cells, but not from murine BMMCs [89, 93]. Both G. duodenalis live trophozoites and total soluble extract (TSE) of trophozoites induce mRNA expression and production of the pro-inflammatory cytokines IL-6 and TNF by the hybrid rat MC line (HRMC) [81]. Further detailed studies demonstrated that distinct protein fractions derived from Giardia trophozoites and designated as F1-F3 exhibited slight variations in their impact on cytokine synthesis by MCs. The findings of this study showed that fraction F2, which contains molecules with important biological activities such as enolase and arginine deiminase (ADI), has the greatest capacity to activate HRMC cells to produce TNF and IL-6 [79]. Also, G. duodenalis has been observed to induce the release of IL-6 from murine BMMCs [82]. The stimulation of HMC-1 cells with the secretory products of another intestinal protozoan, namely E. histolytica, resulted in an increase in CXCL8 mRNA and protein expression in these cells [94]. Living L. major or L. infantum promastigotes enhance the release of TNF from BMMCs [88], whereas LPG from L. mexicana activates those cells to synthesize pro-inflammatory cytokines, including TNF and CCL3, but also anti-inflammatory IL-10 [80]. The ESP and/or live trichomonads of T. vaginalis stimulate rat PMCs and HMC-1 cells to produce, for example, TNF, CXCL8, and CCL2 [83, 85, 86]. Notwithstanding the observed disparities in cytokine and chemokine release, likely attributable to the various parasite species and distinct characteristics of the MC source, the aforementioned data strongly indicate that MCs function as regulators or even initiators of inflammation during protozoan infections. Additional support for this hypothesis comes from some in vivo studies. The idea that MC-derived IL-6 plays an important role in the control of Giardia infection was confirmed by a study conducted by Li et al. [95], which demonstrated that intestinal tissue IL-6 mRNA levels are reduced in infected mice treated with MC blocking antibody compared to infected mice treated with control IgG or not treated with antibody. It was also noted that PMCs obtained from Plasmodium berghei ANKA-infected C57BL/6 mice released elevated amounts of TNF in comparison to MCs derived from control mice [96].
Furthermore, a substantial body of evidence from in vivo and in situ studies substantiates the influence of protozoa on the accumulation of MCs in tissues and/or their local degranulation. One of the initial findings in this context was performed by Im and co-workers [97]. They observed a higher number of MCs and their degranulation in murine mesenteric tissues of the E. histolytica-infected group than the control mice [97]. Further, Rose and colleagues [98] reported an augmented number of MCs in the intestinal lamina propria of chickens after Eimeria sp. oocyst inoculation; however, there was no evidence of MC degranulation.
Infections with other enteric protozoa, such as C. parvum and G. duodenalis, further underscore this trend. The increase in the number of MCs within the intestinal mucosa and histamine level in the serum and intestinal contents of calves following an oral challenge with C. parvum oocysts compared to the animals from the control group was documented [99]. Likewise, G. duodenalis infection in mice was associated not only with higher MC counts in the small intestine but also with degranulation [100].
Malaria parasites induce similarly responses. Elevated MC number in ileal tissues and plasma histamine levels were noted in Rhesus macaques infected with the malaria parasite Plasmodium fragile in comparison to control animals [101]. Wilainam and colleagues [102] present an interesting in vivo study dealing with MCs in patients with Plasmodium infection. They showed that MC degranulation was significantly higher in the skin of patients with the complicated P. falciparum group in comparison to the uncomplicated P. falciparum and control groups. In that case, it has also been proposed that the percentage of MC degranulation correlates significantly with the degree of parasitaemia [102]. An additional study found that MCs promote Plasmodium spreading and that P. berghei infection of mice caused massive MC degranulation in the skin and draining of lymph nodes [103]. Also, a higher number of MCs and degree of MC degranulation were observed in the skin, cervical lymph node, and brain of mice with experimental cerebral malaria induced by the P. berghei ANKA strain than in uninfected mice [104]. It was also shown that MCs are recruited to the ileum in mice infected with Plasmodium yoelii, accompanied by elevated plasma histamine levels in that animal model [105]. It has recently been demonstrated that the activation of MCs and the subsequent release of MC protease-4 (MCPT-4) serve to suppress the host immune response to P. yoelii [106]. Although the aforementioned data suggest that Plasmodium species may induce MC degranulation in vivo, a recent study has demonstrated that the different stages of malarial infection exert varying effects on the murine PMC degranulation mechanism [107].
In vivo studies have also indicated the potential for MCs to play a significant role in the immune response to toxoplasmosis. The use of toluidine blue staining and immunofluorescence staining of tryptase revealed a high number of degranulated/total MCs in the spleen and mesentery tissues from mice infected with tachyzoites of the highly pathogenic T. gondii RH strain [108]. Similar findings were obtained by Ferreira et al. [109] who performed a morphological analysis of rodent PMCs following intraperitoneal injection with the same strain of T. gondii and observed a higher number of degranulated MCs obtained from peritoneal cavities compared to uninfected animals. Simultaneously, they showed the changed size and shape of MCs as well as exhibited lower numbers of granules, with a fusion of their membranes and the formation of intracytoplasmic channels [109]. There is also strong evidence that MCs are required for host survival following oral infection with T. gondii. In studies using MC-deficient (W/W^v) mice orally infected with a low-virulent ME49 T. gondii strain, Cruz and colleagues [110] observed a rapid lethality and decreased serum IFN-γ and IL-12 levels compared to control mice (control +/+ counterparts).
Trypanosoma infections similarly engage MCs, contributing to modulation of host immune responses. In murine experimental trypanosomosis induced by T. brucei or T. cruzi, there have been descriptions of an increase in the number and/or degranulation of MCs in the jejunum and cardiac lesions. This may be associated with a worse prognosis, possibly implying ongoing inflammation and fibrotic processes involving MCs [111–113]. During the T. brucei infection, the levels of histamine in the mucosal tissues of the jejunum of the infected mice were found to be significantly elevated [111]. In an experimental model of Chagas' disease, mice infected with T. cruzi show increased histamine levels in the heart tissues compared to control animals [114] and histological examination revealed the presence of MCs in these mice in regions of fibrosis [115]. Martins et al. [116] found an elevated numbers of MCs and elevated tryptase levels in the colons of Trypanosoma cruzi-infected patients, suggesting MC activation and a potential role in the recruitment and activation of eosinophils.
During Leishmania infection, alterations in MC numbers and degranulation have been also observed. Cutaneous infection with L. major in C57BL/6 and BALB/c mice resulted in a decrease in the number of dermal MCs, but these cells exhibited extensive degranulation [117]. Interestingly, MC degranulation may inhibit leishmaniasis. The intraperitoneal and intrafootpad administration of a well-known MC degranulating agent, compound 48/80, to mice before infection with L. major resulted in a reduction in the incidence of infection, an increase in the popliteal lymph nodes' levels of IFN-γ, CCL2, CCL5, iNOS and a decrease in IL-4 levels [118]. Recently, Sánchez-García and co-workers [119] have conducted fascinating studies regarding the effect of male sex hormones on the MC-mediated response to Leishmania infection. They found that MCs showed a retarded activation pattern associated with slower degranulation and weaker histamine and tryptase staining in response to the infection with L. mexicana combined with vector-salivary proteins, as compared to sham mice in orchiectomized mice [119].
Very little was found in the literature on the question of the exact effects of protozoa on MC proliferation and/or survival. For instance, L. major or L. infantum notably reduced BMMC viability [88], yet no proliferation of dermal MCs from L. major-infected C57BL/6 and BALB/c mice was observed [117]. In turn, analysis of cardiac tissue samples obtained from T. cruzi-infected mice revealed enhanced MC proliferation [115]. Other authors revealed that during the T. cruzi infection, murine cardiac MCs exhibited increased expression of molecules involved in cell death, namely the P2X₇ receptor and Fas [120]. The viability of BM-MMCs remains unchanged in response to soluble Giardia proteins (sGPs) [82].
There is also some data regarding the mechanisms of various killing strategies of parasitic protozoa exerted by MCs. Noteworthy, Naqvi et al. [87] reported that RBL-2H3 cells phagocytose the promastigotes of L. tropica but not of L. donovani. This finding may suggest species-specific interactions between the parasites and the MCs, possibly involving distinct surface molecules or immune evasion strategies. The same authors have demonstrated that RBL-2H3 cells release extracellular structures upon stimulation with promastigotes of L. tropica and L. donovani. These structures are MCETs, which are capable of ensnaring pathogens [87]. Considering that ROS are highly toxic to pathogenic microorganisms, the information that MCs generate free radicals in response to parasites is highly relevant. It has been established that L. tropica and L. donovani stimulate ROS generation by RBL-2H3 cells [87]. Additionally, T. vaginalis-derived ESP has been observed to induce a significant increase in ROS production by HMC-1 cells [84]. HMC-1 cells treated with T. gondii lysate produce greater amounts of NO, which is known to be involved in anti-microbicidal activity [93]. In contrast, Henderson and Chi [90] documented that ROS are not implicated in the rat PMC-mediated toxoplasmacidal activity. Similarly, the production of ROS was not observed in HMC-1 cells stimulated with secretory products derived from E. histolytica [94].
It is well established that the recruitment of MCs represents a crucial aspect of the immune response to infection. However, up to date, the subject that parasitic protozoa-derived substances promote MC chemotactic activity has received minimal attention. T. vaginalis-derived ESP has been demonstrated to function as a potent chemoattractant for rat PMCs and HMC-1 cells [83, 86]. It has been also observed indirect effect on the promotion of MC migration in response to T. vaginalis-secreted cysLTs [85].

Activities of MCs regarding Platyhelminthes
The data indicate that the number of MCs increases in host tissues infected with parasitic flatworms, suggesting that MC infiltration is a common immune response across different hosts and plays a role in the host's defense against parasites from this phylum. Birck and colleagues [121] showed that the extent of MC infiltration was higher in the liver tissues of pigs infected with Schistosoma japonicum compared to the unexposed control group. In turn, a mild to moderate degree of MC infiltration was observed in the majority of hepatic granulomas. Also, it was documented that the number of MCs increased markedly in the peritoneal cavity and liver of mice infected with F. hepatica metacercariae and mice that had been injected with the tegumental coat antigen of F. hepatica [122]. A considerable number of MCs were observed in the cardiac tissues of fish infected with Ichthyocotylurus erraticus metacercariae [123]. The number of MCs was found to be higher in the duodenum and bile duct tissues of mice infected with Hymenolepis microstoma than in uninfected animals [124]. Interestingly, immunostaining of tissues collected during liver biopsies from children with echinococcosis revealed an abundance of tryptase-positive MCs within the cyst capsules and the portal tracts surrounding the cyst [125]. Likewise, an increased number of MCs was observed in the intestinal mucosa of mice infected with Echinostoma hortense, with the most visible rise in the duodenum [126]. Observational studies in individuals vocationally exposed to S. mansoni demonstrated a negative correlation between the number of circulating MC precursors and resistance to reinfection. However, there is a lack of mechanistic explanation of this phenomenon [127].
Studies on host immunity to parasitic flatworms also looked at the in vitro and in vivo processes of MC degranulation. However, the results in this context are ambiguous and dependent on the flatworm species, possibly due to variations in their molecular components and specific mechanisms by which each parasite interacts with MCs. The molecule obtained from the adult worm of S. mansoni (i.e., S. mansoni incubation product, SIP) strongly inhibited rat MC degranulation in both in vitro and in vivo contexts [128]. In contrast, Coelho-Castelo and co-workers [129] evaluated rat peritoneal MC degranulation by exposing these cells to S. mansoni-derived mannose-binding protein, termed Sm60. They reported a high number of degranulated cells determined by their counting using a Neubauer chamber. Also, the stimulation of rat peritoneal MCs with synthetic peptides based on sequences identified in F. hepatica resulted in the degranulation of these cells as evidenced by the release of histamine [130]. In contrast, bone marrow- and peritoneum-derived murine MCs do not degranulate in the presence of F. hepatica tegumental coat antigen [122]. It has been also found that T. crassiceps metacestode-secreted products from the peritoneal cavity of infected mice inhibit the in vitro degranulation of murine and rat MCs, as well as in vivo degranulation in rats [131]. Dezfuli et al. [123] observed a considerable number of MCs and a high rate of degranulation in regions in close proximity to the site of Eubothrium crassum attachment in the caecum of infected fish.
There is no evidence to suggest that molecules derived from flatworms directly promote the migration of MCs. However, Vukman et al. [122] have demonstrated that the tegumental coat antigen of F. hepatica indirectly induces BMMC migration through the action of dendritic cell-derived chemokines, including CCL3 and CXCL2. Furthermore, E. multilocularis-obtained calreticulin, which is known to regulate the host immune system through binding to complement C1q, was found to suppress the chemotactic effect of C1q on HMC-1 cells [132]. These findings imply that E. multilocularis can use calreticulin to interfere with the host immune system's attack mechanisms, potentially representing a strategy of immune evasion.
There is a lack of data concerning the synthesis and function of MC-derived mediators during infection with parasitic flatworms. Only Vukman et al. [133] demonstrated that F. hepatica tegumental coat antigen suppresses TNF and IL-6 expression in LPS- or Bordetella pertussis-stimulated BMMCs and PCMCs. The use of a murine model of Hymenolepis diminuta infection has demonstrated that mice lacking MCs require a longer time to expel the invading parasites entirely [134]. Furthermore, it appears that MC-derived proteases play a role in this process [135].

Effect of Nematode species on MC actions
According to available literature, molecules derived from parasitic nematodes may have the capacity to influence MC degranulation in vitro, potentially exerting either a stimulatory or an inhibitory effect on this process. Stimulation of rat PMCs with antigens derived from the muscle larval stage of T. spiralis (TSL-1 antigens) and a total extract of its adult forms resulted in the release of histamine but not β-hexosaminidase from these cells [136, 137]. On the contrary, synthetically obtained recombinant nematode galectin reduced the secretion of β-hexosaminidase from RBL-2H3 cells [138]. In addition, ES-62, a molecule secreted by filarial nematodes, has been shown to inhibit human BMMC degranulation and β-hexosaminidase release by forming a complex with TLR4 at the plasma membrane [139]. The process of MC degranulation during nematode infections has also been studied in vivo. The earliest study demonstrating that MC numbers in host tissues increase and degranulate during nematode infection was presented by Wells in 1962 [140]. A further report on this phenomenon was presented by Befus and colleagues in 1979 [141]. They observed increased histamine content in the intestinal tissues of rats infected with Nippostrongylus brasiliensis, which correlated with the number of intestinal MCs [141]. Additionally, serum levels of mMCPT-1 were higher in N. brasiliensis-infected mice than in healthy controls [142]. Increased MC density in the murine thoracic cavity and circulating levels of MC protease-1 (MCPT-1) have also been observed during infection with Litomosoides sigmodontis, a parasite that is widely used as a study model for human filarial infections [143]. Furthermore, the accumulation of MCs in infected tissues and/or elevated levels of MC degranulation markers have been reported in animal models infected with T. spiralis, Strongyloides stercoralis, Strongyloides venezuelensis, Ascaridia galli, Toxocara canis, and Heligmosomoides polygyrus [144–151]. The findings obtained by Patrizi et al. [152] indicate that infection with Enterobius vermicularis may act as a trigger for the onset of general cutaneous mastocytosis symptoms or may exacerbate cutaneous mastocytosis due to massive MC degranulation. Although the degranulation of MCs and the release of preformed mediators are generally regarded as crucial for the host's defense against parasites, some in vivo studies indicate that this process may enhance vascular permeability and, consequently, facilitate larval migration. Indeed, it has been demonstrated that the blockade of MC degranulation with MC stabilizers results in a reduction in the burden of L. sigmodontis in mice. This suggests that the release of MC-derived mediators during degranulation improves larval migration through the host skin [153, 154]. Conversely, MCs may promote the expulsion of T. spiralis by increasing the permeability of the gut via mouse MC protease-1 (mMCP-1)-mediated breakdown of epithelial tight junction proteins [144]. The interest of researchers has been also generated in the context of the activity of other MC-derived mediators' in host defense against parasitic nematodes. The stimulation of the rat HRMC-1 line with TSL-1 antigens has been found to increase mRNA expression of TNF and IL-4, while simultaneously reducing the expression of IFN-γ and IL-10 in these cells [155]. It has also been demonstrated that nematode galectin reduces the release of leukotriene C₄ (LTC₄) from RBL-2H3 cells [138]. Conversely, Carlos and colleagues [151] observed elevated circulating LTB₄ levels in rats following T. canis infection, which correlated with the accumulation of MCs and eosinophils. Shimokawa et al. [156] have pointed out the significance of IL-33 produced by MCs in eradicating Heligmosomoides polygyrus in the early stage of infection in mice. It has been established that MC-derived IL-33, following the recognition of tissue damage-derived ATP by the P2X7 receptor, activates ILC2s, which have been shown to contribute to the expulsion of a variety of helminths [156, 157].
There is currently no direct evidence to suggest that parasitic nematodes impact the survival of MCs. However, Knight et al. [145] reported that the expression of stem cell factor (SCF), a well-known MC growth factor, was significantly up-regulated in the epithelium of T. spiralis-infected mice. Very little is known about MC proliferation in response to parasitic nematodes or their molecules in vitro. Only Donskow-Łysoniewska et al. [138] demonstrated that synthetically obtained nematode galectin dose-dependently decreases the proliferation of RBL-2H3 cells.

Conclusion

The current state of knowledge regarding the role of MCs in the host's defense against parasites is not yet clearly defined, due to at least two major reasons. The heterogeneity of MCs employed in in vitro studies does not always yield consistent conclusions as different MC types display various characteristics, including their phenotype, activity, and lifespan. Furthermore, it is important to consider that various parasites possess a vast array of antigens, and there is presently limited information regarding the parasite-derived specific molecules that are responsible for triggering the MC response. Further studies, which consider these variables, will need to be undertaken. Nevertheless, several strong assumptions concerning the role of MCs in anti-parasitic defense mechanisms can be deduced from an analysis of the available research literature. The majority of studies indicate that MCs exert a protective immune response during parasitic infection. The first substantial evidence to support this premise is the observation that MCs accumulate at the site of parasite presence in the host organism. Furthermore, the control of parasitic infections is achieved through the multifaceted actions of MCs (Fig. 2), which range from the elimination of invaders by phagocytosis or MCET formation to the synthesis and/or release of various mediators with direct anti-parasitic activity or which are necessary for the recruitment of other immune cells and their activation. The significance of preformed mediators such as histamine and MC-specific proteases in the context of parasite defense is of particular interest, as evidenced by several in vivo studies (Table 1). Finally, crucial to host defense during parasitic infection is the involvement of MCs in triggering a Th2-associated response [158]. The evidence presented above unequivocally indicates that MCs either initiate or modulate the inflammatory response during parasitic infections. Additional support for this hypothesis can be found in studies on human tissue samples from infected individuals and findings in various animal models. Nevertheless, to gain a comprehensive understanding of the role of MCs in defense mechanisms that develop during parasitic infection, additional studies will be invaluable. Further research should focus on the mechanisms by which MCs recognize parasites and how parasite-derived immunomodulatory factors act on these cells. Such an approach may be used in developing strategies to protect the host against infection and/or the pathological consequences of infection.

Acknowledgements

Funding
This work was supported by grant from the Medical University of Lodz, Poland (Grant No. 503/6-127-07/503-61-001).

Author contributions
Paulina Żelechowska, Conceptualization, Writing – original draft, Writing – review and editing ǀ Aleksandra Góralczyk-Bińkowska, Writing – original draft, Writing – review and editing

References

1	Wong LW, Ong KS, Khoo JR, Goh CBS, Hor JW, Lee SM: Human intestinal parasitic infection: a narrative review on global prevalence and epidemiological insights on preventive, therapeutic and diagnostic strategies for future perspectives. Expert Rev Gastroenterol Hepatol 2020;14:1093-1105. https://doi.org/10.1080/17474124.2020.1806711
2	Feehan J, Plebanski M, Apostolopoulos V: Recent perspectives in clinical development of malaria vaccines. Nat Commun. 2025;16:3565. https://doi.org/10.1038/s41467-025-58963-4
3	Cholewiński M, Derda M, Hadaś E: Parasitic diseases in humans transmitted by vectors. Ann Parasitol 2015;61:137-157.
4	Chulanetra M, Chaicumpa W: Revisiting the mechanisms of immune evasion employed by human parasites. Front Cell Infect Microbiol 2021;11:702125. https://doi.org/10.3389/fcimb.2021.702125
5	Yasmin H, Datta P, Deb A, Willingham AL, Kishore U: Innate immune response to helminth infections. Adv Exp Med Biol 2025;1476:251-273. https://doi.org/10.1007/978-3-031-85340-1_10
6	Wang R, Lan C, Benlagha K, Camara NOS, Miller H, Kubo M, Heegaard S, Lee P, Yang L, Forsman H, Li X, Zhai Z, Liu C: The interaction of innate immune and adaptive immune system. MedComm (2020) 2024;5(10):e714. https://doi.org/10.1002/mco2.714
7	Li NS, Yeh YW, Li L, Xiang Z: Mast cells: key players in host defence against infection. Scand J Immunol 2025;102(2):e70046. https://doi.org/10.1111/sji.70046
8	Suárez Vázquez TA, López López N, Salinas Carmona MC: MASTer cell: chief immune modulator and inductor of antimicrobial immune response. Front Immunol 2024;15:1360296. https://doi.org/10.3389/fimmu.2024.1360296
9	Wiedemann M, Voehringer D: Immunomodulation and immune escape strategies of gastrointestinal helminths and schistosomes. Front Immunol 2020;11:572865. https://doi.org/10.3389/fimmu.2020.572865
10	Ewald S, Nasuhidehnavi A, Feng T, Lesani M, McCall L: The intersection of host in vivo metabolism and immune responses to infection with kinetoplastid and apicomplexan parasites. Microbiol Mol Biol Rev 2024;88:e00164-22. https://doi.org/10.1128/mmbr.00164-22
11	Cuellar P, Hernández-Nava E, García-Rivera G, Chávez-Munguía B, Schnoor M, Betanzos A, Orozco E: Entamoeba histolytica EhCP112 dislocates and degrades claudin-1 and claudin-2 at tight junctions of the intestinal epithelium. Front Cell Infect Microbiol 2017;7:372. https://doi.org/10.3389/fcimb.2017.00372
12	Maia-Brigagão C, Morgado-Díaz JA, de Souza W: Giardia disrupts the arrangement of tight, adherens and desmosomal junction proteins of intestinal cells. Parasitol Int 2012;61:280-287. https://doi.org/10.1016/j.parint.2011.11.002
13	Briceño MP, Nascimento LA, Nogueira NP, Barenco PV, Ferro EA, Rezende-Oliveira K, Goulart LR, Alves PT, Barbosa Bde F, Lima WR, Silva NM: Toxoplasma gondii infection promotes epithelial barrier dysfunction of Caco-2 cells. J Histochem Cytochem 2016;64:459-469. https://doi.org/10.1369/0022155416656349
14	Amat CB, Motta JP, Fekete E, Moreau F, Chadee K, Buret AG: Cysteine protease-dependent mucous disruptions and differential mucin gene expression in Giardia duodenalis infection. Am J Pathol 2017;187:2486-2498. https://doi.org/10.1016/j.ajpath.2017.07.009
15	Lidell ME, Moncada DM, Chadee K, Hansson GC: Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel. Proc Natl Acad Sci U S A 2006;103:9298-9303. https://doi.org/10.1073/pnas.0600623103
16	Hasnain SZ, McGuckin MA, Grencis RK, Thornton DJ: Serine protease(s) secreted by the nematode Trichuris muris degrade the mucus barrier. PLoS Negl Trop Dis 2012;6:e1856. https://doi.org/10.1371/journal.pntd.0001856
17	Carrero JC, Cervantes-Rebolledo C, Aguilar-Díaz H, Díaz-Gallardo MY, Laclette JP, Morales-Montor J: The role of the secretory immune response in the infection by Entamoeba histolytica. Parasite Immunol 2007;29:331-338. https://doi.org/10.1111/j.1365-3024.2007.00955.x
18	Langford TD, Housley MP, Boes M, Chen J, Kagnoff MF, Gillin FD, Eckmann L: Central importance of immunoglobulin A in host defense against Giardia spp. Infect Immun 2002;70:11-18. https://doi.org/10.1128/IAI.70.1.11-18.2002
19	Davids BJ, Palm JE, Housley MP, Smith JR, Andersen YS, Martin MG, Hendrickson BA, Johansen FE, Svärd SG, Gillin FD, Eckmann L: Polymeric immunoglobulin receptor in intestinal immune defense against the lumen-dwelling protozoan parasite Giardia. J Immunol 2006;177:6281-6290. https://doi.org/10.4049/jimmunol.177.9.6281
20	Chu KB, Kim SS, Lee SH, Lee HS, Joo KH, Lee JH, Lee YS, Zheng S, Quan FS: Enhanced protection against Clonorchis sinensis induced by co-infection with Trichinella spiralis in rats. Parasite Immunol 2014;36:522-530. https://doi.org/10.1111/pim.12125
21	Kaneva E, Harizanov R, Velcheva D, Tsvetkova N, Pavlova M, Alexiev I, Dimitrova R, Videnova M, Borisova R, Ivanova A: Studies on the significance of secretory IgA antibodies in the pathogenesis and clinical course of enterobiasis in infected persons from Bulgaria: preliminary findings. Helminthologia 2024;61:277-285. https://doi.org/10.2478/helm-2024-0034
22	Castilla Gómez de Agüero V, Valderas-García E, González Del Palacio L, Giráldez FJ, Balaña-Fouce R, Martínez-Valladares M: Secretory IgA as biomarker for gastrointestinal nematodes natural infection in different breed sheep. Animals (Basel) 2023;13:2189. https://doi.org/10.3390/ani13132189
23	Jenkins TP, Rathnayaka Y, Perera PK, Peachey LE, Nolan MJ, Krause L, Rajakaruna RS, Cantacessi C: Infections by human gastrointestinal helminths are associated with changes in faecal microbiota diversity and composition. PLoS One 2017;12(9):e0184719. https://doi.org/10.1371/journal.pone.0184719
24	Grondin JA, Jamal A, Mowna S, Seto T, Khan WI: Interaction between intestinal parasites and the gut microbiota: Implications for the intestinal immune response and host defence. Pathogens 2024;13(8):608. https://doi.org/10.3390/pathogens13080608
25	Beyhan YE, Yildiz MR: Microbiota and parasite relationship. Diagn Microbiol Infect Dis 2023;106:115954. https://doi.org/10.1016/j.diagmicrobio.2023.115954
26	Leung JM, Graham AL, Knowles SCL: Parasite-microbiota interactions with the vertebrate gut: synthesis through an ecological lens. Front Microbiol 2018;9:843. https://doi.org/10.3389/fmicb.2018.00843
27	Li C, Liu Y, Liu X, Bai X, Jin X, Xu F, Chen H, Zhang Y, Vallee I, Liu M, Yang Y: The gut microbiota contributes to changes in the host immune response induced by Trichinella spiralis. PLOS Negl Trop Dis 2023;17:e0011479. https://doi.org/10.1371/journal.pntd.0011479
28	Boucard AS, Kulakauskas S, Alazzaz J, Chaouch S, Mammeri M, Millan-Oropeza A, Machado C, Henry C, Péchoux C, Richly H, Gassel M, Langella P, Polack B, Florent I, Bermúdez-Humarán LG: Isolation of derivatives from the food-grade probiotic Lactobacillus johnsonii CNCM I-4884 with enhanced anti-Giardia activity. Gut Microbes 2025;17(1):2474149. https://doi.org/10.1080/19490976.2025.2474149
29	Pérez PF, Minnaard J, Rouvet M, Knabenhans C, Brassart D, De Antoni GL, Schiffrin EJ: Inhibition of Giardia intestinalis by extracellular factors from Lactobacilli: an in vitro study. Appl Environ Microbiol 2001;67:5037-5042. https://doi.org/10.1128/AEM.67.11.5037-5042.2001
30	Amer EI, Mossallam SF, Mahrous H: Therapeutic enhancement of newly derived bacteriocins against Giardia lamblia. Exp Parasitol 2014;146:52-63. https://doi.org/10.1016/j.exppara.2014.09.005
31	Keelaghan AP, Charania R, Mead JR: The effect of short-chain fatty acids on growth of Cryptosporidium parvum in vitro. Microorganisms 2022;10:1822. https://doi.org/10.3390/microorganisms10091822
32	Byers J, Faigle W, Eichinger D: Colonic short-chain fatty acids inhibit encystation of Entamoeba invadens. Cell Microbiol 2005;7:269-279. https://doi.org/10.1111/j.1462-5822.2004.00457.x
33	Wang Y, Guo A, Zou Y, Mu W, Zhang S, Shi Z, Liu Z, Cai X, Zhu XQ, Wang S: Interaction between tissue-dwelling helminth and the gut microbiota drives mucosal immunoregulation. NPJ Biofilms Microbiomes 2023;9:43. https://doi.org/10.1038/s41522-023-00410-7
34	Li D, Wu M: Pattern recognition receptors in health and diseases. Signal Transduct Target Ther 2021;6:291. https://doi.org/10.1038/s41392-021-00687-0
35	Krishnegowda G, Hajjar AM, Zhu J, Douglass EJ, Uematsu S, Akira S, Woods AS, Gowda DC: Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J Biol Chem 2005;280:8606-8616. https://doi.org/10.1074/jbc.M413541200
36	Oliveira AC, Peixoto JR, de Arruda LB, Campos MA, Gazzinelli RT, Golenbock DT, Akira S, Previato JO, Mendonça-Previato L, Nobrega A, Bellio M: Expression of functional TLR4 confers proinflammatory responsiveness to Trypanosoma cruzi glycoinositolphospholipids and higher resistance to infection with T. cruzi. J Immunol 2004;173:5688-5696. https://doi.org/10.4049/jimmunol.173.9.5688
37	Maldonado-Bernal C, Kirschning CJ, Rosenstein Y, Rocha LM, Rios-Sarabia N, Espinosa-Cantellano M, Becker I, Estrada I, Salazar-González RM, López-Macías C, Wagner H, Sánchez J, Isibasi A: The innate immune response to Entamoeba histolytica lipopeptidophosphoglycan is mediated by toll-like receptors 2 and 4. Parasite Immunol 2005;27:127-137. https://doi.org/10.1111/j.1365-3024.2005.00754.x
38	Dissanayake S, Amith RS, Shahin A: Taenia crassiceps carbohydrates stimulate IL-6 expression in naïve murine macrophages via Toll-like receptors (TLRs). Mol Immunol 2004;41:391-398. https://doi.org/10.1016/j.molimm.2004.03.020
39	Raetz M, Kibardin A, Sturge CR, Pifer R, Li H, Burstein E, Ozato K, Larin S, Yarovinsky F: Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin. J Immunol 2013;191:4818-4827. https://doi.org/10.4049/jimmunol.1301301
40	Andrade WA, Souza Mdo C, Ramos-Martinez E, Nagpal K, Dutra MS, Melo MB, Bartholomeu DC, Ghosh S, Golenbock DT, Gazzinelli RT: Combined action of nucleic acid-sensing Toll-like receptors and TLR11/TLR12 heterodimers imparts resistance to Toxoplasma gondii in mice. Cell Host Microbe 2013;13:42-53. https://doi.org/10.1016/j.chom.2012.12.003
41	Melo MB, Kasperkovitz P, Cerny A, Könen-Waisman S, Kurt-Jones EA, Lien E, Beutler B, Howard JC, Golenbock DT, Gazzinelli RT: UNC93B1 mediates host resistance to infection with Toxoplasma gondii. PLoS Pathog 2010;6:e1001071. https://doi.org/10.1371/journal.ppat.1001071
42	Caparrós E, Serrano D, Puig-Kröger A, Riol L, Lasala F, Martinez I, Vidal-Vanaclocha F, Delgado R, Rodríguez-Fernández JL, Rivas L, Corbí AL, Colmenares M: Role of the C-type lectins DC-SIGN and L-SIGN in Leishmania interaction with host phagocytes. Immunobiol 2005;210:185-193. https://doi.org/10.1016/j.imbio.2005.05.013
43	van Die I, van Vliet SJ, Nyame AK, Cummings RD, Bank CM, Appelmelk B, Geijtenbeek TB, van Kooyk Y: The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x. Glycobiol 2003;13:471-478. https://doi.org/10.1093/glycob/cwg052
44	Bonne-Année S, Kerepesi LA, Hess JA, Wesolowski J, Paumet F, Lok JB, Nolan TJ, Abraham D: Extracellular traps are associated with human and mouse neutrophil and macrophage mediated killing of larval Strongyloides stercoralis. Microbes Infect 2014;16:502-511. https://doi.org/10.1016/j.micinf.2014.02.012
45	Ramírez-Ledesma MG, Romero-Contreras YJ, Rodríguez MC, Reyes-Cortes R, Cuéllar-Mata P, Avila EE: Trichomonas vaginalis triggers neutrophil extracellular traps reducing parasite integrity and growth. Parasitol Res 2022;121(5):1355-1367. https://doi.org/10.1007/s00436-022-07475-x
46	Omar M, Abdelal H: NETosis in parasitic infections: A puzzle that remains unsolved. Int J Mol Sci 2023;24:8975. https://doi.org/10.3390/ijms24108975
47	Brillantes M, Beaulieu AM: Memory and memory-like NK cell responses to microbial pathogens. Front Cell Infect Microbiol 2020;10:102. https://doi.org/10.3389/fcimb.2020.00102
48	Peng J, Siracusa MC: Basophils in antihelminth immunity. Semin Immunol 2021;53:101529. https://doi.org/10.1016/j.smim.2021.101529
49	Reiss T, Müller F, Pradel G: The impact of human complement on the clinical outcome of malaria infection. Mol Immunol 2022;151:19-28. https://doi.org/10.1016/j.molimm.2022.08.017
50	Filho AAP, Nascimento AAS, Saab NAA, Fugiwara RT, D'Ávila Pessoa GC, Koerich LB, Pereira MH, Araújo RN, Sant'Anna MRV, Gontijo NF: Evasion of the complement system by Leishmania through the uptake of factor H, a complement regulatory protein. Acta Trop 2021;224:106152. https://doi.org/10.1016/j.actatropica.2021.106152
51	Menon SS, Ramirez-Toloza G, Wycoff KL, Ehinger S, Shaughnessy J, Ram S, Ferreira VP: Mechanisms by which factor H protects Trypanosoma cruzi from the alternative pathway of complement. Front Immunol 2024;15:1152000. https://doi.org/10.3389/fimmu.2024.1152000
52	De Marco Verissimo C, Jewhurst HL, Dobó J, Gál P, Dalton JP, Cwiklinski K: Fasciola hepatica is refractory to complement killing by preventing attachment of mannose binding lectin (MBL) and inhibiting MBL-associated serine proteases (MASPs) with serpins. PLoS Pathog 2022;18:e1010226. https://doi.org/10.1371/journal.ppat.1010226
53	Shao S, Sun X, Chen Y, Zhan B, Zhu X: Complement evasion: an effective strategy that parasites utilize to survive in the host. Front Microbiol 2019;10:532. https://doi.org/10.3389/fmicb.2019.00532
54	Terkawi MA, Takano R, Furukawa A, Murakoshi F, Kato K: Involvement of β-defensin 130 (DEFB130) in the macrophage microbicidal mechanisms for killing Plasmodium falciparum. Sci Rep 2017;7:41772. https://doi.org/10.1038/srep41772
55	Johnson CA, Rachakonda G, Kleshchenko YY, Nde PN, Madison MN, Pratap S, Cardenas TC, Taylor C, Lima MF, Villalta F: Cellular response to Trypanosoma cruzi infection induces secretion of defensin α-1, which damages the flagellum, neutralizes trypanosome motility, and inhibits infection. Infect Immun 2013;81:4139-4148. https://doi.org/10.1128/IAI.01459-12
56	Tanaka T, Rahman MM, Battur B, Boldbaatar D, Liao M, Umemiya-Shirafuji R, Xuan X, Fujisaki K: Parasiticidal activity of human alpha-defensin-5 against Toxoplasma gondii. In vitro Cell Dev Biol 2010;46:560-565. https://doi.org/10.1007/s11626-009-9271-9
57	Carryn S, Schaefer DA, Imboden M, Homan EJ, Bremel RD, Riggs MW: Phospholipases and cationic peptides inhibit Cryptosporidium parvum sporozoite infectivity by parasiticidal and non-parasiticidal mechanisms. J Parasitol 2012;98:199-204. https://doi.org/10.1645/GE-2822.1
58	Rico-Mata R, De Leon-Rodriguez LM, Avila EE: Effect of antimicrobial peptides derived from human cathelicidin LL-37 on Entamoeba histolytica trophozoites. Exp Parasitol 2013;133:300-306. https://doi.org/10.1016/j.exppara.2012.12.009
59	Crauwels P, Bank E, Walber B, Wenzel UA, Agerberth B, Chanyalew M, Abebe M, König R, Ritter U, Reiling N, van Zandbergen G: Cathelicidin contributes to the restriction of Leishmania in human host macrophages. Front Immunol 2019;10:2697. https://doi.org/10.3389/fimmu.2019.02697
60	Zaiss DMW, Pearce EJ, Artis D, McKenzie ANJ, Klose CSN: Cooperation of ILC2s and TH2 cells in the expulsion of intestinal helminth parasites. Nat Rev Immunol 2024;24(4):294-302. https://doi.org/10.1038/s41577-023-00942-1
61	Rasquinha MT, Sur M, Lasrado N, Reddy J: IL-10 as a Th2 cytokine: Differences between mice and humans. J Immunol 2021;207(9):2205-2215. https://doi.org/10.4049/jimmunol.2100565
62	Nutman TB: Looking beyond the induction of Th2 responses to explain immunomodulation by helminths. Parasite Immunol 2015;37:304-313. https://doi.org/10.1111/pim.12194
63	Kima PE, Soong L: Interferon gamma in leishmaniasis. Front Immunol 2013;4:156. https://doi.org/10.3389/fimmu.2013.00156
64	Stephens R, Langhorne J: Effector memory Th1 CD4 T cells are maintained in a mouse model of chronic malaria. PLoS Pathog 2010;6:e1001208. https://doi.org/10.1371/journal.ppat.1001208
65	Friedrich N, Hagedorn M, Soldati-Favre D, Soldati T: Prison break: pathogens' strategies to egress from host cells. Microbiol Mol Biol Rev 2012;76:707-720. https://doi.org/10.1128/MMBR.00024-12
66	Ribatti D: Mast cells are at the interface between the external environment and the inner organism. Front Med (Lausanne) 2024;10:1332047. https://doi.org/10.3389/fmed.2023.1332047
67	Pastwińska J, Agier J, Dastych J, Brzezińska-Błaszczyk E: Mast cells as the strength of the inflammatory process. Pol J Pathol 2017;68(3):187-196. https://doi.org/10.5114/pjp.2017.71526
68	Xu H, Bin NR, Sugita S: Diverse exocytic pathways for mast cell mediators. Biochem Soc Trans 2018;46(2):235-247. https://doi.org/10.1042/BST20170450
69	Agier J, Brzezińska-Błaszczyk E: Cathelicidins and defensins regulate mast cell antimicrobial activity. Postepy Hig Med Dosw (Online) 2016;70:618-636. https://doi.org/10.5604/17322693.1205357
70	Swindle EJ, Metcalfe DD: The role of reactive oxygen species and nitric oxide in mast cell-dependent inflammatory processes. Immunol Rev 2007;217:186-205. https://doi.org/10.1111/j.1600-065X.2007.00513.x
71	Katsoulis-Dimitriou K, Kotrba J, Voss M, Dudeck J, Dudeck A: Mast cell functions linking innate sensing to adaptive immunity. Cells 2020;9(12):2538. https://doi.org/10.3390/cells9122538
72	Elieh Ali Komi D, Kuebler WM: Significance of mast cell formed extracellular traps in microbial defense. Clin Rev Allergy Immunol 2022;62(1):160-179. https://doi.org/10.1007/s12016-021-08861-6
73	Möllerherm H, Von Köckritz-Blickwede M, Branitzki-Heinemann K: Antimicrobial activity of mast cells: role and relevance of extracellular DNA traps. Front Immunol 2016;7:265. https://doi.org/10.3389/fimmu.2016.00265
74	Jiménez M, Cervantes-García D, Córdoba-Dávalos LE, Pérez-Rodríguez MJ, Gonzalez-Espinosa C, Salinas E: Responses of mast cells to pathogens: Beneficial and detrimental roles. Front Immunol 2021;12:685865. https://doi.org/10.3389/fimmu.2021.685865
75	Agier J, Pastwińska J, Brzezińska-Błaszczyk E: An overview of mast cell pattern recognition receptors. Inflamm Res 2018;67:737-746. https://doi.org/10.1007/s00011-018-1164-5
76	Xie G, Wang F, Peng X, Liang Y, Yang H, Li L: Modulation of mast cell Toll-Like receptor 3 expression and cytokines release by histamine. Cell Physiol Biochem 2018;46:2401-2411. https://doi.org/10.1159/000489646
77	Furuta T, Imajo-Ohmi S, Fukuda H, Kano S, Miyake K, Watanabe N: Mast cell-mediated immune responses through IgE antibody and Toll-like receptor 4 by malarial peroxiredoxin. Eur J Immunol 2008;38:1341-1350. https://doi.org/10.1002/eji.200738059
78	Köllisch G, Solis FV, Obermann HL, Eckert J, Müller T, Vierbuchen T, Rickmeyer T, Muche S, Przyborski JM, Heine H, Kaufmann A, Baumeister S, Lingelbach K, Bauer S: TLR8 is activated by 5'-methylthioinosine, a Plasmodium falciparum-derived intermediate of the purine salvage pathway. Cell Rep 2022;39:110691. https://doi.org/10.1016/j.celrep.2022.110691
79	Muñoz-Cruz S, Gomez-García A, Matadamas-Martínez F, Alvarado-Torres JA, Meza-Cervantez P, Arriaga-Pizano L, Yépez-Mulia L: Giardia lamblia: identification of molecules that contribute to direct mast cell activation. Parasitol Res 2018;117:2555-2567. https://doi.org/10.1007/s00436-018-5944-1
80	Villaseñor-Cardoso MI, Salaiza N, Delgado J, Gutiérrez-Kobeh L, Pérez-Torres A, Becker I: Mast cells are activated by Leishmania mexicana LPG and regulate the disease outcome depending on the genetic background of the host. Parasite Immunol 2008;30:425-434. https://doi.org/10.1111/j.1365-3024.2008.01042.x
81	Muñoz-Cruz S, Gómez-García A, Millán-Ibarra J, Giono-Cerezo S, Yépez-Mulia L: Giardia lamblia: interleukin 6 and tumor necrosis factor-alpha release from mast cells induced through an Ig-independent pathway. Exp Parasitol 2010;126:298-303. https://doi.org/10.1016/j.exppara.2010.06.013
82	Li Z, Peirasmaki D, Svärd S, Åbrink M: Giardia excretory-secretory proteins modulate the enzymatic activities of mast cell chymase and tryptase. Mol Immunol 2019;114:535-544. https://doi.org/10.1016/j.molimm.2019.07.024
83	Im SJ, Ahn MH, Han IH, Song HO, Kim YS, Kim HM, Ryu JS: Histamine and TNF-α release by rat peritoneal mast cells stimulated with Trichomonas vaginalis. Parasite 2011;18:49-55. https://doi.org/10.1051/parasite/2011181049
84	Narantsogt G, Min A, Nam YH, Lee YA, Kim KA, Agvaandaram G, Dorjsuren T, El-Benna J, Shin MH: Activation of MAPK is required for ROS generation and exocytosis in HMC-1 cells induced by Trichomonas vaginalis-derived secretory products. Korean J Parasitol 2015;53:597-603. https://doi.org/10.3347/kjp.2015.53.5.597
85	Lee YA, Nam YH, Min A, Shin MH: Trichomonas vaginalis-secreted cysteinyl leukotrienes promote migration, degranulation and MCP-1 production in mast cells. Parasite Immunol 2020;42:e12789. https://doi.org/10.1111/pim.12789
86	Han IH, Park SJ, Ahn MH, Ryu JS: Involvement of mast cells in inflammation induced by Trichomonas vaginalis via crosstalk with vaginal epithelial cells. Parasite Immunol 2012;34:8-14. https://doi.org/10.1111/j.1365-3024.2011.01338.x
87	Naqvi N, Ahuja K, Selvapandiyan A, Dey R, Nakhasi H, Puri N: Role of mast cells in clearance of Leishmania through extracellular trap formation. Sci Rep 2017;7:13240. https://doi.org/10.1038/s41598-017-12753-1
88	Bidri M, Vouldoukis I, Mossalayi MD, Debré P, Guillosson JJ, Mazier D, Arock M: Evidence for direct interaction between mast cells and Leishmania parasites. Parasite Immunol 1997;19:475-483. https://doi.org/10.1046/j.1365-3024.1997.d01-153.x
89	Bidri M, Conti M, Hanoun N, Kuen RL, Feger F, Taoufiq B, Arock M, Mazier D, Vouldoukis I: c-Kit ligand promotes mast cell infection by Toxoplasma gondii. Open Parasitol J 2008;2:43-50. https://doi.org/10.2174/1874421400802010043
90	Henderson WR Jr, Chi EY: The importance of leukotrienes in mast cell-mediated Toxoplasma gondii cytotoxicity. J Infect Dis 1998;177:1437-1443. https://doi.org/10.1086/517833
91	Smith NL, Abi Abdallah DS, Butcher BA, Denkers EY, Baird B, Holowka D: Toxoplasma gondii inhibits mast cell degranulation by suppressing phospholipase Cγ-mediated Ca2+ mobilization. Front Microbiol 2013;4:179. https://doi.org/10.3389/fmicb.2013.00179
92	Rogerio AP, Anibal FF: Role of leukotrienes on protozoan and helminth infections. Mediators Inflamm 2012;2012:595694. https://doi.org/10.1155/2012/595694
93	Park EA, Han IH, Kim JH, Park SJ, Ryu JS, Ahn MH: Production of inflammatory cytokines and nitric oxide by human mast cells incubated with Toxoplasma gondii lysate. Korean J Parasitol 2019;57:201-206. https://doi.org/10.3347/kjp.2019.57.2.201
94	Lee YA, Nam YH, Min A, Kim KA, Nozaki T, Saito-Nakano Y, Mirelman D, Shin MH: Entamoeba histolytica-secreted cysteine proteases induce IL-8 production in human mast cells via a PAR2-independent mechanism. Parasite 2014;21:1. https://doi.org/10.1051/parasite/2014001
95	Li E, Zhou P, Petrin Z, Singer SM: Mast cell-dependent control of Giardia lamblia infections in mice. Infect Immun 2004;72:6642-6649. https://doi.org/10.1128/IAI.72.11.6642-6649.2004
96	Furuta T, Kikuchi T, Iwakura Y, Watanabe N: Protective roles of mast cells and mast cell-derived TNF in murine malaria. J Immunol 2006;177:3294-3302. https://doi.org/10.4049/jimmunol.177.5.3294
97	Im KI, Hwang HK, Soh CT: Behaviour of mast cells in mice in the course of Entamoeba histolytica infection by strains. Kisaengchunghak Chapchi 1975;13:115-122. https://doi.org/10.3347/kjp.1975.13.2.115
98	Rose ME, Ogilvie BM, Bradley JW: Intestinal mast cell response in rats and chickens to coccidiosis, with some properties of chicken mast cells. Int Arch Allergy Immunol 1980;63:21-29. https://doi.org/10.1159/000232606
99	Li S, Li W, Yang Z, Song S, Yang J, Gong P, Zhang W, Liu K, Li J, Zhang G, Zhang X: Infection of cattle with Cryptosporidium parvum: mast cell accumulation in small intestine mucosa. Vet Pathol 2013;50:842-848. https://doi.org/10.1177/0300985813476055
100	Li Z, Peirasmaki D, Svärd S, Åbrink M: The chymase mouse mast cell protease-4 regulates intestinal cytokine expression in mature adult mice infected with Giardia intestinalis. Cells 2020;9:925. https://doi.org/10.3390/cells9040925
101	Potts RA, Tiffany CM, Pakpour N, Lokken KL, Tiffany CR, Cheung K, Tsolis RM, Luckhart S: Mast cells and histamine alter intestinal permeability during malaria parasite infection. Immunobiology 2016;221:468-474. https://doi.org/10.1016/j.imbio.2015.11.003
102	Wilainam P, Nintasen R, Viriyavejakul P: Mast cell activation in the skin of Plasmodium falciparum malaria patients. Malar J 2015;14:67. https://doi.org/10.1186/s12936-015-0568-8
103	Huang B, Huang S, Chen X, Liu XB, Wu Q, Wang Y, Li X, Li K, Gao H, Cen S, Lin R, Liu Z, Jin X: Activation of mast cells promote Plasmodium berghei ANKA infection in murine model. Front Cell Infect Microbiol 2019;9:322. https://doi.org/10.3389/fcimb.2019.00322
104	Huang K, Huang L, Zhang X, Zhang M, Wang Q, Lin H, Yu Z, Li X, Liu XB, Wu Q, Wang Y, Wang J, Jin X, Gao H, Han X, Lin R, Cen S, Liu Z, Huang B: Mast cells-derived exosomes worsen the development of experimental cerebral malaria. Acta Trop 2021;224:106145. https://doi.org/10.1016/j.actatropica.2021.106145
105	Chau JY, Tiffany CM, Nimishakavi S, Lawrence JA, Pakpour N, Mooney JP, Lokken KL, Caughey GH, Tsolis RM, Luckhart S: Malaria-associated L-arginine deficiency induces mast cell-associated disruption to intestinal barrier defenses against nontyphoidal Salmonella bacteremia. Infect Immun 2013;81:3515-3526. https://doi.org/10.1128/IAI.00380-13
106	Céspedes N, Donnelly EL, Lowder C, Hansten G, Wagers D, Briggs AM, Schauer J, Haapanen L, Åbrink M, Van de Water J, Luckhart S: Mast cell chymase/Mcpt4 suppresses the host immune response to Plasmodium yoelii, limits malaria-associated disruption of intestinal barrier integrity and reduces parasite transmission to Anopheles stephensi. Front Immunol 2022;13:801120. https://doi.org/10.3389/fimmu.2022.801120
107	Xiong-Hang K, Haynes CL: Plasmodium chabaudi affects mast cell degranulation as measured by carbon-fiber microelectrode amperometry. ACS Infect Dis 2021;7:1650-1656. https://doi.org/10.1021/acsinfecdis.0c00820
108	Huang B, Huang S, Chen Y, Zheng H, Shen J, Lun ZR, Wang Y, Kasper LH, Lu F: Mast cells modulate acute toxoplasmosis in murine models. PLoS One 2013;8:e77327. https://doi.org/10.1371/journal.pone.0077327
109	Ferreira GLS, Mineo JR, Oliveira JG, Ferro EA, Souza MA, Santos AA: Toxoplasma gondii and mast cell interactions in vivo and in vitro: experimental infection approaches in Calomys callosus (Rodentia, Cricetidae). Microbes Infect 2004;6:172-181. https://doi.org/10.1016/j.micinf.2003.11.007
110	Cruz A, Mendes ÉA, de Andrade MV, do Nascimento VC, Cartelle CT, Arantes RM, Melo JR, Gazzinelli RT, Ropert C: Mast cells are crucial in the resistance against Toxoplasma gondii oral infection. Eur J Immunol 2014;44:2949-2954. https://doi.org/10.1002/eji.201344185
111	Ben-Rashed M, Ingram GA, Pentreath VW: Mast cells, histamine and the pathogenesis of intestinal damage in experimental Trypanosoma brucei brucei infections. Ann Trop Med Parasitol 2003;97:803-809. https://doi.org/10.1179/000349803225002444
112	Meuser-Batista M, Correa JR, Soares MJ, Henriques-Pons A: Isolation of cardiac mast cells in experimental Trypanosoma cruzi infection. Tissue Cell 2008;40:309-316. https://doi.org/10.1016/j.tice.2008.02.006
113	Kannen V, Sakita JY, Carneiro ZA, Bader M, Alenina N, Teixeira RR, de Oliveira EC, Brunaldi MO, Gasparotto B, Sartori DC, Fernandes CR, Silva JS, Andrade MV, Silva WA Jr, Uyemura SA, Garcia SB: Mast cells and serotonin synthesis modulate Chagas disease in the colon: Clinical and experimental evidence. Dig Dis Sci 2018;63:1473-1484. https://doi.org/10.1007/s10620-018-5015-6
114	Pires JG, Milanez MC, Pereira FE: Histamine levels in tissues of Trypanosoma cruzi-infected mice. Agents Actions Suppl 1992;36:96-98.
115	Postan M, Correa R, Ferrans VJ, Tarleton RL: In vitro culture of cardiac mast cells from mice experimentally infected with Trypanosoma cruzi. Int Arch Allergy Immunol 1994;105:251-257. https://doi.org/10.1159/000236765
116	Martins PR, Nascimento RD, Lopes JG, Santos MM, de Oliveira CA, de Oliveira EC, Martinelli PM, d'Ávila Reis D: Mast cells in the colon of Trypanosoma cruzi-infected patients: are they involved in the recruitment, survival and/or activation of eosinophils? Parasitol Res 2015;114:1847-1856. https://doi.org/10.1007/s00436-015-4371-9
117	Wershil BK, Theodos CM, Galli SJ, Titus RG: Mast cells augment lesion size and persistence during experimental Leishmania major infection in the mouse. J Immunol 1994;152:4563-4571. https://doi.org/10.4049/jimmunol.152.9.4563
118	Romão PR, Da Costa Santiago H, Ramos CD, De Oliveira CF, Monteiro MC, De Queiroz Cunha F, Vieira LQ: Mast cell degranulation contributes to susceptibility to Leishmania major. Parasite Immunol 2009;31:140-146. https://doi.org/10.1111/j.1365-3024.2008.01084.x
119	Sánchez-García L, Pérez-Torres A, Muñoz-Cruz S, Salaiza-Suazo N, Morales-Montor J, Becker I: Mast-cell response to Leishmania mexicana and sand-fly salivary proteins is modulated by orchiectomy. Pathogens 2022;11:398. https://doi.org/10.3390/pathogens11040398
120	Meuser-Batista M, Corrêa JR, Carvalho VF, de Carvalho Britto CF, Moreira OC, Batista MM, Soares MJ, Filho FA, E Silva PM, Lannes-Vieira J, Silva RC, Henriques-Pons A: Mast cell function and death in Trypanosoma cruzi infection. Am J Pathol 2011;179:1894-1904. https://doi.org/10.1016/j.ajpath.2011.06.014
121	Birck MM, Pors S, Johansen MV, Iburg T: Distribution of mast cells in relation to Schistosoma japonicum induced lesions in pigs. Southeast Asian J Trop Med Public Health 2006;37:630-640.
122	Vukman KV, Adams PN, Dowling D, Metz M, Maurer M, O'Neill SM: The effects of Fasciola hepatica tegumental antigens on mast cell function. Int J Parasitol 2013;43:531-539. https://doi.org/10.1016/j.ijpara.2013.01.011
123	Dezfuli BS, Lui A, Boldrini P, Pironi F, Giari L: The inflammatory response of fish to helminth parasites. Parasite 2008;15:426-433. https://doi.org/10.1051/parasite/2008153426
124	Novak M, Buchanan LG, Howlader H: Effects of cyclophosphamide and dexamethasone on mast cell populations in Hymenolepis microstoma-infected mice. Parasitology 1990;100 Pt 2:337-343. https://doi.org/10.1017/S0031182000061357
125	Gulubova M, Vlaykova T, Kalinova K, Vodenicharov A, Vasilev I, Velev V: Liver tryptase-positive mast cells and fibrosis in children with hepatic echinococcosis. J Indian Assoc Pediatr Surg 2005;10:237-243. https://doi.org/10.4103/0971-9261.19273
126	Park KY, Lee KJ, Kim IS, Yang EJ, Lim SJ, Lim BH, Ryang YS: Reaction of mast cells and goblet cells in the small intestine of C57BL/6 and C3H/HeN mice infected with Echinostoma hortense. Korean J Biomed Lab Sci 2005;11:259-266.
127	Ganley-Leal LM, Mwinzi PN, Cetre-Sossah CB, Andove J, Hightower AW, Karanja DM, Colley DG, Secor WE: Higher percentages of circulating mast cell precursors correlate with susceptibility to reinfection with Schistosoma mansoni. Am J Trop Med Hyg 2006;75:1053-1057. https://doi.org/10.4269/ajtmh.2006.75.1053
128	Mazingue C, Camus D, Dessaint JP, Capron M, Capron A: In vitro and in vivo inhibition of mast cell degranulation by a factor from Schistosoma mansoni. Int Arch Allergy Immunol 1980;63:178-189. https://doi.org/10.1159/000232624
129	Coelho-Castelo AA, Panunto-Castelo A, Moreno AN, Dias-Baruffi M, Jamur MC, Oliver C, Roque-Barreira MC, Rodrigues V: Sm60, a mannose-binding protein from Schistosoma mansoni with inflammatory property. Int J Parasitol 2002;32:1747-1754. https://doi.org/10.1016/S0020-7519(02)00211-4
130	Trudgett A, Watt AP, Harriott P, Ennis M: Liver fluke (Fasciola hepatica)-derived peptides activate rat peritoneal mast cells. Int Immunopharmacol 2003;3:775-781. https://doi.org/10.1016/S1567-5769(03)00079-1
131	Seifert B, Geyer E: Inhibition of in vitro and in vivo mast cell degranulation by Taenia crassiceps metacestodes in vitro incubation products. Zentralbl Bakteriol 1989;271:521-531. https://doi.org/10.1016/S0934-8840(89)80114-8
132	Xian S, Chen L, Yan Y, Chen J, Yu G, Shao Y, Zhan B, Wang Y, Zhao L: Echinococcus multilocularis calreticulin interferes with C1q-mediated complement activation. Trop Med Infect Dis 2023;8:47. https://doi.org/10.3390/tropicalmed8010047
133	Vukman KV, Adams PN, Metz M, Maurer M, O'Neill SM: Fasciola hepatica tegumental coat impairs mast cells' ability to drive Th1 immune responses. J Immunol 2013;190:2873-2879. https://doi.org/10.4049/jimmunol.1203011
134	González MI, Lopes F, McKay DM, Reyes JL: Mast cell deficiency in mice results in biomass overgrowth and delayed expulsion of the rat tapeworm Hymenolepis diminuta. Biosci Rep 2018;38:BSR20180687. https://doi.org/10.1042/BSR20180687
135	McLauchlan PE, Roberts HC, Loxton NJ, Wastling JM, Newlands GF, Chappell LH: Mucosal mast cell responses and release of mast cell protease-I in infections of mice with Hymenolepis diminuta and H. microstoma: modulation by cyclosporin A. Parasite Immunol 1999;21:151-161. https://doi.org/10.1046/j.1365-3024.1999.00214.x
136	Yépez-Mulía L, Montaño-Escalona C, Fonseca-Liñán R, Muñoz-Cruz S, Arizmendi-Puga N, Boireau P, Ortega-Pierres G: Differential activation of mast cells by antigens from Trichinella spiralis muscle larvae, adults, and newborn larvae. Vet Parasitol 2009;159:253-257. https://doi.org/10.1016/j.vetpar.2008.10.039
137	Arizmendi-Puga NG, Enciso JA, Ortega-Pierres G, Zhao Z, Duszyk M, Ulanova M, Befus AD, Yépez-Mulia L: Trichinella spiralis: histamine secretion induced by TSL-1 antigens from unsensitized mast cells. Exp Parasitol 2006;114:67-76. https://doi.org/10.1016/j.exppara.2006.02.016
138	Donskow-Łysoniewska K, Maruszewska-Cheruiyot M, Krawczak-Wójcik K, Gonzalez JF, Hernández JN, Stear MJ: Nematode galectin binds IgE and modulates mast cell activity. Vet Parasitol 2022;311:109807. https://doi.org/10.1016/j.vetpar.2022.109807
139	Melendez AJ, Harnett MM, Pushparaj PN, Wong WS, Tay HK, McSharry CP, Harnett W: Inhibition of FcɛRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat Med 2007;13:1375-1381. https://doi.org/10.1038/nm1654
140	Wells PD: Mast cell, eosinophil and histamine levels in Nippostrongylus brasiliensis infected rats. Exp Parasitol 1962;12:82-101. https://doi.org/10.1016/S0014-4894(62)80002-2
141	Befus AD, Johnston N, Bienenstock J: Nippostrongylus brasiliensis: mast cells and histamine levels in tissues of infected and normal rats. Exp Parasitol 1979;48:1-8. https://doi.org/10.1016/0014-4894(79)90048-1
142	Ohnmacht C, Voehringer D: Basophils protect against reinfection with hookworms independently of mast cells and memory Th2 cells. J Immunol 2010;184:344-350. https://doi.org/10.4049/jimmunol.0901841
143	Linnemann LC, Reitz M, Feyerabend TB, Breloer M, Hartmann W: Limited role of mast cells during infection with the parasitic nematode Litomosoides sigmodontis. PLoS Negl Trop Dis 2020;14:e0008534. https://doi.org/10.1371/journal.pntd.0008534
144	McDermott JR, Bartram RE, Knight PA, Miller HR, Garrod DR, Grencis RK: Mast cells disrupt epithelial barrier function during enteric nematode infection. Proc Natl Acad Sci U S A 2003;100:7761-7766. https://doi.org/10.1073/pnas.1231488100
145	Knight PA, Brown JK, Wright SH, Thornton EM, Pate JA, Miller HR: Aberrant mucosal mast cell protease expression in the enteric epithelium of nematode-infected mice lacking the integrin αvβ6, a transforming growth factor-β1 activator. Am J Pathol 2007;171:1237-1248. https://doi.org/10.2353/ajpath.2007.061245
146	Barrett KE, Neva FA, Gam AA, Cicmanec J, London WT, Phillips JM, Metcalfe DD: The immune response to nematode parasites: modulation of mast cell numbers and function during Strongyloides stercoralis infections in nonhuman primates. Am J Trop Med Hyg 1988;38:574-581. https://doi.org/10.4269/ajtmh.1988.38.574
147	Sasaki Y, Yoshimoto T, Maruyama H, Tegoshi T, Ohta N, Arizono N, Nakanishi K: IL-18 with IL-2 protects against Strongyloides venezuelensis infection by activating mucosal mast cell-dependent type 2 innate immunity. J Exp Med 2005;202:607-616. https://doi.org/10.1084/jem.20042202
148	Darmawi DBU, Hambal M, Frengki F, Priosoeryanto BP: Mucosal mast cells response in the jejunum of Ascaridia galli-infected laying hens. Media Peternakan 2013;36:113-119. https://doi.org/10.5398/medpet.2013.36.2.113
149	Hepworth MR, Daniłowicz-Luebert E, Rausch S, Metz M, Klotz C, Maurer M: Hartmann S: Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines. Proc Natl Acad Sci U S A 2012;109:6644-6649. https://doi.org/10.1073/pnas.1112268109
150	Alizadeh H, Murrell KD: The intestinal mast cell response to Trichinella spiralis infection in mast cell-deficient w/wv mice. J Parasitol 1984;70:767-773. https://doi.org/10.2307/3281760
151	Carlos D, Machado ER, De Paula L, Sá-Nunes A, Sorgi CA, Jamur MC, Oliver C, Lima WT, Faccioli LH: Evidence for eosinophil recruitment, leukotriene B4 production and mast cell hyperplasia following Toxocara canis infection in rats. Braz J Med Biol Res 2011;44:319-326. https://doi.org/10.1590/S0100-879X2011007500027
152	Patrizi A, Virdi A, Neri I: Cutaneous mastocytosis exacerbated by pinworms in a young boy. Pediatr Dermatol 2012;29:229-230. https://doi.org/10.1111/j.1525-1470.2011.01530.x
153	Muhsin M, Ajendra J, Gentil K, Berbudi A, Neumann AL, Klaas L, Schmidt KE, Hoerauf A, Hübner MP: IL-6 is required for protective immune responses against early filarial infection. Int J Parasitol 2018;48:925-935. https://doi.org/10.1016/j.ijpara.2018.05.011
154	Specht S, Frank JK, Alferink J, Dubben B, Layland LE, Denece G, Bain O, Förster I, Kirschning CJ, Martin C, Hoerauf A: CCL17 controls mast cells for the defense against filarial larval entry. J Immunol 2011;186:4845-4852. https://doi.org/10.4049/jimmunol.1000612
155	Arizmendi N, Yépez-Mulia L, Cedillo-Rivera R, Ortega-Pierres MG, Muñoz O, Befus D, Enciso-Moreno JA: Interleukin mRNA changes in mast cells stimulated by TSL-1 antigens. Parasite 2001;8(2 Suppl):S114-S116. https://doi.org/10.1051/parasite/200108s2114
156	Shimokawa C, Kanaya T, Hachisuka M, Ishiwata K, Hisaeda H, Kurashima Y, Kiyono H, Yoshimoto T, Kaisho T, Ohno H: Mast cells are crucial for induction of group 2 innate lymphoid cells and clearance of helminth infections. Immunity 2017;46:863-874.e4. https://doi.org/10.1016/j.immuni.2017.04.017
157	Herbert DR, Douglas B, Zullo K: Group 2 innate lymphoid cells (ILC2): Type 2 immunity and helminth immunity. Int J Mol Sci 2019;20:2276. https://doi.org/10.3390/ijms20092276
158	Ryan NM, Oghumu S: Role of mast cells in the generation of a T-helper type 2 dominated anti-helminthic immune response. Biosci Rep 2019;39:BSR20181771. https://doi.org/10.1042/BSR20181771