Mast cells are abundant in tissues exposed to the external environment, including the skin (45). Malaria parasites may promote malaria pathogenesis by triggering MCs. Plasmodium berghei-infected Anopheles gambiae mosquito saliva can trigger mouse dermal MC degranulation as little as 5 min after the mosquito bite. One hour after the bite, MCs were observed in the vicinity of sporozoites on skin sections from mice bitten by P. berghei-infected An. gambiae mosquitoes (17). Saliva-induced activation of dermal MCs causes lymph node swelling via the recruitment of T cells, B cells, dendritic cells (DC), and monocytes/macrophages (Mφ) as well as neutrophils (46, 47). Importantly, it was shown that there was an increase in MC activation and degranulation in the skin dermis of severe Plasmodium falciparum malaria patients, compared to controls. The percentage of MC degranulation was significantly correlated with parasitemia and disease severity, which are relevant to MC mediators (16).

Mast cells are found in the central nervous system, especially along the blood vessels and leptomeninges (48). Kenyan children with mild and severe malaria were shown to have increased plasma levels of Flt3 ligand (Flt3L) (15). Elevated serum Flt3L levels and DC expansion were found in patients infected by P. falciparum and mice with Plasmodium infection. MCs are an important source of Flt3L, a soluble cytokine that influences DC function, with the subsequent activation of pathogenic CD8⁺ T cells, a critical effector of the disease (49). After infection with P. berghei ANKA, compared to MC-deficient WBB6F₁-W/W^v mice, the control littermate WBB6F₁^+/+ C57BL/6 mice had lower parasitemia and mortality with higher tumor necrosis factor (TNF) levels. Malarial antigens from P. berghei ANKA are able to stimulate Mφ and MCs to secrete TNF in vitro. An in vivo study further demonstrated that MCs are a critical source of TNF in addition to Mφ and T cells in murine malaria. Therefore, MCs and MC-derived TNF play an important role in protection against experimental cerebral malaria (ECM) (18). Furthermore, P. berghei ANKA peroxiredoxin induces a significant amount of MC-derived TNF secretion from IgE-mediated protection through FcεRI on MCs and innate immunity by means of toll-like receptor (TLR) 4 with myeloid differentiation primary response gene 88 and MD-2 and plays a role in innate and acquired immune responses in malaria (50). Conversely, one study reported that malaria developed in MC-deficient and basophil-depleted C57BL/6 mice infected with P. berghei ANKA was similar to that developed in wild-type mice, suggesting that MCs and basophils were not involved in malaria pathogenesis in this model (19).

Histamine has four different receptors, namely H1R, H2R, H3R, and H4R, which mediate numerous different effects (51). Histamine is the major MC mediator in malaria, and its signaling has been associated with the severity of P. falciparum malaria (21). In addition, the significant elevation of the blood concentrations of IgE and IgE-antimalarial antibodies has also been linked to the disease severity in falciparum malaria patients (52). As a DC modulator, especially during early phases of the immune response, histamine causes increased vascular permeability and subsequent extensive vascular damage to endothelial cells during malaria infection (47). Experiments have demonstrated that histamine binding to H1R and H2R increases the susceptibility of infection with P. berghei in H1R^−/− and H2R^−/− mice (21). H3R^−/− mice infected with P. berghei ANKA have an accelerated onset of CM and mortality, accompanied by an earlier loss of blood–brain barrier integrity, earlier formation of hemorrhagic lesions, higher sequestration of CD4⁺ and CD8⁺ T cells in the brain, and higher serum histamine levels compared to C57BL/6 wild-type mice. The severity of CM is related to the increased plasmatic levels of histamine in H3R^−/− mice during the infection (20). Mice genetically deficient in the histidine decarboxylase (HDC^−/−) gene, thus lacking histamine, were highly resistant to lethal infection by P. berghei ANKA and P. berghei NK65, associated with decreased brain-infiltrating T cells and expression of adhesion molecules. After treatment with antihistamine drugs, mice infected with P. berghei had prolonged survival compared to infected mice without antihistamine treatment (21).

Vascular endothelial growth factor (VEGF) is both neuroprotective and pro-inflammatory in the brain. VEGF was shown to accumulate intracellularly in P. falciparum-infected red blood cells in vitro, and inhibition of VEGF receptor (VEGFR)-2 signaling reduced intraerythrocytic growth of P. falciparum (53). VEGF and soluble VEGFR (sVEGFR)-2 are increased in CM patients compared to healthy adults (54). Plasma VEGF concentrations in Kenyan children with CM are associated with an increased risk of neurological sequelae (55). sVEGFR-1 may play a pathological role during chronic placenta malaria and hypertension in first-time mothers (56). Both P. falciparum and Plasmodium vivax crude antigens induce VEGF release from the human MC line HMC-1 or the human basophilic cell line KU812 in vitro. Increased parasitemia of P. berghei ANKA was observed in anti-VEGF Ab-treated mice compared to non-treated mice (54). Furthermore, VEGF was shown to promote malaria-associated acute lung injury induced by P. berghei ANKA in mice (57). The pro-inflammatory cytokine interleukin (IL)-33 is strongly enhanced in infants (<5 years) with severe malaria from P. falciparum infection (58). IL-33 contributes to the stimulation and release of VEGF in human MCs (hMCs) (59). Conversely, IL-33 prevents the development of ECM in C57BL/6 mice infected with P. berghei ANKA and reduces the production of inflammatory mediators IFN-γ, IL-12, and TNF-α (60).

In the gastrointestinal tract, MCs regulate vascular and epithelial permeability, ion secretion, angiogenesis, peristalsis, fibrosis, tissue repair, and innate and adaptive immunity (61). Increased numbers of mucosal MCs (MMCs) in the ileal villi and crypts and increased histamine levels in the ileum were detected in Plasmodium yoelii-infected mice. The increase in ileal MMCs was positively correlated with elevated parasitemia and IL-4 mRNA levels in the same tissue. An additional study found that P. yoelii nigeriensis-infected mice develop an l-arginine deficiency, which is associated with intestinal mastocytosis, elevated levels of plasma histamine, and enhanced intestinal permeability (22). Plasmodium fragile-infected rhesus macaques have been shown to exhibit ileal mastocytosis and increased plasma histamine levels. Antihistamine treatment during P. yoelii infection results in decreased intestinal permeability in CBA/J mice, suggesting that MCs and histamine are involved in increased intestinal permeability during Plasmodium infection (23).

Cutaneous leishmaniasis is an important public health concern in many parts of the world, especially in Africa (63). MCs degranulate and release inflammatory mediators such as TNF-α after infection and recruit polymorphonuclear leukocytes (PMNs) to the site of infection (64). MCs can be important in cutaneous leishmaniasis and are involved in healing lesions. The MC count was higher in the skin biopsy of patients with cutaneous leishmaniasis caused by Leishmania braziliensis with earlier healing after treatment, and there was a positive association between the disease duration and MC count (24).

After infection of Leishmania amazonensis in susceptible (C57BL/10 and CBA), relatively resistant (DBA/2), and resistant (C3H.He) mice, the primary lesions in footpads and draining lymph nodes showed a predominance of eosinophils and MCs in the initial phase of infection in all the infected mice (65). MC numbers increased significantly in the upper dermis in susceptible (BALB/c) but not in resistant (C57BL/6 and CBA/T6T6) mice after L. major infection. However, the number of degranulating MCs was higher in CBA/T6T6 mice during early L. major infection. In addition, MC-derived cytokines, such as TNF-α, play a proparasitic role in a susceptible strain (BALB/c) of mice, but an antiparasitic role in resistant strains (C57BL/6 and CBA/T6T6) of mice, suggesting that the susceptible and resistant mouse strains may have different modes of producing the antileishmanial immune response by differential regulation of MC function (25). After L. major inoculation, MC activation and parasite uptake by skin-resident Mφ occurred, followed by neutrophil and monocyte immigration and DC activation. Therefore, MC-dependent recruitment of Mφ, PMN, and DC to the skin is involved in controlling leishmaniasis (66). Furthermore, using MC-deficient Kit^W-sh/Kit^W-sh mice for infection with L. major promastigotes results in a worse disease outcome, e.g., significantly enhanced lesion progression and lesional parasite burdens, accompanied by significantly decreased levels of IFN-γ and IL-17A, but significantly increased IL-4 and IL-10, compared to wild-type mice, indicating that MCs play a crucial role against Leishmania parasites by promoting Th1 and Th17 responses in vivo (26). L. infantum/chagasi-infected skins, from dogs of two different leishmaniasis endemic areas of Brazil, showed different skin infection patterns; however, dogs from both areas showed dermic inflammatory infiltrates composed of numerous degranulated MCs compared to normal skin, indicating that MCs modulate the immune response and participate in the host defense against Leishmania infection (27). Dogs naturally infected with L. infantum showed increased inflammatory infiltrates in the skin of animals with severe forms of canine visceral leishmaniasis and a high parasite density. The increased number of Mφ and decreased number of lymphocytes, eosinophils, and MCs in the skin correlate with clinical progression of canine visceral leishmaniasis (28).

After susceptible BALB/c and resistant C57BL/6 mice were infected with L. major and pretreated with compound 48/80 (a MC activator), both BALB/c and C57BL/6 mice displayed smaller lesions in footpads compared to controls, indicating that MC degranulation contributes to susceptibility to L. major infection, and in the absence of granulated MCs, BALB/c and C57BL/6 mice had increased resistance to L. major infection. Although IL-4 and MC degranulation are important to Leishmania-associated pathogenesis, the MC-mediated susceptibility seems to be independent of IL-4 (67). MC-deficient C57BL/6-Kit^W/Kit^W-v mice and congenic wild-type Kit^+/+ mice were infected with metacyclic promastigotes of L. major by intradermal injections, resulted in significantly increased lesion sizes and lesional parasitic loads, and significantly reduced locally infiltrating cells in Kit^W/Kit^W-v mice. In addition, pronounced MC degranulation was observed in infected skin sites after intradermal injection of L. major in C57BL/6 mice, indicating that MCs provide protection against L. major infection (29). An in vitro study showed that stimulation with Leishmania mexicana lipophosphoglycan led to a significant increase in degranulation in bone marrow-derived MCs (BMMCs) from BALB/c mice compared to BMMCs from C57BL/6 mice. Moreover, an in vivo study showed that after infection with L. mexicana, the number of MCs increased more rapidly and to a greater level, with significantly higher levels of parasites in the lesions of BALB/c mice compared to C57BL/6 mice. This indicates that MCs regulate the outcome of leishmaniasis and is dependent on the genetic background of the host (68). Conversely, a recent study showed that MC has no impact on the severity of cutaneous leishmaniasis in mice infected with L. major. By using Kit mutant mice with different genetic backgrounds, it was shown that MC deficiency did not affect lesion size development after L. major infection, suggesting that MCs are not involved in murine cutaneous Leishmania infections (30).

Visceral leishmaniasis is a serious public health problem that causes high morbidity and mortality (69). Analysis of Th1, Th2, and Th17 cytokine responses by cultured peripheral blood mononuclear cells from patients who had developed kala-azar caused by Leishmania donovani, or who were protected against kala-azar, showed that IL-17 and IL-22 are the cytokines most strongly associated with protection against kala-azar (70). It has been reported that higher numbers of plasma cells, lymphocytes, and Mφ but lower number of MCs are present in the lamina propria of gastrointestinal tract of dogs naturally infected with L. infantum compared to non-infected controls, in all gastrointestinal tract segments (31). Thus, MCs may play different roles in visceral leishmaniasis and cutaneous leishmaniasis.

Mucosal leishmaniasis is a chronic infection that affects the upper respiratory tract and/or the oral mucosa (71). Some patients diagnosed with mucosal leishmaniasis have oral lesions. Scraping cytology examination in patients with oral leishmaniasis presented free Leishman-Donovan bodies or Mφ loaded with Leishman-Donovan bodies, acute and chronic inflammatory cells, histiocytes, multinucleated giant cells, MCs, and plasma cells (72).

Ocular involvement is an unusual presentation of leishmaniasis and commonly limited to the eyelid skin (73). Both C57BL/10 and BALB/c mice are susceptible to leishmaniasis, infected with L. amazonensis by intravitreal injection and instillation, respectively. Independent of the infective routes, C57BL/10 mice infected intravitreally presented an intense inflammatory reaction in the epithelium of the eyelids, as well as the presence of many intact MCs in the conjunctiva of the eyes from 30 days postinfection (p.i.). On the other hand, BALB/c mice infected via the instillation route presented no lesions but an enhancement of intact MCs in the conjunctival region at 30 days p.i., and a discreet inflammatory infiltrate and degranulated MCs were observed in the conjunctival region at 60 days p.i. (32).

To date, the regulatory effect of MCs on the pathogenesis of leishmaniasis is still unclear. The clearance of L. major strongly depends on TLRs (24). TLR9-deficient Mφ had reduced expressions of CD40, IL-12, and TNF-α (74). MCs respond to TLR ligands by secreting cytokines, chemokines, and lipid mediators, and some studies have found that TLR ligands can also cause MC degranulation (75). The HMC-1 stimulated by promastigotes of L. braziliensis has a significantly greater release of histamine and IL-4 compared to control cells treated with medium (76). MCs release IL-3 and IL-4 to render Mφ susceptible to Leishmania infection in vitro (25).

Megacolon is frequently observed in patients with Chagas disease caused by T. cruzi infection, which has been considered a consequence of an inflammatory process, and inflammatory infiltrates are composed of lymphocytes, Mφ, natural killer cells, MCs, and eosinophils. Morphometric analyses in the lamina propria, muscle layer, or myenteric plexus region revealed that the numbers of both tryptase-immunoreactive MCs and eosinophils are significantly increased in patients with megacolon compared to uninfected individuals. MC and eosinophil activation, as well as their physical interaction, were observed by electron microscopy (33). T. cruzi-induced injury resulted in intramuscular fibrosis and increased thickness of the colon wall in patients with chagasic megacolon, and there was a greater MC count and more fibrosis in the circular colon musculature of chronic Chagas patients with megacolon compared to Chagas cases without megacolon (34). The density of MCs was significantly higher in the esophagus and large intestine in patients with AIDS plus Chagas disease reactivation compared to chronic chagasic patients without AIDS. This suggests that MCs may play a major role in esophageal and intestinal inflammation during Chagas disease reactivation in HIV-coinfected patients (77). MC-specific proteases (tryptase and chymase) influence the activation of inflammatory cells. Increased numbers of tryptase-immunoreactive MCs were found in the esophagus sections of T. cruzi-infected individuals with or without megaesophagus. However, increased numbers of chymase-immunoreactive MCs were only found in the esophagus sections of infected individuals without megaesophagus compared to the control groups. Therefore, patients with megaesophagus had increased levels of tryptase-immunoreactive MCs (14).

One animal study showed that, after infection with the Y strain of T. cruzi, there were no significant differences in MC counts in the acute phase in Swiss mice. However, there was a significant increase in the number of MCs in the muscular layer of chronically infected Swiss mice with chagasic megacolon compared to non-infected control mice, accompanied by increased thickness of the colon wall, diffuse muscle cell hypertrophy, and increased collagen deposition (35), which may be associated with MC functions.

The density of MCs in the myocardium was shown to be significantly higher in the chronic chagasic patients compared to control groups (77). The autopsied chagasic patient group showed higher MC chymase and MC tryptase densities and a higher percentage of collagen in the lingual muscles and myocardium compared to the non-chagasic patient group, and MC chymase level was associated with the intensity of myocardium fibrosis of chronic Chagas disease (37). Infiltrated T cells, Mφ, B cells, and MCs were all observed in the myocardium of patients with Chagas cardiopathy, who died at an early mean age or at older ages. However, the numbers of T-lymphocytes and MCs were significantly higher in the cases who suffered early cardiac death (78).

One animal study showed that T. cruzi-infected CBA mice treated with cromolyn (a MC stabilizer) presented much greater parasitemia and IFN-γ levels, higher mortality, myocarditis, and cardiac damage, indicating that MCs control blood and tissue parasitemia, IFN-γ production, cardiac inflammation, and susceptibility to infection, suggesting that MCs are involved in resistance to this infection (36).

Trypanosoma brucei is a protozoan parasite that causes human African trypanosomiasis. Rats initially infected with T. brucei, followed by infection with Trichinella spiralis, showed that T. brucei infection does not significantly alter the number of MCs generated by T. spiralis infection, while the intestinal MC numbers in rats infected with only T. brucei were similar to those in uninfected rats (38).

Toxoplasmic encephalitis in patients with AIDS is a life-threatening disease, mostly due to the reactivation of T. gondii cysts in the brain (79). It has been reported that a patient with meningoencephalitic toxoplasmosis was associated with systemic cutaneous and gastrointestinal mastocytosis, suggesting a possible relationship between MC proliferation and the parasitic infection (39).

Calomys callosus (Rodentia: Cricetidae) animals were inoculated intraperitoneally or via the conjunctiva with tachyzoites of the RH strain of T. gondii, resulting in the presence of the parasites and inflammatory cells and a significant increase in the number of MCs. Furthermore, MC activation in the ocular tissues was observed after infection, suggesting that MCs play an important role in the acute inflammatory response against T. gondii (40).

Oral infection is the natural toxoplasmosis route, and the MC population is highly abundant in intestinal mucosa. In MC-deficient mice (W/W^v) and their control +/+ counterparts orally infected with cysts of the ME49 strain of T. gondii, rapid lethality and decreased IFN-γ levels were observed in the serum of infected mice in the absence of MCs. This demonstrated that MCs play a primordial role in resistance to oral infection with T. gondii, and MCs are required for survival of mice after oral infection with T. gondii (41). RBL-2H3 MCs infected with T. gondii type I (RH), II (PTG), or III (CTG or VEG) tachyzoites showed that acute T. gondii infection inhibits antigen-mediated MC degranulation, irrespective of the genotype of parasite used, and that tachyzoite attachment but not invasion is necessary for inhibiting degranulation. Ca²⁺ mobilization is a central and well-studied aspect of IgE/FcεRI-mediated signaling in MCs, and T. gondii infection has been shown to inhibit MC degranulation by suppressing antigen-mediated Ca²⁺ responses (80).

After intraperitoneal infection with the RH strain of T. gondii, the number of non-degranulated MCs was significantly lower than that of degranulated cells in the peritoneal cavity, submandibular and dorsal lymph nodes, and ileum in infected C. callosus compared to uninfected animals. After the MC degranulation, a remarkable increase in the influx of neutrophils and Mφ but a decrease in lymphocyte influx toward the peritoneal cavity of the infected animals were observed. MCs were observed interacting with other parasitized cells including Mφ, and extracellular parasites were destroyed during the interaction with MCs exhibiting degranulation. This suggests that MC is an important cell type during the inflammatory response against T. gondii (42). The use of MC-deficient Kit^W/Kit^W-v mice demonstrated that the influx of Ly6G⁺ cells toward the peritoneal cavity was significantly reduced compared to control littermates, indicating that MCs are an important chemokine source driving PMN recruitment to the peritoneal cavity during T. gondii infection (43). In both wild-type and serglycin-deficient mice, intraperitoneal infection with T. gondii resulted in highly increased extracellular levels of glycosaminoglycans, including hyaluronan and chondroitin sulfate A, suggesting that serglycin proteoglycan is dispensable for normal secretion and activity of MC proteases in response to T. gondii infection (81). A murine model showed that infection of T. gondii increased not only the number of MCs at the site of infection but also a noticeable degree of MC degranulation. Kunming outbred mice were infected intraperitoneally with the RH strain of T. gondii and treated by compound 48/80 or disodium cromoglycate (a MC stabilizer). The MC activator aggravated the pathology and increased the parasitic load, accompanied by upregulated mRNA levels of Th1 cytokines (IFN-γ, IL-12p40, or TNF-α) in the livers and spleens of T. gondii-infected mice. Conversely, the MC stabilizer improved the pathology and decreased the parasitic load, accompanied by increased mRNA levels of Th2 cytokines (IL-4 and IL-10) in the livers and spleens of mice infected with this parasite. In addition, significantly increased inflammatory foci of neutrophil infiltrates in different tissues occurred as a result of MC degranulation after the parasite infection (44). Thus, the activation or inhibition of MCs is a key factor determining the fate of the infection and associated immunopathology.

When T. gondii tachyzoites and MCs were incubated together, the tachyzoites adhered to the surface of the MCs, followed by MC degranulation. MC histamine and LTB₄ release was significantly increased after incubation with the tachyzoites, which resulted in damage to the tachyzoites. MC-treated tachyzoites were found to be incapable of infection and replication in murine peritoneal Mφ. Therefore, LTB₄ released by MCs and other inflammatory cells may be a key factor in the host defense against T. gondii (82). hMCs co-cultured with T. gondii RH tachyzoites that were opsonized with IgG directed against the surface antigen 1 exhibited a polarized degranulation toward the invading parasites and resulted in the death of more than 70% of the parasites during the process. On the other hand, non-opsonized T. gondii rapidly infected MCs without triggering any detectable degranulation process, and only 20% of the parasites died during the process. hMC treated with a chymase inhibitor did not affect parasite mortality, whereas hMC treated with a tryptase inhibitor significantly decreased the number of dead parasites in contact with degranulated MCs. Thus, IgG-opsonized T. gondii resulted in tryptase-dependent parasite death (83). TS-4 strain T. gondii infection significantly increased the expression of metalloproteinases (MMP)-2 and MMP-9 in P815 murine mastocytoma cells, and the invading parasites can elicit Erk1/2 phosphorylation, leading to NF-κB activation in the cytoplasm. This pathway for generating MMP-2 and MMP-9 is important in host defense mechanisms against T. gondii (84). The mediators of activated MCs play an important role in modulating acute inflammatory pathogenesis and parasite clearance in T. gondii infection (85).