Mast cell-derived IL-10 protects intestinal barrier integrity during malaria in mice and regulates parasite transmission to Anopheles stephensi with a female-biased immune response

Nora Céspedes; Erinn L Donnelly; Gretchen Hansten; Abigail M Fellows; Megan Dobson; Hannah L Kaylor; Taylor A Coles; Joseph Schauer; Judy Van de Water; Shirley Luckhart

doi:10.1128/iai.00360-23

. 2024 Feb 1;92(3):e00360-23. doi: 10.1128/iai.00360-23

Mast cell-derived IL-10 protects intestinal barrier integrity during malaria in mice and regulates parasite transmission to Anopheles stephensi with a female-biased immune response

Nora Céspedes ^1,^✉, Erinn L Donnelly ², Gretchen Hansten ¹, Abigail M Fellows ¹, Megan Dobson ¹, Hannah L Kaylor ¹, Taylor A Coles ¹, Joseph Schauer ³, Judy Van de Water ³, Shirley Luckhart ^1,²

Editor: De'Broski R Herbert⁴

PMCID: PMC10929420 PMID: 38299826

ABSTRACT

Malaria is strongly predisposed to bacteremia, which is associated with increased gastrointestinal permeability and a poor clinical prognosis. We previously identified mast cells (MCs) as mediators of intestinal permeability in malaria and described multiple cytokines that rise with parasitemia, including interleukin (IL)-10, which could protect the host from an inflammatory response and alter parasite transmission to Anopheles mosquitoes. Here, we used the Cre-loxP system and non-lethal Plasmodium yoelii yoelii 17XNL to study the roles of MC-derived IL-10 in malaria immunity and transmission. Our data suggest a sex-biased and local inflammatory response mediated by MC-derived IL-10, supported by early increased number and activation of MCs in females relative to males. Increased parasitemia in female MC IL-10 (−) mice was associated with increased ileal levels of chemokines and plasma myeloperoxidase (MPO). We also observed increased intestinal permeability in female and male MC IL-10 (−) mice relative to MC IL-10 (+) mice but no differences in blood bacterial 16S DNA levels. Transmission success of P. yoelii to A. stephensi was higher in female relative to male mice and from female and male MC IL-10 (−) mice relative to MC IL-10 (+) mice. These patterns were associated with increased plasma levels of pro-inflammatory cytokines in female MC IL-10 (−) mice and increased plasma levels of chemokines and markers of neutrophil activation in male MC IL-10 (−) mice. Overall, these data suggest that MC-derived IL-10 protects intestinal barrier integrity, regulates parasite transmission, and controls local and systemic host immune responses during malaria, with a female bias.

KEYWORDS: malaria, mast cells, interleukin 10, bacteremia, transmission, Anopheles

INTRODUCTION

Malaria is a parasitic disease caused by infection with Plasmodium spp. transmitted by Anopheles mosquitoes. The disease is endemic in tropical and subtropical regions, affecting around 45% of the global population. In 2021, there were an estimated 247 million cases and 619,000 malaria deaths, mainly attributable to Plasmodium falciparum, with children under the age of 5 years accounting for 76% of malaria deaths (1). Several studies have indicated that malaria predisposes to the development of concurrent bacteremia, leading to a higher case-fatality rate (15.0%) among patients with co-infection (2 –6).

We have shown that bacteremia is functionally associated with increased intestinal infiltration of mast cells (MCs) or mastocytosis in mouse and non-human primate malaria models and with increased intestinal permeability in mice associated with rising levels of MC-activating type-2 cytokines interleukin (IL)-3, -4, -5,-9, -10, and -13 (7 –9). Furthermore, MC-deficient mice with malaria had decreased intestinal permeability and bacteremia compared to controls (8), supporting the contribution of MCs in malaria-induced gut barrier disruption. MCs are innate immune cells of the myeloid lineage (10) that play an important role in many allergic and inflammatory diseases, and their activation can result in the synthesis of a variety of mediators (11 –13) including the regulatory cytokine, IL-10.

Our previous studies demonstrated the role of IL-10 in malaria-induced bacteremia. Specifically, we showed that mice co-infected with P. yoelii and non-typhoidal Salmonella enterica serovar Typhimurium (NTS) exhibited increased bacterial loads in liver and blood by 2 and 4 days post-infection (PI), respectively, compared to mice colonized with NTS alone. This was associated with significantly fewer neutrophils and high levels of circulating IL-10 in co-infected mice relative to mice with only NTS (14, 15). Neutralization of IL-10 reduced bacterial loads in co-infected mice, while mice with IL-10-deficient LysM⁺ myeloid cells, most likely macrophages, were better able to control systemic S. Typhimurium infection (14). These observations suggested that IL-10 produced in response to malaria increased susceptibility to disseminated NTS infection by suppressing myeloid cell control of bacterial infection (14).

Beyond regulation of the intestinal barrier, IL-10 plays more central roles in malaria, including the induction of parasite-specific, germinal center-derived humoral responses during infection (16). Perhaps not surprisingly, given the variety of cell types that can produce IL-10, this biology has been reported to depend on the synthesis of IL-10 by both regulatory B cells (17, 18) and extrafollicular CD4+ T cells (19). MC-derived IL-10, however, can suppress germinal center-derived antibody synthesis (20), suggesting that distinct cellular sources of IL-10 might tune germinal center activity. Parasite-specific IL-10-producing type 1 regulatory T (Tr1) cells also increase rapidly following controlled human malaria infection (CHMI), protecting the host from damaging inflammation and dampening anti-parasite immunity (21, 22), perhaps following activation of Tr1 cells by MC-derived IL-10 (23). This complex mammalian response likely also affects parasite transmission to the mosquito host. Notably, successful human parasite transmission to Anopheles stephensi in CHMI occurs well beyond peak levels of Tr1 cells and plasma IL-10 levels (20–24 days PI). Furthermore, increased IL-10 levels observed during the acute phase of malaria have been linked to the inhibition of transmission of P. vivax to Anopheles darlingi mosquitoes (24).

Based on these observations, we hypothesized that MC-derived IL-10 modifies the host immune response to malaria, reduces malaria-induced damage to the intestinal barrier, and contributes to the control of parasite transmission from infected mice. To test these hypotheses, we used male and female P. y. yoelii 17XNL-infected mice with IL-10-deficient MCs [Cpa3-Cre (+) IL-10flox/flox mice], matched genotype controls [Cpa3-Cre (−) IL-10flox/flox mice] as well as uninfected controls. We observed that MC-derived IL-10 maintains intestinal barrier integrity during early parasite infection in both male and female mice. However, we noted sex-specific differences in MC-derived IL-10-dependent regulation of parasite infection and transmission to A. stephensi, patterns that were associated with sex-specific immune responses to parasite infection over time. Notably, these patterns are consistent with MC-driven differences in male and female host responses in other mouse models and humans, which to our knowledge, would connect MCs to sex-specific patterns of the host response to malaria for the first time.

RESULTS

Parasitemia was transiently increased in female MC IL-10 (−) mice relative to other groups, while MC activation was female-biased during P. y. yoelii 17XNL infection

We selected P. yoelii as this model resembles non-lethal human malaria-associated bacteremia observed in both adolescents and adults (6). In addition, we have demonstrated that P. y. yoelii 17XNL-infected red blood cells accumulate in the intestinal microvasculature with evidence of sequestration (25), an event that likely contributes to the elaboration of infection-associated signals for MC accumulation in the ileum.

As previously described (9), all mice injected with P. y. yoelii 17XNL developed parasitemia by day 2 PI, which increased with the course of infection (Fig. 1). Parasitemia was significantly higher in female MC IL-10 (−) mice relative to both female MC IL-10 (+) mice and male MC IL-10 (−) mice on day 8 PI (Fig. 1). However, there were no differences in parasitemia between male MC IL-10 (−) mice and male MC IL-10 (+) mice at any time point (Fig. 1). Assuming that these curves accurately represent parasitemia across these time points, the presence of MC-derived IL-10 was associated with a slower rise in parasitemia over time in female mice.

Fig 1 — *P. y. yoelii* 17XNL parasitemias were sex- and genotype-dependent. Data were analyzed using Brown-Forsythe and Welch ANOVA tests followed by multiple comparisons between MC IL-10 (−) and MC IL-10 (+) mice at each time point. P values ≤ 0.05 were considered significant *P ≤ 0.05.

Given that MCs respond to both autocrine and paracrine signaling by IL-10 and that IL-10 can promote MC survival, development, and proliferation (26 –28), we sought to determine whether the depletion of MC-derived IL-10 impacted MC numbers in the ileum during the course of infection. To assess this, we counted NASDCE-positive ileal MCs and evaluated plasma Mcpt1 levels as a marker of MC activation. Relative to uninfected female controls, MC counts in ileum sections increased at 6 and 8 days PI in female MC IL-10 (−) mice and at 6, 8, and 10 days PI in female MC IL-10 (+) mice (Fig. 2A, left table). Furthermore, MC numbers for both female genotypes were higher than those in the male genotypes at day 6 PI (Fig. 2A). In male mice, MC numbers were significantly higher than those in uninfected controls at 8 and 10 days PI in MC IL-10 (+) and MC IL-10 (−) mice, respectively (Fig. 2A, right table). No significant differences were observed between genotypes for female or male mice at any time point (Fig. 2A).

Fig 2 — Patterns of mast cell influx in the ileum and plasma Mcpt1 levels were sex-specific during *P. y. yoelii* 17XNL infection. (A) Numbers of ileal MCs per high-powered field (HPF) from ileum sections stained with naphthol AS-D chloroacetate esterase (NASDCE). (B) Plasma levels of MC protease 1 (Mcpt1) as determined by ELISA. Each dot represents a single mouse. Data were analyzed using Brown-Forsythe and Welch ANOVA tests followed by multiple comparisons versus uninfected mice or between MC IL-10 (−) and MC IL-10 (+) mice at specific time points; bars represent the mean. P values ≤ 0.05 were considered significant. *P ≤ 0.05, **P ≤ 0.01, U: uninfected control mice, ns: not significant.

Relative to uninfected female mice, increased levels of plasma Mcpt1 were observed at 6 and 8 days PI in female MC IL-10 (−) mice, with a nearly significant increase at 10 days PI; in female MC IL-10 (+) mice, increased Mcpt1 levels relative to uninfected females were observed at 4, 6, 8, and 10 days PI (Fig. 2B, left table). Higher concentrations of plasma Mcpt1 were observed in female MC IL-10 (−) mice relative to male MC IL-10 (−) mice at 6 days PI, and in female MC IL-10 (+) mice relative to male MC IL-10 (+) mice at 10 days PI (Fig. 2B). In male MC IL-10 (+) mice, plasma Mcpt1 levels were increased relative to uninfected controls at 4 and 6 days PI with a trend at 8 days PI (Fig. 2B, right table). In male MC IL-10 (−) mice, Mcpt1 levels were increased relative to uninfected controls at 10 days PI (Fig. 2B, right table). No significant differences in Mcpt1 levels were observed between genotypes at any time point in female or male mice (Fig. 2B). These data suggested that ileal MC numbers and MC activation were not affected by the depletion of MC-derived IL-10 but that relative states of MC activation were higher in females compared to males, regardless of genotype. Furthermore, relative to uninfected controls, MC activation in infected males and females was more frequently detected in the presence of MC IL-10.

MC IL-10-dependent intestinal permeability was evident in both males and females, while bacterial 16S DNA levels were independent of sex and genotype during infection

We previously reported that increased MC-dependent intestinal permeability in mice following P. yoelii infection (7 –9, 29) was accompanied by rising bacteremia and plasma IL-10 levels as the infection progressed (9, 29). These observations suggested that MC-derived IL-10 might contribute to the control of intestinal barrier integrity and bacterial translocation during malaria. To test this hypothesis, we estimated intestinal permeability as levels of FITC-dextran in plasma after oral gavage and bacteremia in blood via bacterial 16S qPCR for male and female mice of both genotypes before and after infection.

Plasma FITC-dextran levels were significantly higher in female MC IL-10 (−) mice relative to female MC IL-10 (+) mice at 4 and 6 days PI; the same patterns were observed in male mice at the same time points (Fig. 3A). Relative to uninfected mice, plasma FITC-dextran levels in both female and male MC IL-10 (−) mice were increased: in female mice, this was evident at 4 and 6 days PI (Fig. 3A, left table), and in male mice, this was noted at 4, 6, and 8 days PI (Fig. 3A, right table). There were no significant differences in plasma FITC-dextran levels in infected male and female MC IL-10 (+) mice relative to uninfected controls (Fig. 3A, right and left tables).

As expected, bacterial 16S levels increased over time following infection in male and female mice of both genotypes (Fig. 3B), with significant differences relative to uninfected controls by 8 and 10 days PI in female MC IL-10 (−) mice, male MC IL-10 (−) and MC IL-10 (+) mice, while in female MC IL-10 (+) 16S levels were significantly different from uninfected controls by 10 days PI (Fig. 3B, left and right tables). There were no differences in bacterial 16S DNA levels in blood between genotypes or between female and male mice at any time point (Fig. 3B).

In contrast to patterns of MC numbers and plasma Mcpt1 levels, patterns of plasma FITC-dextran and bacterial 16S copies showed no sex-specific differences over the course of infection. Taken together, our data suggested that MC-derived IL-10, in the context of increased MCs and MC activation in females relative to males (Fig. 2), protects the intestinal barrier to a similar degree in both sexes early in infection (Fig. 3A). Accordingly, similar patterns of increased bacteremia relative to uninfected controls might result from distinct sex- and genotype-specific host responses to a damaged barrier during parasite infection.

Neutrophil MPO levels were increased in female MC IL-10 (−) mice at time points following increased intestinal permeability

During malaria, neutrophils play a key role in limiting bacteremia, and this defense is regulated by IL-10 (14). To determine whether neutrophil activation in our model was dependent on MC-derived IL-10, we measured plasma levels of the antimicrobial effectors MPO and NE as markers for neutrophil activation (30, 31). As noted above, intestinal permeability was increased relative to uninfected mice by 4 days PI in female and male MC IL-10 (−) mice (Fig. 3A) and bacteremia levels were significantly increased relative to uninfected controls in female MC IL-10 (−) mice, and male mice of both genotypes by 8 days PI and in female MC IL-10 (+) by day 10 PI (Fig. 3B).

Relative to uninfected females, plasma MPO levels were increased at 4, 6, and 10 days PI in female MC IL-10 (−) mice, and at 4 and 6 days PI in female MC IL-10 (+) mice (Fig. 4A, left table). Moreover, MPO was significantly higher in female MC IL-10 (−) mice than in female MC IL-10 (+) mice on days 8 and 10 PI (Fig. 4A). In male mice, MPO was increased in both MC IL-10 (−) and MC IL-10 (+) mice on day 4 PI relative to male uninfected controls (Fig. 4A, right table) but there were no significant differences between male genotypes within any time point (Fig. 4A). Elevated plasma NE levels relative to uninfected controls were noted at all time points in both male and female MC IL-10 (−) mice, while they were significantly elevated at 4, 6, and 10 days PI in female MC IL-10 (+) mice and at 4 and 10 days PI in male MC IL-10 (+) mice (Fig. 4B, left and right tables). Furthermore, unlike plasma MPO levels in female mice (Fig. 4A), NE levels did not differ by genotype within any time point in either male or female mice (Fig. 4B).

Fig 4 — Female MC IL-10 (−) mice exhibited increased neutrophil myeloperoxidase activation following *P. y. yoelii* 17XNL infection. (A) Plasma myeloperoxidase (MPO) detection by ELISA. (B) Plasma neutrophil elastase (NE) as determined by ELISA. Data were analyzed using Brown-Forsythe and Welch ANOVA tests followed by multiple comparisons between infected mice at each time point and uninfected control, or between MC IL-10 (−) and MC IL-10 (+) mice at specific time points. Each dot represents a single mouse, and bars correspond to the mean. P values ≤ 0.05 were considered significant. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. U: uninfected control mice, ns: not significant.

Taken together, increased MPO levels relative to uninfected controls were more frequently observed in infected females compared to infected males. Furthermore, when bacteremia levels were significantly increased relative to uninfected controls (8 and 10 days PI; Fig. 4B, left and right tables), MPO levels in female mice were significantly higher in MC IL-10 (−) compared to MC IL-10 (+) mice (Fig. 4A), time points also associated with a more steeply rising parasitemia in female MC IL-10 (−) versus MC IL-10 (+) mice (Fig. 1). Increased plasma NE levels in infected mice were more frequently detected in MC IL-10 (−) mice compared to MC IL-10 (+) mice but this pattern was not sex-dependent (Fig. 4B, left and right tables). Based on these observations, we speculated that a more steeply rising parasitemia in female MC IL-10 (−) mice, together with increased MPO levels following increased intestinal permeability, suggested the possibility of a more robust immune response to a damaged barrier in female MC IL-10 (−) mice.

MC-derived IL-10-dependent changes in ileum and plasma cytokines and chemokines during P. y. yoelii 17XNL infection

To study the impact of MC-derived IL-10 on the immune response to malaria, homeostasis of barrier integrity, and bacterial translocation, we evaluated both systemic and cellular/tissue levels of cytokines in plasma and ileum, respectively. On day 8 PI, when bacteremia levels were initially increased relative to uninfected controls (Fig. 3B, left and right tables), higher ileum levels of the chemokines MCP1 (CCL2) (Fig. 5A), MIP-1α (CCL3) (Fig. 5B), MIP-1β (CCL4) (Fig. 5C), RANTES (CCL5) (Fig. 5D), and the Th2 cytokine IL-5 (Fig. 5E), chemokines and cytokines involved in eosinophil recruitment (32), were observed in female MC IL-10 (−) mice relative to female MC IL-10 (+) mice. Eosinophils are known for their role in allergic inflammation but are also involved in the control of bacterial infection in the gastrointestinal mucosa (33). Although no genotype-specific patterns were evident within time points for ileal IL-4, female mice had higher levels of ileal IL-4 relative to male mice over the course of infection (Fig. 5F). Female MC IL-10 (−) mice also had higher levels of KC (CXCL1) relative to male MC IL-10 (−) mice at 8 days PI (Fig. 5G). In general, these chemokines and cytokines were more frequently increased relative to uninfected controls in female MC IL-10 (−) mice, and somewhat less so in female MC IL-10 (+), compared to male mice of either genotype (Fig. 5A through G, left and right tables). For IL-12p40 and IL-10, ileal levels were increased in infected mice relative to uninfected controls more frequently in female mice versus male mice (Fig. 5H and I, left and right tables). As expected, there were no differences in the levels of ileum IL-10 between MC IL-10 (−) and MC IL-10 (+) mice, mast cells are not the only source of IL-10; other cell types, including T CD4+ cells, monocytes, macrophages, dendritic cells, NK cells, neutrophils, and eosinophils, can produce IL-10 after a stimulus.

Fig 5 — Ileum cytokines and chemokines from *P. y. yoelii* 17XNL-infected MC IL-10 (−) and MC IL-10 (+) mice and uninfected controls. (A to I) the y-axis represents the concentrations of MCP-1 (CCL2) (A), MIP-1α (CCL3) (B), MIP-1β (CCL4) (C), RANTES (CCL5) (D), IL-5 (E), IL-4 (F), KC (CXCL1) (G), IL-12p40 (H), and IL-10 (I). Data (A to H) were analyzed using Brown-Forsythe and Welch ANOVA tests, while (I) was analyzed using the Kruskal-Wallis test followed by multiple comparisons between infected mice at each time point and uninfected control, or between MC IL-10 (−) and MC IL-10 (+) mice at specific time points. Each dot represents a single mouse, and bars correspond to the mean. P values ≤ 0.05 were considered significant. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. U: uninfected control mice, ns: not significant.

Across the four sex/genotype groups, other cytokines and chemokines were not elevated relative to uninfected levels or were elevated in only one group at one time point (Fig. S1A through L).

In plasma samples, on day 8 PI, we observed increased levels of G-CSF (Fig. 6A), a cytokine that promotes granulocyte proliferation and survival (34), and MIP-1α (CCL3), C-C chemokine involved in neutrophil recruitment (35) (Fig. 6B). On day 10 PI, we observed increased levels of TNF-α (Fig. 6C), a proinflammatory cytokine associated with parasite clearance (36), in female MC IL-10 (−) mice relative to female MC IL-10 (+). In male mice, G-CSF levels showed contrasting differences by genotype at 4 and 6 days PI (Fig. 6A) and differences in IL-4 by genotype at 6 days PI (Fig. 6D). For these cytokines and chemokines, levels were increased relative to uninfected controls more frequently in females of both genotypes compared to males (Fig. 6A through D, left and right tables), with males exhibiting lower levels than females at specific time points PI (Fig. 6A through D).

Plasma levels of IL-10 and IFN-γ were higher in MC IL-10 (-) females at 8 and 10 days PI, respectively (Fig. 6E and F), and plasma levels of IL-12p70 and IL-13 were higher in females than males at 10 days PI (Fig. 6G and H), suggesting a distinctive but stronger inflammatory response mediated by MC-derived IL-10 in females relative to males. Of interest was the fact that the IL-10 and IFN-γ levels were only observed in the MC-IL-10 (−) mice. While it is not anticipated that MC-derived IL-10 would mediate a strong inflammatory response, it is suggestive that in the context of malaria infection, MC-IL-10 could have a greater impact on the particular cytokines noted herein, especially in females. IFN-γ levels were similarly increased in infected female and male MC IL-10 (-) mice relative to uninfected controls, while levels in female MC IL-10 (+) mice were increased more frequently than male mice of the same genotype (Fig. 6F, left and right tables). More striking differences were noted for plasma levels of IL-10 and IL-12p70. IL-10 was undetected in uninfected male MC IL-10 (+) mice (Fig. 6E, right table), while plasma IL-12p70 was undetected in male MC IL-10 (+) mice and detected only in individual male MC IL-10 (−) mice at 6 and 8 days PI (Fig. 6G). These patterns precluded statistical analyses relative to uninfected controls but were the strongest sex-specific differences observed during infection. Eotaxin (CCL11) levels in female MC IL-10 (+) mice were higher than those in male MC IL-10 (+) mice at 8 days PI, but levels in infected relative to uninfected mice were increased similarly across both sexes and genotypes (Fig. 6I, left and right tables). Among the remaining plasma chemokines and cytokines, there were no differences in levels between genotypes or between males and females, and few to no differences between infected and uninfected mice (Fig. S2A through L).

Taken together, our observations (Fig. 1 to 6) suggested that MC-derived IL-10 regulates the host response to a damaged intestinal barrier and parasite infection, with a sex bias in which females are more likely to exhibit these patterns. Furthermore, these data suggest that MC-derived IL-10 functions largely as an anti-inflammatory cytokine in the ileum, while systemic changes appear to include both pro- and anti-inflammatory effects of MC-derived IL-10 (37) during the observed course of infection. Based on early changes in some plasma cytokines and chemokines relative to uninfected controls at 4 days PI (Fig. 6), a time point within 24 h of observed peak parasite exflagellation and transmissibility in this model (29, 38 –40), we sought to test whether MC-derived IL-10 could impact transmission of P. y. yoelii 17XNL to A. stephensi.

MC-derived IL-10 distinctly controls male and female host responses to infection at the time of peak parasite transmissibility to A. stephensi

We previously demonstrated that basophils and MCs can control parasite transmission to A. stephensi in studies with mice lacking MC chymase Mcpt4 (29), mice without basophils (39), and mice with basophils lacking the IL-18 receptor (40). To study the effects of MC-derived IL-10 on P. y. yoelii 17XNL transmission, we fed female A. stephensi on infected male and female MC IL-10 (−) and MC IL-10 (+) mice at 3 days PI, a time of optimal exflagellation and transmissibility in this model (41, 42). Only mice with equivalent levels of parasite exflagellation were used for these studies (data not shown) and the same mice were used for analyses of plasma cytokines, chemokines, and neutrophil markers, extending and complementing our cytokine and chemokine analyses from days 4–10 PI to better understand the longitudinal response.

Mosquitoes infected after feeding on female MC IL-10 (−) mice had significantly more oocysts per midgut than infected mosquitoes fed on female MC IL-10 (+) mice and mosquitoes fed on male MC IL-10 (−) mice (Fig. 7A). Furthermore, mosquitoes that fed on female MC IL-10 (−) mice had the highest percentage of infected mosquitoes, while the lowest percentage of infected mosquitoes were observed following feeding on male MC IL-10 (+) mice (Fig. 7B). The percentages of infected mosquitoes that fed on female MC IL-10 (+) mice and male MC IL-10 (−) mice were intermediate between these groups (Fig. 7B). There were no differences in parasitemia (Fig. 7C) or gametocytemia (Fig. 7D) among male and female mice of either genotype at 3 days PI. While concordance between infection and transmission is common, differences in host immunity can affect gametocyte maturity and sex ratio, and mosquito responsiveness to ingested blood factors can control mosquito defenses to infection (43 –46). In this context, transmission patterns of parasites to the mosquito host can vary independently of patterns of parasitemia and gametocytemia (29, 39, 40).

Fig 7 — Transmission of *P. y. yoelii* 17XNL to *A. stephensi* was increased in mosquitoes that fed on MC IL-10 (−) mice. Numbers of oocysts per midgut (A). Proportions of infected mosquitoes (B). Percentages of mouse erythrocytes infected with sexual stage gametocytes (C) and asexual stages (D) on the day of mosquito infection (day 3 PI). Data from oocysts (mosquitoes with zero oocysts excluded), parasitemia, and gametocytemia were analyzed by the Kruskal-Wallis test. The percentages of infected mosquitoes were analyzed with Fisher’s exact test. P values ≤ 0.05 were considered significant. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.

To examine the possibility that host immunity on the day of parasite transmission to A. stephensi at 3 days PI might help to explain mosquito infection patterns, we examined levels of plasma cytokines, chemokines, and neutrophil markers in the mice on the same day that mice were used for mosquito feeding. Plasma levels of IL-1β and IL-6 were increased in infected female MC IL-10 (−) mice relative to female MC IL-10 (+) mice on the day of mosquito feeding (Fig. 8A and B). Male MC IL-10 (−) mice, on the other hand, had higher levels of IL-12p40, KC (CXCL1), MIP-1β (CCL4), RANTES (CCL5), MCP1 (CCL2), MPO and NE (Fig. 8C through I) on the day of mosquito infection when compared to male MC IL-10 (+) mice. Finally, increased plasma IL-17A and lower levels of eotaxin (CCL11) were observed in the plasma of infected female MC IL-10 (−) mice relative to male MC IL-10 (−) mice on the day of mosquito feeding (Fig. 8J and K), while higher levels of MCP1 (CCL2) and G-CSF were observed in the plasma of infected female MC IL-10 (+) relative to male MC IL-10 (+) mice on the same day (Fig. 8G and L). These data revealed that MC-derived IL-10 alters the host immune response on the day of mosquito feeding, with distinct patterns by sex and genotype.

Fig 8 — Markers associated with transmission of *P. y. yoelii* 17XNL from infected MC IL-10 (−) and MC IL-10 (+) mice to *Anopheles stephensi*. (A to L) the y-axis represents the concentrations in plasma of IL-1β (A), IL-6 (B), IL-12p40 (C), KC (CXCL1) (D), MIP-1β (CCL4) (E), RANTES (CCL5) (F), MCP1 (CCL2) (G), MPO (H), NE (I), IL-17A (J), EOTAXIN (CCL11) (K), G-CSF (L) on the day of mosquito infection (day 3 PI). Data were analyzed by the Kruskal-Wallis test. P values ≤ 0.05 were considered significant, *P ≤ 0.05.

DISCUSSION

Here we present evidence from a mouse model that MC-derived IL-10 contributes to the regulation of parasitemia and protection of the intestinal barrier during infection, controls local and systemic host immune responses, and regulates parasite transmission to A. stephensi with a female bias. In one of the few studies of its kind, Briggs et al. (47) reported that female Ugandan study participants cleared asymptomatic P. falciparum infections at a faster rate than male participants with no differences in behavioral risk factors, incidence of malaria, or force of infection by sex, suggesting that biological sex-based differences control the host response to infection. Similar findings suggested a female bias toward protection in mouse malaria. Specifically, adult female C3H mice vaccinated with irradiated Plasmodium berghei sporozoites were better protected against sporozoite challenge than age-matched males, with differences in protection being associated with greater malaria-specific antibody and CD8+ T-cell responses in females compared with males (48). Despite our understanding that MCs in male and female mice differ substantially in their transcriptomes and the synthesis and storage of MC granule mediators (49) and that host response to infection are sex-biased in both humans and mouse models, no studies to date have associated MCs or MC function with observed sex biases in malaria parasite infection.

Many MC-related disorders have a strong sex bias in which females are more susceptible, such as irritable bowel syndrome (50), allergy/anaphylaxis and asthma (51 –55), migraine (56), interstitial cystitis (57), and fibromyalgia (58), all of which occur more frequently in women (59). This includes autoimmune disorders such as multiple sclerosis (MS) (60) and rheumatoid arthritis (61), which also have a female sex bias, occurring in women at four times the rate of men (62, 63). Given the wide variety of mediators produced by MCs, many of which are context-specific and time-dependent (64, 65), attributing the effects of MCs to specific mediators can be challenging.

The regulatory cytokine IL-10 is produced by a variety of cells, including MCs (66 –69), which we have associated with restriction of enteric bacterial translocation in mouse malaria (7, 8). We also showed that IL-10 promoted susceptibility to disseminated invasive bacterial infection by inhibiting the function of myeloid cells (14). IL-10 is well known for its regulation of intestinal homeostasis (70) and altered IL-10 levels have been linked to inflammatory bowel diseases (71, 72) and colitis in humans (69, 73, 74). However, the downstream signaling pathways and molecular mechanisms implicated in IL-10-induced intestinal homeostasis have not been fully defined. According to some studies, IL-10 alters macrophage function by promoting the clearance of damaged mitochondria and modulating cellular metabolism (69, 75, 76). Others have suggested that IL-10 helps to maintain barrier integrity by modulating intercellular junctions and promoting cell repair (77, 78), promoting Paneth cell and goblet cell development and function (79), regulating apoptosis (80, 81), and modulating the inflammatory response by limiting the synthesis of chemokines by intestinal epithelial cells (70, 82). In agreement with some of these effects, we observed increased ileal levels of the chemokines MCP1 (CCL2), MIP-1α (CCL3), MIP-1β (CCL4), and RANTES (CCL5) (Fig. 5A through D) in female MC IL-10 (−) mice relative to female MC IL-10 (+) mice, but only at day 8 PI, when substantial increased ileal MCs were also observed.

Consistent with our observations of multiple roles for MC-derived IL-10 in malaria, some studies have shown that MC deficiency in IL-10 knockout mice results in inflammation in the intestine, impaired barrier function, and more severe Th1-mediated colitis when compared to mice with only IL-10 deficiency (83, 84). Other studies have shown that MC-derived IL-10 can suppress the adaptive immune response, resulting in enhanced persistence of Escherichia coli (85, 86). Although we observed increased FITC-dextran translocation in MC IL-10 (−) mice, we did not observe differences in bacterial 16S DNA levels relative to MC IL-10 (+) mice at any time point (Fig. 3B). However, in female mice, bacterial 16S DNA levels rose earlier in female MC IL-10 (−) mice (day 8 PI) than in female MC IL-10 (+) mice (Fig. 3B), while no differences were observed in male mice. We speculate that the absence of significant differences in bacteremia over time in the presence of intestinal permeability could be attributed to sex- and genotype-specific differences in neutrophil activation. In mice co-infected with malaria and non-typhoidal Salmonella, we reported that decreased inflammation during bacterial colonization was mediated by IL-10, and this was associated with decreased neutrophil influx (15). In the present study, plasma MPO levels were significantly increased in female MC IL-10 (−) mice relative to female MC IL-10 (+) mice on days 8 and 10 PI (Fig. 4A), time points also marked by increased levels of the cytokine G-CSF (Fig. 6A) and chemokine MIP-1α (CCL3), which have been implicated in neutrophil survival (34) and neutrophil recruitment and proliferation (35), respectively. Together, these data suggest that IL-10 derived from MCs suppresses the neutrophilic response to bacterial translocation.

In our studies of parasite transmission to A. stephensi from infected mice at 3 days PI, levels of IL-1β and IL-6 (Fig. 8A and B) were elevated in infected female MC IL-10 (−) mice, while male MC IL-10 (−) mice had increased levels of IL-12p40, KC (CXCL1), MIP-1β (CCL4), MCP1 (CCL2), MPO, and NE (Fig. 8C through I) relative to their sex-matched MC IL-10 (+) controls. These patterns were associated with increased infection success in A. stephensi fed on both male and female MC IL-10 (−) mice compared to sex-matched genotype controls. This infection success in mosquitoes fed on MC IL-10 (−) mice, however, was associated with increased but distinct inflammatory responses in female and male mice. Female MC IL-10 (−) mice exhibited increased levels of plasma IL-1β and IL-6, cytokines associated with severe disease (87, 88), whereas male MC IL-10 (−) mice had higher plasma levels of neutrophil and macrophage chemoattractants as well as markers of neutrophil activation. Given that neutrophils in the bloodmeal can kill malaria parasite gametes in the mosquito midgut (89), neutrophil activation in male MC IL-10 (−) mice could help to explain their lower transmission success relative to females when no differences in gametocytemia or parasitemia were observed. Increased human-to-mosquito P. falciparum transmission success has been associated with increased transcription of pfap2-g, a master regulator of gametocytogenesis (90). In this study, pfap2-g transcription was also positively correlated with inflammatory markers that increase in response to stress or tissue injury, including IL-6 and MCP-1 (CCL2), connecting specific inflammatory mediators with parasite transmission (90). Transmission success has also been associated with gametocyte density (91, 92), gametocyte sex ratio (93, 94), anemia, age, immune status (95 –97), and gametocyte maturation (98). Mammalian blood factors ingested by the mosquito can also affect transmission success (38, 44, 45, 99, 100). Although we identified a sex bias in parasite transmission to A. stephensi mediated by MC-derived IL-10, additional studies are needed to elucidate the mechanism(s) of these observations.

In conclusion, our data revealed that MC-derived IL-10 regulates the host response to infection, contributes to the protection of intestinal barrier integrity, and controls parasite transmission to A. stephensi with a female bias. While a sex bias in host immune responses and protection in malaria have been documented (47, 48), it is unclear how MCs, and specifically MC-derived IL-10, affect females and males differently in the context of this disease. More studies are needed to identify the mechanisms by which MC-derived IL-10 controls infection and homeostasis in malaria. This sex-specific biology could reveal novel therapeutic targets for limiting susceptibility to malaria-induced bacteremia and controlling parasite transmission.

MATERIALS AND METHODS

Mouse strains

Male and female, 7- to 8-week-old mice with MCs deficient for IL-10 [MC IL-10 (−)] were generated by crossing MC-targeted knockouts C57BL/6-Tg(Cpa3-cre)4Glli/J (Jackson Laboratory no. 026828) with IL10^flox/flox mice (B6-IL10^tm3Cgn) (101), after breeding onto the C57BL/6J background for six generations (102). Cre-negative littermate mice (IL10^flox/flox) expressing functional IL-10 [MC IL-10 (+)] were used as controls. Flow cytometry was used to confirm the depletion of IL-10 on MCs (Fig. S3).

Mice were housed in ventilated micro-isolator cages and provided food and water ad libitum. All procedures were approved by the Institutional Animal Care and Use Committee of the University of Idaho (IACUC Protocol 2020–10, approved on March 30, 2020, and renewed as IACUC-2023–08 on February 27, 2023) and all efforts were made to minimize suffering and pain. All animals were observed daily for any adverse signs of infection (weight loss >20%, hunching, lack of grooming). Any mice exhibiting signs of lethal morbidity were humanely euthanized by cervical dislocation under anesthesia.

Mouse genotyping

Transgenic mice were identified by PCR genotyping using DNA extracted from 5 mm tail biopsy samples from 10- to 14-day-old mice using MyTaq Extract-PCR Kit (Bioline), according to the manufacturer’s instructions. Tail snips were also taken from mice at death for genotype confirmation. Primers used to genotype mice as well as the expected size of amplicons are listed in Table S1.

Mouse infection and monitoring

A total of 100 mice from two biological replicates were distributed into five subgroups (n = 10, 6 females and 4 males) per genotype, per replicate, and injected intraperitoneally with 150 µL of P. y. yoelii 17XNL-infected red blood cells (iRBCs, 1 × 10⁶ parasites) or uninfected RBCs as controls as described (9). Mice were sacrificed at 4, 6, 8, or 10 days PI and daily parasitemias were recorded from microscopic examination of Giemsa-stained thin blood films. Blood, plasma, and ileum samples were also collected at these time points and processed as described below.

Bacterial 16S qPCR

Bacterial 16S copy numbers were determined by qPCR in blood samples (n = 100) of infected and uninfected mice as described (9). Briefly, DNA was isolated from whole blood collected into EDTA on the day of necropsy using the DNeasy Blood and Tissue kit (Qiagen) according to the manufacturer’s protocol. Samples were analyzed in triplicate using DNA SYBR Green/ROX qPCR Master Mix (2X) (Bio-Rad) with 16S primers (9) and quantified against a 16S bacterial DNA plasmid standard curve using a QuantStudio 6 Flex Applied Biosystems qPCR (9), using the following cycling conditions: 50°C for 2 min, 95°C for 10 min, and 40 cycles of 95°C for 15 s and 60°C for 1 min.

Intestinal permeability

Mice fasted for 4 h were exposed to 4 kDa fluorescein isothiocyanate (FITC)-dextran through oral gavage, and blood samples (n = 100) were collected into EDTA at 3 h post-treatment. The fluorescence of these blood samples was quantified using a microplate reader (Molecular Devices LLC, San Jose, CA) at excitation/emission wavelengths of 490/520 nm against a standard curve of serially diluted FITC-dextran in normal mouse plasma with PBS (1:2 vol/vol) as described (9).

Cytokines and chemokines in plasma and ileum samples

Concentrations of plasma and ileum cytokines and chemokines (IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, IFN-γ), TNF-α, MCP-1 (CCL2), MIP-1α (CCL3), MIP-1β (CCL4), RANTES (CCL5), eotaxin (CCL11), GM-CSF, KC (CXCL1), collected at necropsy for each time point (n = 100) (ileum sections ~ 2 cm long), were determined for infected and uninfected mice using a Bio-Plex Pro Luminex assay on a Bio-Plex 200 system (Bio-Rad Laboratories) using Bio-Plex Manager software (Bio-Rad Laboratories) as described (9, 29).

ELISAs

Levels of plasma Mcpt1 (eBioscience), neutrophil elastase (NE) (Abcam), and myeloperoxidase (MPO) (Abcam) were determined for individual mice (n = 100) using commercial ELISAs according to the manufacturer’s instructions and a microplate reader (Molecular Devices, LLC).

Ileum histochemistry

Ileum samples from individual mice (n = 100) were formalin-fixed and embedded in paraffin (IHC World), then subjected to detection of MC chymase activity by naphthol AS-D chloroacetate esterase (NASDCE) activity (Sigma-Aldrich) according to the manufacturer’s instructions.

Mosquito infection

Anopheles stephensi Liston was reared and allowed to feed on P. y. yoelii 17XNL-infected mice as described (38). Briefly, MC IL-10 (−) (n = 10) and MC IL-10 (+) (n = 10) mice in two biological replicates were injected intraperitoneally with 150 µL of P. y. yoelii 17XNL iRBCs (1 × 10⁶ parasites) (29). At 3 days PI, levels of blood-stage parasitemia, gametocytemia, and exflagellation were recorded as described (38) and each mouse was used to infect 3- to 5-day-old female A. stephensi (~60 mosquitoes/group). Mice were then sacrificed, and plasma was collected and processed for cytokines, chemokines, neutrophil elastase (NE), and myeloperoxidase (MPO). At 10 days post-feeding, ~30 fed mosquitoes/group were dissected and microscopically examined for the presence of oocysts in the midgut. Midgut oocysts were counted by microscopic examination at 20× magnification.

Statistical analyses

Normality was tested using the Shapiro-Wilk test, then Brown-Forsythe and Welch ANOVA tests were applied to compare groups with a normal distribution, while the non-parametric Kruskal-Wallis test was applied to non-normally distributed data. Parasitemia, MCs per high power field (HPF), Mcpt1, plasma FITC-dextran, bacterial 16S DNA copies per µL of blood, plasma NE and MPO as well as ileum and plasma cytokines and chemokines, with some exceptions noted below, were analyzed in female and male mice separately by Brown-Forsythe and Welch ANOVA tests followed by multiple comparisons between MC IL-10 (−) and MC IL-10 (+) mice between time points and relative to uninfected mice. Females and males were also compared within genotypes at different time points. Ileum IL-6, IL-9, IL-10, and IL-13, as well as plasma IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-10, IL-12p70, IL-13, IL-17, and MCP1 (CCL2) were analyzed by Kruskal-Wallis test followed by multiple comparisons as noted above. Percentages of infected mosquitoes fed on MC IL-10 (−) and MC IL-10 (+) mice were analyzed using Fisher’s exact test separately for female and male mice between genotypes and between female and male mice within genotypes. The numbers of oocysts per midgut from mosquitoes fed on MC IL-10 (−) and MC IL-10 (+) infected mice, as well as parasitemia, gametocytemia and plasma cytokines and chemokines for MC IL-10 (−) and MC IL-10 (+) mice on day 3 PI, were analyzed using Kruskal-Wallis test followed by multiple comparisons between MC IL-10 (−) and MC IL-10 (+) for each sex and between female and male mice within genotypes. P values ≤ 0.05 were considered significant. The individual mouse was considered the experimental unit within all the studies.

ACKNOWLEDGMENTS

The authors acknowledge the members of the Luckhart lab as well as the staff of the Laboratory Animal Research Facility (LARF), University of Idaho.

This work was funded by NIH NIAID RO1 AI131609 and RO1 AI165481 to S.L. and by Randall Women in Science (RWiS) to N.C. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Contributor Information

Nora Céspedes, Email: nora@uidaho.edu.

De'Broski R. Herbert, University of Pennsylvania, Philadelphia, Pennsylvania, USA

SUPPLEMENTAL MATERIAL

The following material is available online at https://doi.org/10.1128/iai.00360-23.

Supplemental material. iai.00360-23-s0001.pdf.

Figures S1 to S3; Table S1.

iai.00360-23-s0001.pdf^{(619.9KB, pdf)}

DOI: 10.1128/iai.00360-23.SuF1

ASM does not own the copyrights to Supplemental Material that may be linked to, or accessed through, an article. The authors have granted ASM a non-exclusive, world-wide license to publish the Supplemental Material files. Please contact the corresponding author directly for reuse.

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Supplementary Materials

Supplemental material. iai.00360-23-s0001.pdf.

Figures S1 to S3; Table S1.

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DOI: 10.1128/iai.00360-23.SuF1

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PERMALINK

Mast cell-derived IL-10 protects intestinal barrier integrity during malaria in mice and regulates parasite transmission to Anopheles stephensi with a female-biased immune response

Nora Céspedes

Erinn L Donnelly

Gretchen Hansten

Abigail M Fellows

Megan Dobson

Hannah L Kaylor

Taylor A Coles

Joseph Schauer

Judy Van de Water

Shirley Luckhart

Roles

ABSTRACT

INTRODUCTION

RESULTS

Parasitemia was transiently increased in female MC IL-10 (−) mice relative to other groups, while MC activation was female-biased during P. y. yoelii 17XNL infection

Fig 1.

Fig 2.

MC IL-10-dependent intestinal permeability was evident in both males and females, while bacterial 16S DNA levels were independent of sex and genotype during infection

Fig 3.

Neutrophil MPO levels were increased in female MC IL-10 (−) mice at time points following increased intestinal permeability

Fig 4.

MC-derived IL-10-dependent changes in ileum and plasma cytokines and chemokines during P. y. yoelii 17XNL infection

Fig 5.

Fig 6.

MC-derived IL-10 distinctly controls male and female host responses to infection at the time of peak parasite transmissibility to A. stephensi

Fig 7.

Fig 8.

DISCUSSION

MATERIALS AND METHODS

Mouse strains

Mouse genotyping

Mouse infection and monitoring

Bacterial 16S qPCR

Intestinal permeability

Cytokines and chemokines in plasma and ileum samples

ELISAs

Ileum histochemistry

Mosquito infection

Statistical analyses

ACKNOWLEDGMENTS

Contributor Information

SUPPLEMENTAL MATERIAL

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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