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

An increase in mast cells (MCs) and MCs mediators has been observed in malaria-associated bacteremia, however, the role of these granulocytes in malarial immunity is poorly understood. Herein, we studied the role of mouse MC protease (Mcpt) 4, an ortholog of human MC chymase, in malaria-induced bacteremia using knockout ( ) mice and C57BL/6J controls, and the non-lethal mouse parasite 17XNL. Significantly lower parasitemia was observed in mice compared with controls by day 10 post infection (PI). Although bacterial 16S DNA levels in blood were not different between groups, increased intestinal permeability to FITC-dextran and altered ileal adherens junction E-cadherin were observed in mice. Relative to infected mice, ileal MC accumulation in mice occurred two days earlier and IgE levels were higher by days 8-10 PI. Increased levels of circulating myeloperoxidase were observed at 6 and 10 days PI in but not mice, affirming a role for neutrophil activation that was not predictive of parasitemia or bacterial 16S copies in blood. In contrast, early increased plasma levels of TNF-α, IL-12p40 and IL-3 were observed in mice, while levels of IL-2, IL-10 and MIP1β (CCL4) were increased over the same period in mice, suggesting that the host response to infection was skewed toward a type-1 immune response in mice and type-2 response in mice. Spearman analysis revealed an early (day 4 PI) correlation of parasitemia with TNF-α and IFN-γ, inflammatory cytokines known for their roles in pathogen clearance, a pattern that was observed in mice much later (day 10 PI). Transmission success of 17XNL to was significantly higher from infected mice compared with infected mice, suggesting that Mcpt4 also impacts transmissibility of sexual stage parasites. Together, these results suggest that early MCs activation and release of Mcpt4 suppresses the host immune response to 17XNL, perhaps degradation of TNF-α and promotion of a type-2 immune response that concordantly protects epithelial barrier integrity, while limiting the systemic response to bacteremia and parasite transmissibility.