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

Abstract

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 usingMcpt4knockout (Mcpt4-/-) mice andMcpt4+/+C57BL/6J controls, and the non-lethal mouse parasitePlasmodium yoelii yoelii17XNL. Significantly lower parasitemia was observed inMcpt4-/-mice compared withMcpt4+/+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 inMcpt4-/-mice. Relative to infectedMcpt4+/+mice, ileal MC accumulation inMcpt4-/-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 inMcpt4+/+but notMcpt4-/-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 inMcpt4-/-mice, while levels of IL-2, IL-10 and MIP1β (CCL4) were increased over the same period inMcpt4+/+mice, suggesting that the host response to infection was skewed toward a type-1 immune response inMcpt4-/-mice and type-2 response inMcpt4+/+mice. Spearman analysis revealed an early (day 4 PI) correlation ofMcpt4-/-parasitemia with TNF-α and IFN-γ, inflammatory cytokines known for their roles in pathogen clearance, a pattern that was observed inMcpt4+/+mice much later (day 10 PI). Transmission success ofP. y. yoelii17XNL toAnopheles stephensiwas significantly higher from infectedMcpt4-/-mice compared with infectedMcpt4+/+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 toP. y. yoelii17XNL, perhapsviadegradation 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.