AUTHOR=Céspedes Nora , Donnelly Erinn L. , Lowder Casey , Hansten Gretchen , Wagers Delaney , Briggs Anna M. , Schauer Joseph , Haapanen Lori , Åbrink Magnus , Van de Water Judy , Luckhart Shirley 

TITLE=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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.801120

DOI=10.3389/fimmu.2022.801120

ISSN=1664-3224

ABSTRACT=<p>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 <italic>Mcpt4</italic> knockout (<italic>Mcpt4</italic><sup>-/-</sup>) mice and <italic>Mcpt4</italic><sup>+/+</sup> C57BL/6J controls, and the non-lethal mouse parasite <italic>Plasmodium yoelii yoelii</italic> 17XNL. Significantly lower parasitemia was observed in <italic>Mcpt4</italic><sup>-/-</sup> mice compared with <italic>Mcpt4</italic><sup>+/+</sup> 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 <italic>Mcpt4</italic><sup>-/-</sup> mice. Relative to infected <italic>Mcpt4</italic><sup>+/+</sup> mice, ileal MC accumulation in <italic>Mcpt4</italic><sup>-/-</sup> 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 <italic>Mcpt4</italic><sup>+/+</sup> but not <italic>Mcpt4</italic><sup>-/-</sup> 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 <italic>Mcpt4</italic><sup>-/-</sup> mice, while levels of IL-2, IL-10 and MIP1β (CCL4) were increased over the same period in <italic>Mcpt4</italic><sup>+/+</sup> mice, suggesting that the host response to infection was skewed toward a type-1 immune response in <italic>Mcpt4</italic><sup>-/-</sup> mice and type-2 response in <italic>Mcpt4</italic><sup>+/+</sup> mice. Spearman analysis revealed an early (day 4 PI) correlation of <italic>Mcpt4</italic><sup>-/-</sup> parasitemia with TNF-α and IFN-γ, inflammatory cytokines known for their roles in pathogen clearance, a pattern that was observed in <italic>Mcpt4</italic><sup>+/+</sup> mice much later (day 10 PI). Transmission success of <italic>P. y. yoelii</italic> 17XNL to <italic>Anopheles stephensi</italic> was significantly higher from infected <italic>Mcpt4</italic><sup>-/-</sup> mice compared with infected <italic>Mcpt4</italic><sup>+/+</sup> 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 <italic>P. y. yoelii</italic> 17XNL, perhaps <italic>via</italic> 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.</p>