The Interaction of <i>Pneumocystis</i> with the C-Type Lectin Receptor Mincle Exerts a Significant Role in Host Defense against Infection

Abstract

<i>Pneumocystis</i> pneumonia (PCP) remains a major cause of morbidity and mortality within immunocompromised patients. In this study, we examined the potential role of macrophage-inducible C-type lectin (Mincle) for host defense against <i>Pneumocystis</i> Binding assays implementing soluble Mincle carbohydrate recognition domain fusion proteins demonstrated binding to intact <i>Pneumocystis carinii</i> as well as to organism homogenates, and they purified major surface glycoprotein/glycoprotein A derived from the organism. Additional experiments showed that rats with PCP expressed increased Mincle mRNA levels. Mouse macrophages overexpressing Mincle displayed increased binding to <i>P. carinii</i> life forms and enhanced protein tyrosine phosphorylation. The binding of <i>P. carinii</i> to Mincle resulted in activation of FcRγ-mediated cell signaling. RNA silencing of Mincle in mouse macrophages resulted in decreased activation of Syk kinase after <i>P. carinii</i> challenge, critical in downstream inflammatory signaling. Mincle-deficient CD4-depleted (Mincle^-/-) mice showed a significant defect in organism clearance from the lungs with higher organism burdens and altered lung cytokine responses during <i>Pneumocystis murina</i> pneumonia. Interestingly, Mincle^-/- mice did not demonstrate worsened survival during PCP compared with wild-type mice, despite the markedly increased organism burdens. This may be related to increased expression of anti-inflammatory factors such as IL-1Ra during infection in the Mincle^-/- mice. Of note, the <i>P. murina</i>-infected Mincle^-/- mice demonstrated increased expression of known C-type lectin receptors Dectin-1, Dectin-2, and MCL compared with infected wild-type mice. Taken together, these data support a significant role for Mincle in <i>Pneumocystis</i> modulating host defense during infection.