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

Abstract

Pneumocystis pneumonia (PCP) remains a major cause of morbidity and mortality within immunocompromised patients. In this study, we examined the potential role of Mincle (Macrophage inducible C-type lectin) for host defense against Pneumocystis. Binding assays implementing soluble Mincle Carbohydrate Recognition Domain (CRD) fusion proteins demonstrated binding to intact Pneumocystis carinii (Pc) as well as to organism homogenates, and purified major surface glycoprotein/glycoprotein A derived from the organism. Additional experiments showed that rats with Pneumocystis pneumonia (PCP) expressed increased Mincle mRNA levels. Mouse macrophages over-expressing Mincle displayed increased binding to Pc life forms and enhanced protein tyrosine phosphorylation. The binding of Pc to Mincle resulted in activation of Fc receptor γ (FcRγ) mediated cell signaling. RNA silencing of Mincle in mouse macrophages resulted in decreased activation of Syk kinase after Pc challenge, critical in downstream inflammatory signaling. Mincle deficient CD-4 depleted (Mincle−/−) mice showing a significant defect in organism clearance from the lungs with higher organism burdens and altered lung cytokine responses during Pneumocystis murina (Pm) pneumonia. Interestingly, Mincle−/− did not demonstrate worsened survival during PCP compared to 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 Pm infected Mincle−/− mice demonstrated increased expression of known C-type lectin receptors Dectin-1, Dectin-2, and MCL compared to infected wild type mice. Taken together, these data support a significant role for Mincle in Pneumocystis modulating host defense during infection.

Immunity against fungi

“…This MDM2-dependent pathway impairs Th1 responses and may contribute to the chronicity of chromoblastomycosis. During murine pneumocystosis and candidiasis, mincle signaling enhances fungal clearance but is dispensable for survival (57,58).…”

Combination Immunotherapy with Passive Antibody and Sulfasalazine Accelerates Fungal Clearance and Promotes the Resolution ofPneumocystis-Associated Immunopathogenesis

“…Consistent with this idea, the bioactive metabolite of SSZ, 5-aminosalicylic acid, is an activating ligand for the pro-M2 transcription factor peroxisome proliferatoractivated receptor gamma (61). Thus, it is possible that anti-Pneumocystis antibody and SSZ together elicit a specific M2-like program in alveolar macrophages that not only results in the reversal of immunopathogenesis but may also augment the phagocytic clearance of Pneumocystis by alveolar macrophages either directly (via Dectin-1 or other c-type lectins [62][63][64][65]) or indirectly (via increased antibody-mediated clearance).…”

Pneumocystis jiroveci

“…The role of the CLR Mincle (macrophageinducible Ca 2þ -dependent lectin receptor) in clearance of Pneumocystis is more evident in the absence of effective CD4 þ T cell responses. 95 However, Mincle may downregulate other CLRs during Pneumocystis infection. 95 Based on studies of myeloid differentiation primary response 88 (MyD88) deficient mice, toll-like receptors and scavenger receptors also participate in control of the inflammatory response to Pneumocystis.…”

“…95 However, Mincle may downregulate other CLRs during Pneumocystis infection. 95 Based on studies of myeloid differentiation primary response 88 (MyD88) deficient mice, toll-like receptors and scavenger receptors also participate in control of the inflammatory response to Pneumocystis. [96][97][98] In our laboratory, dysfunctional alveolar macrophages in GM-CSF knockout mice have been shown to bind and ingest organisms but cannot kill or digest them, resulting in distended cells containing multiple cysts or trophozoites but with incomplete clearance of infection (►Fig.…”