Abstract
Cryptococcus neoformans is a leading cause of invasive fungal infections among immunocompromised patients. However, the cellular constituents of the innate immune response that promote clearance versus progression of infection upon respiratory acquisition of C. neoformans remain poorly defined. In this study, we found that during acute C. neoformans infection, CCR2+ Ly6Chi inflammatory monocytes (IM) rapidly infiltrate the lungs and mediate fungal trafficking to lung-draining lymph nodes. Interestingly, this influx of IM is detrimental to the host, since ablating IM or impairing their recruitment to the lungs improves murine survival and reduces fungal proliferation and dissemination. Using a novel conditional gene deletion strategy, we determined that MHC class II expression by IM did not mediate their deleterious impact on the host. Furthermore, although ablation of IM reduced the number of lymphocytes, innate lymphoid cells, and eosinophils in the lungs, the effects of IM were not dependent on these cells. We ascertained that IM in the lungs upregulated transcripts associated with alternatively activated (M2) macrophages in response to C. neoformans, consistent with the model that IM assume a cellular phenotype that is permissive for fungal growth. We also determined that conditional knockout of the prototypical M2 marker arginase 1 in IM and deletion of the M2-associated transcription factor STAT6 were not sufficient to reverse the harmful effects of IM. Overall, our findings indicate that C. neoformans can subvert the fungicidal potential of IM to enable the progression of infection through a mechanism that is not dependent on lymphocyte priming, eosinophil recruitment, or downstream M2 macrophage polarization pathways. These results give us new insight into the plasticity of IM function during fungal infections and the level of control that C. neoformans can exert on host immune responses.
Highlights
The ubiquitous encapsulated yeast Cryptococcus neoformans causes invasive fungal infections in immunocompromised patients, those with AIDS, solid organ transplants, and cancer [1]
Our findings indicate that C. neoformans can subvert the fungicidal potential of inflammatory monocytes (IM) to enable the progression of infection through a mechanism that is not dependent on lymphocyte priming, eosinophil recruitment, or downstream M2 macrophage polarization pathways
dendritic cells (DCs) in chemokine receptor 2 (CCR2)-DTR mice returned in numbers comparable to non-transgenic littermate controls (WT) by day 14 p.i., while macrophages exhibited a slower return toward WT levels (S2 Fig)
Summary
The ubiquitous encapsulated yeast Cryptococcus neoformans causes invasive fungal infections in immunocompromised patients, those with AIDS, solid organ transplants, and cancer [1]. CCR2-dependent signals mediate the accumulation of DCs and macrophages in the lungs [11,12,13] The latter express inducible nitric oxide synthase (NOS2) and tumor necrosis factor (TNF) and appear to act in a fungicidal manner in vitro [13]. More recent work indicates that IM and macrophages may play important roles in protective immune responses generated by candidate vaccine strains of C. neoformans [16,17,18,19]. These data suggest that IM and their derivatives may play beneficial roles in innate immunity during subacute and chronic cryptococcal infections
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