Host Immune Responses to Fungal Pathogens

Abstract

Fungal infections are an increasing threat to global public health. Worldwide, more than one billion fungal infections are diagnosed each year and result in 1.5 million deaths annually. This number is expected to rise as advances in medical care for immunocompromised patients continue to be made. Furthermore, limited antifungal treatment options, coupled with the emergence of new and resistant fungal species, is anticipated to exacerbate this issue. For these reasons, it is essential to understand the dynamic interactions between host and fungus that contribute to fungal pathogenesis. The following work examined the role of IL-27 on T cell regulation in the lungs during infection with Aspergillus fumigatus, and in the brain during infection with Cryptococcus neoformans. In contrast to most infection settings demonstrating that IL-27 is anti-inflammatory, we report that this cytokine is proinflammatory in both the lung and the brain during infection with A. fumigatus and C. neoformans respectively. Genetic ablation of IL-27Rα in mice resulted in higher fungal burdens in the lung during Aspergillus infection and in the brain during Cryptococcus infection. These were associated with reduced IFN-γ production, as well as a fewer CD4+ T cells in target organs. In the case of C. neoformans infection, IL-27 signaling enhanced T cell accumulation by promoting T cell proliferation early during infection, and inhibiting T cell death at later time points. These suggest that IL-27 promotes T cell responses required for fungal clearance during infection with A. fumigatus or C. neoformans. In addition, the work presented here also characterized lung resident macrophage responses during infection with C. neoformans. Here, we report that cryptococcal infection induced the accumulation of CD68hi macrophages in the lungs of infected mice. Approximately 10% of these cells were alveolar macrophages, while nearly 90% were interstitial macrophages. Both of these populations were observed to interact with fungi and upregulated their expression of arginase 1. The absence of either macrophage in transgenic mice, or following pharmacological depletion, significantly reduced fungal burdens in the lungs of mice, indicating that these cells enhance fungal growth and may represent attractive targets aimed at limiting the pathogenesis of C. neoformans.