Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Cryptococcus neoformans Promotes Alternative Activation of Pulmonary Lymph Node CD11b+ Conventional Dendritic Cells and Non-Protective Th2 Bias

Jintao Xu,John J Osterholzer,Michal A Olszewski,Bethany B Moore,Lori M Neal,Adam Flaczyk,Mike Ivey,Daphne Cheng,Jeffrey L Curtis,Zhenzong Fa

doi:10.3389/fimmu.2017.01231

Abstract

Macrophage receptor with collagenous structure (MARCO) contributes to fungal containment during the early/innate phase of cryptococcal infection; however, its role in adaptive antifungal immunity remains unknown. Using a murine model of cryptococcosis, we compared host adaptive immune responses in wild-type and MARCO−/− mice throughout an extended time course post-infection. Unlike in early infection, MARCO deficiency resulted in improved pulmonary fungal clearance and diminished cryptococcal dissemination during the efferent phase. Improved fungal control in the absence of MARCO expression was associated with enhanced hallmarks of protective Th1-immunity, including higher frequency of pulmonary TNF-α-producing T cells, increased cryptococcal-antigen-triggered IFN-γ and TNF-α production by splenocytes, and enhanced expression of M1 polarization genes by pulmonary macrophages. Concurrently, we found lower frequencies of IL-5- and IL-13-producing T cells in the lungs, impaired production of IL-4 and IL-10 by cryptococcal antigen-pulsed splenocytes, and diminished serum IgE, which were hallmarks of profoundly suppressed efferent Th2 responses in MARCO-deficient mice compared to WT mice. Mechanistically, we found that MARCO expression facilitated early accumulation and alternative activation of CD11b+ conventional DC (cDC) in the lung-associated lymph nodes (LALNs), which contributed to the progressive shift of the immune response from Th1 toward Th2 at the priming site (LALNs) and local infection site (lungs) during the efferent phase of cryptococcal infection. Taken together, our study shows that MARCO can be exploited by the fungal pathogen to promote accumulation and alternative activation of CD11b+ cDC in the LALN, which in turn alters Th1/Th2 balance to promote fungal persistence and dissemination.

Highlights

Cryptococcus neoformans is an environmental fungal pathogen that causes severe meningoencephalitis with mortality rates of up to 20–60%, despite the availability of antifungal drugs [1]
Our results demonstrate that Macrophage receptor with collagenous structure (MARCO) expression promotes pulmonary fungal persistence and systemic dissemination during the efferent phase of C. neoformans infection
Though MARCO deficiency had no effect on the T cell expansion in lung-associated lymph nodes (LALNs) at 10 dpi (Figure 5A), we found reduced expression of IL-13 by the LALN leukocytes of infected MARCO−/− mice compared to WT mice (Figure 5B)

Summary

Introduction

Cryptococcus neoformans is an environmental fungal pathogen that causes severe meningoencephalitis with mortality rates of up to 20–60%, despite the availability of antifungal drugs [1]. During C. neoformans infection, pulmonary CD11b+ conventional DC (cDC) are the primary cellular population responsible for non-protective Th2 cell polarization [14, 15]. Skewing of Th2 responses is one well-established effect of cryptococcal virulence factors [6,7,8, 12, 15], very few loopholes in the host immune system that can be exploited by C. neoformans to promote non-protective responses have been identified [15,16,17]. Identification of host factors that contribute to non-protective responses and enable fungal persistence may reveal new targets for promoting effective T cell responses that are crucial for combat fungal infections

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Results

Conclusion