Macrophage and Dendritic Cell Activation and Polarization in Response to Coccidioidesposadasii Infection.

Anh L Diep,Katrina K Hoyer,Susana Tejeda-Garibay,Nadia Miranda

doi:10.3390/jof7080630

Anh L Diep, Katrina K Hoyer + Show 2 more

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https://doi.org/10.3390/jof7080630

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Abstract

Coccidioidomycosis is a fungal, respiratory disease caused by Coccidioides immitis and Coccidioides posadasii. The host immune responses that define disease outcome during infection are largely unknown, although T helper responses are required. Adaptive immunity is influenced by innate immunity as antigen-presenting cells activate and educate adaptive responses. Macrophage and dendritic cell (DC) recognition of pathogen surface molecules are critical for Coccidioides clearance. We characterize the broad innate immune responses to Coccidioides by analyzing macrophage and dendritic cell responses to Coccidioides arthroconidia using avirulent, vaccine Coccidioides strain NR-166 (Δcts2/Δard1/Δcts3), developed from parental virulent strain C735. We developed a novel flow cytometry-based method to analyze macrophage phagocytosis to complement traditional image-scoring methods. Our study found that macrophage polarization is blocked at M0 phase and activation reduced, while DCs polarize into proinflammatory DC1s, but not anti-inflammatory DC2, following interaction with Coccidioides. However, DCs exhibit a contact-dependent reduced activation to Coccidioides as defined by co-expression of MHC-II and CD86. In vivo, only modest DC1/DC2 recruitment and activation was observed with avirulent Coccidioides infection. In conclusion, the vaccine Coccidioides strain recruited a mixed DC population in vivo, while in vitro data suggest active innate immune cell inhibition by Coccidioides.

Highlights

Coccidioides immitis and Coccidioides posadasii are the causative agents of coccidiomycosis, known as Valley fever or Desert fever
Our study shows that macrophages and dendritic cell (DC) in vitro appear to be blocked at various polarization phases and fail to upregulate activation/maturation markers CD86 and MHC-II, suggesting a novel virulence mechanism where Coccidioides arthroconidia inhibit DC activation and maturation
We sought to characterize the innate immune responses to NR-166 avirulent Coccidioides posadasii (∆cts2/∆ard1/∆cts3) by characterizing how macrophages and dendritic cells response to Coccidioides. This strain is used widely in vaccine studies with protective responses in murine models, little is known about the innate immune responses to this strain

Summary

Introduction

Coccidioides immitis and Coccidioides posadasii are the causative agents of coccidiomycosis, known as Valley fever or Desert fever. Most infected individuals are asymptomatic and clear the infection with little to no medical intervention. 40% of infections presents across a clinical spectrum from acute pneumonia to chronic lung nodules to disseminated disease [1]. Chronic coccidioidomycosis severely decreases quality of life, and there is no cure for this infection. Broad-spectrum antifungals are currently the only treatment for chronic disease and induce severe side effects such as nausea, skin lesions, hair loss, and nervous system complications [1,2]. Coccidioides infections are on the rise, underreported, and often misdiagnosed [3]

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