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Characterizing Innate and Adaptive Immune Responses to vaccine strain Coccidioides posadasii (cts2/ard1/cts3Δ)

  • Author(s): Diep, Anh Loan
  • Advisor(s): Hoyer, Katrina K.
  • et al.
Abstract

Coccidiomycosis, colloquially known as Valley fever and Desert fever, is a respiratory fungal disease caused by Coccidioides immitis and Coccidioides posadasii. In the United States this fungus is endemic to the California San Joaquin Valley, most of Arizona, and the American Southwest. Infection cases are increasing but there is still no effective vaccine or new therapeutics against severe chronic and disseminated coccidiomycosis. Tremendous work has been done over the years to elucidate infection pathogenesis, fungal genetics, and fungal immunity. However, more work must be done to deeply characterize effective and ineffective immune responses to Coccidioides to further enhance therapeutics and fungal vaccine development. We assess host immune response to Coccidioides posadasii (cts2/ard1/cts3Δ), an avirulent vaccine strain previously characterized to provide effective protection. We show that avirulent Coccidioides posadasii infection in in vitro cell-based assays demonstrate macrophages hold no bias towards pro-inflammatory (M1) or anti-inflammatory (M2) polarization while DCs become proinflammatory (DC1). Macrophages and DCs show decreased MHC-II and CD86 co-expression after culture with avirulent Coccidioides, suggesting a novel virulence mechanism by which Coccidioides can block immune activation by inhibiting antigen presenting cell (APC) activation and maturation. In vivo infections show a promising mixed DC1/DC2, pro- and anti-inflammatory, response with no changes in APC activation/maturation, suggesting other immune cells contribute to protective immunity. Our adaptive experiments suggests that Tregs play a detrimental role in Coccidioides clearance. When adoptively transferred, Tregs increase fungal burden in the lungs and enhance DC2 frequency. These results highlight the complicated nature of vaccine development and suggest that the effective, protective avirulent strain induce immune activation that is inhibited by Treg presence. This work contributes to characterizing vaccine-induced immune responses to Coccidioides infection. This thesis work builds a foundation for future immune studies aimed at manipulating host immunity to reduce disease severity.

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