Macrophage phagocytosis of <i>Coccidioides</i> promotes its differentiation into the parasitic form

ABSTRACT Coccidioides is an endemic fungus that is increasing in prevalence and causes life-threatening diseases in immunocompetent people. In the environment, the spores (arthroconidia) develop into hyphae; however, when they are inhaled by a mammalian host, they develop into a unique form called the spherule. The transition to spherule can be triggered in vitro with elevated temperatures and high CO 2 levels, but how the host triggers Coccidioides spherulation is not known. We used live imaging to investigate how macrophages affect the fate of Coccidioides arthroconidia. Under tissue culture conditions, arthroconidia quickly developed into hyphae. Remarkably, the addition of macrophages promoted spherule development and delayed hyphal formation. Macrophage supernatants were not sufficient to promote spherule development, and chemical blockade of phagocytosis inhibited spherule formation. Transcriptomics analysis of Coccidioides co-cultured with macrophages revealed a signature concordant with spherules grown in vitro and allowed the identification of a core set of 143 spherule-specific transcripts. Additionally, we identified 229 Coccidioides transcripts with significantly higher abundance in the presence of macrophages compared to in vitro generated spherules, suggesting that these factors may be needed for growth in the presence of innate immune cells; 48 induced transcripts were predicted to encode secreted proteins, suggesting a function at the host-pathogen interface. Taken together, this work highlights the capacity of macrophages to promote development of the parasitic form of Coccidioides and lays a foundation for uncovering host-pathogen signaling as well as Coccidioides factors that are critical for pathogenesis. IMPORTANCE Valley Fever is a disease caused by inhalation of the spores of the fungus, Coccidioides spp. It can present like the flu, pneumonia, bone infections, or meningitis. Once inhaled, the spores change into a pathogenic form that allows the fungus to spread throughout the body and cause disease. How the spores make this transition in the body is not well understood. We investigated how immune cells affected this transition. We found that engulfment of spores by innate immune cells stimulated the transition to the pathogenic form of the fungus. We determined which fungal genes are induced during interactions with innate immune cells, potentially identifying genes that may be critical for the development of the pathogenic form. This work helps us understand how this pathogen is taking advantage of our immune system to survive and cause disease.