Macrophages inhibit extracellular hyphal growth of through Rac2 GTPase signaling.

Macrophages act as a first line of defense against pathogens. Against , a fungus with pathogenic potential in immunocompromised patients, macrophages can phagocytose fungal spores and inhibit spore germination to prevent the development of tissue-invasive hyphae. However, the cellular pathways that macrophages use to accomplish these tasks and any roles macrophages have later in infection against invasive forms of fungi are still not fully known. Rac-family Rho GTPases are signaling hubs for multiple cellular functions in leukocytes, including cell migration, phagocytosis, reactive oxygen species (ROS) generation, and transcriptional activation. We therefore aimed to further characterize the function of macrophages against in an vertebrate infection model by live imaging of the macrophage behavior in -infected mutant zebrafish larvae. While Rac2-deficient zebrafish larvae are susceptible to infection, Rac2 deficiency does not impair macrophage migration to the infection site, interaction with and phagocytosis of spores, spore trafficking to acidified compartments, or spore killing. However, we reveal a role for Rac2 in macrophage-mediated inhibition of spore germination and control of invasive hyphae. Re-expression of Rac2 under a macrophage-specific promoter rescues the survival of -infected mutant larvae through increased control of germination and hyphal growth. Altogether, we describe a new role for macrophages against extracellular hyphal growth of and report that the function of the Rac2 Rho GTPase in macrophages is required for this function.