Background

Fungal infections are pathogens pose an increasingly relevant threat, despite availability of cytotoxic antifungals. The innate immune system is the first line of host. A major output of innate immune response, the first line of host defense against invading fungi, including, is production of Type I interferons (IFNs), which has been linked to human Candida albicans (Ca) infections. We aim to understand how the STING pathway, an IFN-producing and DNA-sensing pathway, is involved in host responses to Ca. We demonstrated that mice lacking STING pathway elements are resistant to Ca infection.

Methods

The extent to which DNA-carrying extracellular vesicles (EVs) from Ca induces the STING pathway was identified by Western blotting and ELISA. Nanostring technology was utilized to uncover transcriptional responses to pathway activating. Finally, I examine functional consequences of activation with phagocytosis, fungal burden, and inflammation assays.

Results

Ca EVs induced expression of Viperin, an IFN-stimulated gene and known STING pathway output, in macrophages. This induction was cGAS- and STING-dependent. Nanostring analysis identified that 70% of known ISGs are turned on in a cGAS- and STING- dependent manner in response to EVs. Finally, we demonstrated that anti-inflammatory steroid treatment in macrophages dampens STING activation.

Conclusions

Overall, these studies reveal a novel mechanism of STING-pathway activation and provides better understanding of early, innate immune response to a clinically significant fungal pathogen.