-Derived Volatile Sulfur Compounds Promote Distal Growth and a Synergistic Pathogen-Pathogen Interaction That Increases Pathogenicity in Co-infection.

Pathogen-pathogen interactions in polymicrobial infections are known to directly impact, often to worsen, disease outcomes. For example, co-infection with and , respectively the most common bacterial and fungal pathogens isolated from cystic fibrosis (CF) airways, leads to a worsened prognosis. Recent studies of microbial cross-talk demonstrated that -derived volatile sulfur compounds (VSCs) can promote growth . However, the mechanistic basis of such cross-talk and its physiological relevance during co-infection remains unknown. In this study we combine genetic approaches and GC-MS-mediated volatile analysis to show that assimilates VSCs via cysteine (CysB)- or homocysteine (CysD)-synthase. This process is essential for utilization of VSCs as sulfur sources, since -derived VSCs trigger growth of wild-type, but not of a ΔΔ mutant, on sulfur-limiting media. produces VSCs when infecting and co-infection with in this model results in a synergistic increase in mortality and of fungal and bacterial burdens. Interestingly, the increment in mortality is much greater with the wild-type than with the ΔΔ mutant. Therefore, ability to assimilate derived VSCs significantly triggers a synergistic association that increases the pathobiology of infection. Finally, we show that can promote fungal growth when growing on substrates that resemble the lung environment, which suggests that this volatile based synergism is likely to occur during co-infection of the human respiratory airways.