Mucorales fungi suppress nitric oxide production by macrophages

ABSTRACT Mucormycosis is classified by the National Institute of Allergy and Infectious Diseases as an emerging disease and is caused by Mucorales fungi. Despite the high morbidity and mortality rates associated with the disease, little is known about the host-pathogen interactions that dictate disease progression. The recent surge of mucormycosis cases among COVID-19 patients has thrust the disease and the lack of available treatments into the spotlight. Despite severe fungal angioinvasion and tissue necrosis during infection, clinical observations suggest a lack of pro-inflammatory responses. Understanding immune evasion mechanisms in mucormycosis can help guide potential therapeutic options. In this study, we demonstrate that Mucorales fungi can suppress the accumulation of nitric oxide (NO) in lipopolysaccharide- and interferon gamma-stimulated macrophages despite robust expression of the Nos2 mRNA and inducible nitric oxide synthase protein. This suppressive activity requires fungal viability and direct contact with macrophages and is not due to restricted access to L-arginine substrate. While Mucorales fungi appear to be able to remove NO from its environment, it does not account for the full suppression that we observe and suggests that Mucorales employs at least two mechanisms. Future experiments will elucidate the mechanisms by which Mucorales fungi deplete NO accumulation by macrophages and the implications of this depletion in mucormycosis pathogenesis. IMPORTANCE In October 2022, Mucorales fungi were listed in the “High Priority Group” on the first-ever list of fungal priority pathogens by the World Health Organization. As the causative agent of mucormycosis, Mucorales have become of great clinical and public health importance with growing mucormycosis numbers, notably with the exponential rise of COVID-19-associated mucormycosis cases. Despite the dire need, there are limited therapeutic options to treat mucormycosis. Our research fills in critical gaps of knowledge about how Mucorales fungi evade the host immune system. Specifically, we offer evidence that Mucorales block nitric oxide production, which is a key mediator and signaling molecule of the mammalian innate immune response to microbial pathogens. Our work offers new insight into immune evasion mechanisms by Mucorales fungi.