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.