The goal of this exploratory work is to develop foundations for understanding innate immunity defenses in Mucoromycotina fungi, with a particular focus on the mechanisms triggering programmed cell death (PCD). We expect that these processes will become future targets for controlling mucormycoses, which are human infections caused by Mucoromycotina. Mucormycoses are increasingly frequent, highly destructive, and often fatal in immune-compromised individuals. Some clinical isolates of Mucoromycotina harbor endosymbiotic bacteria (EB) that can be isolated and cultivated independently. Our recent work generated insights into fungal responses to such isolated EB that were perceived by fungi as mutualists versus antagonists. In mutualisms, bacteria enter fungal cells and manipulate cellular processes of permissive hosts. In antagonisms, bacterial infections of non-host fungi are blocked by fungal responses that resemble innate immunity of animals and plants. In animals and plants, innate immunity mechanisms prevent bacterial invasions of cellular environment and suppress those invasions by initiating PCD. To accomplish our goal of unraveling novel mechanisms of innate immunity in Mucoromycotina, we will use isolated EB as a tool to elicit fungal defense responses. We will test whether Mucoromycotina are able to: (i) sense microbes, (iii) deploy defense modules that prevent bacterial entry, and (iii) when faced with bacteria capable of breaching these primary defenses, trigger PCD to eliminates intruders. To test these hypotheses, we will address the following specific aims: (1) determine the roles of candidate innate immunity sensors in bacterial infection of non-host strains and (2) identify novel genes responsible for elimination of bacterial infections, including genes that control defense and PCD modules. In addition to their profound health impacts, Mucoromycotina present a remarkably convenient study system for elucidating fungal-bacterial interactions in polymicrobial disorders. Expected outcomes of the project include determination of the molecular bases of fungal innate immunity and PCD, which, in the future, could be targeted to eradicate Mucoromycotina infections.
Mucormycosis incidence is on the rise, with the overall mortality rate of over 50%, and disseminated disease being nearly universally fatal. The goal of this exploratory work is to develop foundations for understanding of innate immunity defenses in Mucoromycotina fungi, with a particular focus on the mechanisms that trigger programmed cell death. Findings of this project are expected to inform future mycosis therapies targeting fundamental cellular processes underlying innate immunity of Mucoromycotina.
