Host-pathogen transcriptomics of macrophages, Mucorales and their endosymbionts: a polymicrobial pas de trois

Abstract

Mucorales spores, the causative agents of mucormycosis, interact with the innate immune system to cause acute, chronic, or resolving infection. Understanding the factors that influence disease initiation and progression is key to understanding mucormycosis and developing new treatments. Complicating this, mucormycosis can be caused by a number of species that span the Mucorales order and may be host to bacterial endosymbionts. This study sets out to examine the differences between two species in the Mucorales order by characterising their differential interactions with the innate immune system, and their interactions with environmental bacterial endosymbionts. Through a holistic approach, this study examines the transcriptional responses of Rhizopus delemar and Rhizopus microsporus, two of the most commonly diagnosed species, to innate immune cells. This study also examines the immune cell response and assesses the variation in these responses, given the presence or absence of bacterial endosymbionts within the fungi. We see that the fungal response is driven by interaction with innate immune cells. Moreover, the effect of the bacterial endosymbiont on the fungus is species-specific and strongly influences fungal transcription during phagocyte stress. The macrophage response varies depending on the infecting fungal species, and depending on endosymbiont status. Macrophages are better able to survive when germination is inhibited, or upon a pro-inflammatory response. This work reveals species-specific host responses to related Mucorales spores and shows that bacterial endosymbionts have an important role to play by impacting both innate immune cell response, and fungal response when under stress.