Loss of pulmonary tissue protection and neutrophil microbicidal defects promote severe Aspergillus fumigatus infection during influenza A virus infection.

Invasive pulmonary aspergillosis (IPA) is a severe fungal disease caused by Aspergillus fumigatus (Af) that may spread hematogenously to extrapulmonary organs. IPA is typically associated with a broad spectrum of immunocompromised conditions and constitutes a high mortality rate. While the association of influenza as a risk for secondary bacterial infections is well appreciated, emerging evidence indicates that influenza-hospitalized patients demonstrate increased susceptibility to severe aspergillosis infection. In this study, we developed a murine Influenza A Virus (IAV)-Af co-infection model and investigated the role of IAV host response in promoting invasive Af infection. Our data show that IAV temporarily suppresses neutrophil recruitment in the early phase of Af co-infection (24 hours), followed by a subsequent increase in neutrophil levels (48 hours). RNA sequencing analysis of neutrophils from IAV-Af co-infected lungs (48 hours) reveals enrichment of pathways regulating inflammatory responses and phagocytosis. Despite higher inflammatory response and phagocytosis, the host response from IAV-Af co-infected lungs had suppressive effects on neutrophil conidial killing, correlating with lung fungal load and invasion. However, the increased fungal invasion observed at 24 hours post co-infection, despite similar fungal loads in both groups (Af vs. IAV-Af), suggests that IAV-induced pathologic lung inflammation and vascular damage likely promote Af invasiveness during the initial phase of co-infection, and subsequently, the defects in neutrophil fungicidal response and exacerbated lung damage lead to sustained and fatal IPA pathogenesis in the later phase of co-infection.