Loss of pulmonary tissue protection promotes severe Aspergillus fumigatus infection during Influenza A Virus

Invasive pulmonary aspergillosis (IPA) is a severe fungal disease caused by Aspergillus spp. (particularly A. fumigatus or Af) that may spread hematogenously to extrapulmonary organs. IPA is typically associated with a broad spectrum of immunocompromised conditions and immunologic disorders 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 severe Af infection. Our data show that in a co-infection setting, while IAV suppresses Af-induced CXCL1 and early neutrophil recruitment, no defects in neutrophil phagocytic responses were observed. On the contrary, despite similar fungal burdens and conidial germination between single Af and co-infected lungs, there was greater fungal invasiveness in the early phase of IAV-Af co-infection. These findings suggest that enhanced lung inflammation, vascular injury, and loss of tissue protection in IAV-infecetd lung likely contribute to severe secondary Af infection. Overall design: We infected age-matched male and female C57BL/6 mice with a sublethal dose of 250 PFUs of IAV (PR8). The IAV-infected mice were co-infected seven days later with Af resting conidia (strain NIH 5233). Co-infection with conidia resulted in approximately 70% mortality in co-infected mice, compared to nearly sublethal outcomes with single Af or IAV infections