Influenza A Virus as a Predisposing Factor for Cryptococcosis

Abstract

Influenza A virus (IAV) infects millions of people annually and predisposes to secondary bacterial infections. Inhalation of fungi within the <i>Cryptococcus</i> complex causes pulmonary disease with secondary meningo-encephalitis. Underlying pulmonary disease is a strong risk factor for development of <i>C. gattii</i> cryptococcosis though the effect of concurrent infection with IAV has not been studied. We developed an <i>in vivo</i> model of Influenza A H1N1 and <i>C. gattii</i> co-infection. Co-infection resulted in a major increase in morbidity and mortality, with severe lung damage and a high brain fungal burden when mice were infected in the acute phase of influenza multiplication. Furthermore, IAV alters the host response to <i>C. gattii</i>, leading to recruitment of significantly more neutrophils and macrophages into the lungs. Moreover, IAV induced the production of type 1 interferons (IFN-α4/β) and the levels of IFN-γ were significantly reduced, which can be associated with impairment of the immune response to <i>Cryptococcus</i> during co-infection. Phagocytosis, killing of cryptococci and production of reactive oxygen species (ROS) by IAV-infected macrophages were reduced, independent of previous IFN-γ stimulation, leading to increased proliferation of the fungus within macrophages. In conclusion, IAV infection is a predisposing factor for severe disease and adverse outcomes in mice co-infected with <i>C. gattii</i>.