Influenza and dengue virus co‐infection impairs monocyte recruitment to the lung, increases dengue virus titers, and exacerbates pneumonia

Co‐infections of influenza virus and bacteria are known to cause severe disease, but little information exists on co‐infections with other acute viruses. Seasonal influenza and dengue viruses (DENV) regularly co‐circulate in tropical regions. The pandemic spread of influenza virus H1N1 (hereafter H1N1) in 2009 led to additional severe disease cases that were co‐infected with DENV. Here, we investigated the impact of co‐infection on immune responses and pathogenesis in a new mouse model. Co‐infection of otherwise sublethal doses of a Nicaraguan clinical H1N1 isolate and two days later with a virulent DENV2 strain increased systemic DENV titers and caused 90% lethality. Lungs of co‐infected mice carried both viruses, developed severe pneumonia, and expressed a unique pattern of host mRNAs, resembling only partial responses against infection with either virus alone. A large number of monocytes were recruited to DENV‐infected but not to co‐infected lungs, and depletion and adoptive transfer experiments revealed a beneficial role of monocytes. Our study shows that co‐infection with influenza and DENV impairs host responses, which fail to control DENV titers and instead, induce severe lung damage. Further, our findings identify key inflammatory pathways and monocyte function as targets for future therapies that may limit immunopathology in co‐infected patients.