Respiratory viral co-infections manipulate host immune responses to reduce disease severity.

Abstract

Patients with respiratory infections are frequently co-infected by more than one virus, but it is unknown how co-infection alters immune responses and disease outcomes compared to infection by the individual viruses. Our lab recently found that infection of mice with a mild rhinovirus pathogen (RV1B) two days before a more virulent virus (influenza A virus, PR8, or pneumonia virus of mice, PVM) reduced disease severity. In this study, we expanded these observations to determine how the timing of RV1B co-infection affects protection. Mice were inoculated with RV1B simultaneously with or two days after inoculation with PR8 or PVM. RV1B inoculated simultaneously with PR8 or PVM reduced disease whereas RV1B inoculated two days after PR8 and PVM increased the severity of PR8 and PVM. Next, mice were inoculated with RV1B two days before PR8 and then euthanized on days 4, 7 and 10 to quantify viral loads in the lungs. By day 7, co-infected mice had cleared PR8 while mice inoculated with PR8 alone had detectable virus. To identify immune cell populations that correspond with disease protection, groups of mice were inoculated with RV1B or mock two days before PR8 or PVM and flow cytometry analysis was performed on whole lungs on days 0, 2, 4, and 6 after the second virus. Co-infection by RV1B generated a stronger early innate response that contracted sooner than infection by PR8 or PVM alone. RV1B and PVM co-infection also had a stronger CD4 and CD8 T cell response later in infection. These data provide evidence that protection conferred by co-infection may be attributed to an earlier inflammatory cell response that contracts sooner, leading to faster clearance of the pathogenic virus while reducing immune-mediated pathology.