Swine influenza A virus infection sets the local immunological landscape in subsequent infection with porcine reproductive and respiratory syndrome virus

Farmed pigs are frequently exposed to respiratory infections, with swine influenza A virus (swIAV) and porcine reproductive and respiratory syndrome virus (PRRSV) being key drivers. Most co-infection studies with these viruses have focused on PRRSV infection followed by swIAV. However, the reverse scenario, where swIAV is given first and then PRRSV, has not been explored. This infection sequence is plausible under natural conditions and warrants further study, especially given that influenza A virus has been shown in mice to impair alveolar macrophages, which are the target cells for PRRSV. This study aimed to evaluate the impact of swIAV infection on the alveolar macrophage population, clinical signs, immune responses, and viral loads during a secondary infection with PRRSV initiated 7 days after the initial swIAV exposure. Results demonstrated that primary swIAV infection did not exacerbate the clinical progression of PRRSV infection, nor did it result in significant differences in PRRSV loads or affect the alveolar macrophage population in the lungs of super-infected pigs as compared to those of pigs infected with PRRSV alone. However, swIAV pre-infection was associated with an increase in the number of conventional dendritic cells type 1 (cDC1), perforin-expressing T cells and NK-related lymphocytes in bronchoalveolar lavage. This coincided with an increase of PRRSV-specific IFN-γ producing CD4 T cells in blood detected 7 days post-PRRSV infection. These findings suggest that a swIAV infection could enhance immune responses during subsequent PRRSV infection by recruiting cDC1 and inducing IL-12, promoting a type-1 immune response, highlighting the complex interplay and often unexpected outcomes of viral co-infections occurring in close temporal proximity.