PRRSV Fetal Infection in Pigs as a Risk Factor for the Emergence of More Efficient Zoonotic Hosts for Swine-Origin...

Domestic pigs are susceptible to avian, swine, and human influenza A viruses (IAVs). This facilitates co-infections of different IAVs that result in genetic reassortment. In combination with husbandry practices such as high-density farming and frequent human-pig interactions, pigs serve as efficient zoonotic hosts for IAV. Despite significance in zoonotic transmission, factors influencing IAV pathogenesis, evolution, and transmission in pigs remain poorly studied. One factor that may alter IAV dynamics in pigs is co-infection with endemic swine viruses such as porcine reproductive and respiratory syndrome virus (PRRSV; Betaarterivirus; Nidovirales) that causes widespread disease in pigs on farms globally. During initial outbreaks, PRRSV triggers transplacental infections and massive fetal loss in naïve herds. Once herd immunity or vaccination is established, PRRSV may persist in affected herds, resulting in transplacental infections and the birth of piglets that appear normal or weak. These piglets are concerning from a zoonotic perspective because they may be immunocompromised and potentially serve as more efficient hosts for IAV, characterized by prolonged IAV shedding, enhanced viral replication, impaired seroconversion, and consequently extended co-infection windows that favor reassortment. Here, I summarize studies supporting the hypothesis that fetal exposure to PRRSV can alter IAV pathogenesis in surviving piglets, potentially enhancing IAV pathogenesis and transmission. I also highlight key experiments that need to be conducted to validate or invalidate a causal relationship between fetal PRRSV infection, persistent immunopathology in surviving piglets, and the resulting permissive environment for enhanced IAV evolution and transmission. Addressing this knowledge gap is essential for advancing our understanding of PRRSV and IAV biology in its zoonotic pig host and for developing effective strategies to mitigate the risk of IAV spillovers to humans.