Abstract
Respiratory and encephalitic virus infections represent a significant risk to public health globally. Detailed investigations of immunological responses and disease outcomes during sequential virus infections are rare. Here, we define the impact of influenza virus infection on a subsequent virus encephalitis. We used a model system in which mice were given influenza A virus (IAV) infection 8 days prior to Semliki Forest virus (SFV) infection (IAV→SFV). IAV infection clearly attenuated the subsequent SFV infection with reduced titers of infectious SFV and lower levels of cytokines and chemokines in the central nervous system (CNS). In contrast, the SFV viremia in both IAV→SFV and SFV-only mice was comparable. Increased type I interferon (IFN) levels in the CNS after IAV infection might have contributed to some level of protection towards SFV infection in the CNS, suggesting that early control of SFV replication in the CNS during IAV→SFV infection led to reduced adaptive response, given the lower number of CD8+ T cells recruited to the brain in IAV→SFV infection. In lungs, however, prior IAV infection elicited effector CD8+ T cells with highly activated CD38 and/or CD25 phenotypes, while SFV-only infection elicited distinct effector CD8+ T cells with increased frequencies of KLRG1 expression, a hallmark of short-lived effector T cells. Taken together, our findings demonstrate that prior IAV infection can confer protective immunity toward secondary SFV infection, confirmed by reduced disease severity and inflammatory immune responses in the brain. Our work provides important insights into therapies and vaccine regimens directed against unrelated pathogens. Importance: Influenza viruses are medically important human pathogens that caused epidemics and pandemics throughout history. Conversely, encephalitic arthropod-borne virus (arboviral) diseases affect both humans and domestic animals, creating massive public health issues. Influenza viruses circulate globally while arboviruses dominate tropical regions. Given both influenza virus and encephalitic arboviruses, such as alphaviruses, circulate in many regions globally, co-infections are likely to occur. In addition, arthropod-borne neurotropic infections are generally mild or asymptomatic, hence are likely to be unnoticed as a risk factor during influenza infection. However, the consequences of such co-infections are unclear. Our recent study showed that alphavirus infection preceding Influenza A virus (IAV) infection negatively impacted immune responses to the influenza virus in mice. Here, we aim to investigate the immune responses when the order of sequential infection with IAV and alphavirus are swapped. Altogether, our findings will provide key insights to improved diagnostics, preventative vaccines, and antiviral therapies.