Background
Immunity to viral infections is generally studied in isolation by measuring immune responses towards a single pathogen. However, we can harbour more than one infection at any given time, in sequence or concurrently, can affect immune responses to subsequent infection or vaccination. There is a paucity of knowledge on co-infections with unrelated viruses, especially neurotropic viruses.
Methods
We delineated anti-viral immunity during viral co-infection using two unrelated viruses, neurotropic Semliki Forest virus (SFV) and respiratory influenza A (IAV) in two key tissues: the brain and the lung. We used a mouse model infected with either SFV, IAV, or co-infected sequentially/simultaneously (SFV→IAV, IAV→SFV or SFV+IAV).
Results
We showed that SFV→IAV co-infection results in redirection of IAV-specific T-cell from the lung to the brain, increased cytokine levels and viral replication in the lungs, and exacerbated lung pathology. Prior SFV infection leads to perturbed proliferation of IAV-specific CD8+ T-cells in lymph node and lungs, and to antigen presenting cell paralysis. Analysis of IAV-specific TCR repertoires in the lung and brain revealed a heterogenous response in co-infection comprising suboptimal TCRs. Conversely, prior IAV infection attenuated subsequent SFV infection with reduced SFV titres and inflammation in the brain. This could be attributed to the increased type I interferon levels after IAV infection contributing to enhanced anti-SFV protection. Simultaneous SFV+IAV infection did not lead to exacerbated or attenuated respiratory or encephalitic disease. Nevertheless, there was enhanced IAV replication and elevated lung inflammation in co-infected mice indicating that simultaneous co-infection can hamper IAV-specific immune responses.
Conclusions
Our study provides evidence that the balance between protective antiviral immunity versus immunopathology is dictated by the timing and sequence of viral co-infections, including neurotropic infections. Given the intricate interplay between viral infections and the immune system, understanding immunity to co-infections remains a crucial area of research.