Hierarchical effects of pro-inflammatory cytokines on the post-influenza susceptibility to pneumococcal coinfection

In the course of influenza A virus (IAV) infections, a secondary bacterial infection frequently leads to serious respiratory conditions provoking high hospitalization and death tolls. Although abundant pro-inflammatory responses have been reported as key contributing factors for these severe dual infections, the relative contribution of cytokines remain largely unclear. In the current study, mathematical modelling on in vivo experimental data highlight IFN- γ as a decisive candidate responsible for impaired bacterial clearance, thereby promoting bacterial growth and systemic dissemination during acute IAV infection. Moreover, we found a time-dependent detrimental role of IL-6 in curtailing bacterial outgrowth which was however not as distinct as for IFN- γ . Importantly, our results furthermore challenge current beliefs that the TNF- α response or the increased availability of nutrients modulated by IAV infection have a central role to the bacterial outgrowth. Ultimately, our findings contribute to a detailed understanding of the mechanisms underlying impaired bacterial clearance following influenza infection.