Virulence factors, such as the recently discovered PB1-F2, contribute to the pathogenesis and comorbidity of influenza A virus. In this issue of Cell Host & Microbe, McAuley et al. characterize the role of PB1-F2, including in the pandemic 1918 virus, in causing increased lung pathology and fatal pneumococcus infection in mice. This work sheds light on the mechanisms of pathogenicity during influenza A virus infections.