Abstract
Alveolar macrophages (AMs) help defend the lungs against infection, but during pneumonia many alveolar macrophages die. In this issue of the JCI, Malainou et al. explored the mechanism underpinning AM death during viral pneumonia and its effect on the outcomes of bacterial superinfection, a secondary infection that occurs before the first infection is cleared. In mouse models of influenza A infection, recruited neutrophils secreted TNF superfamily member 14 (TNFSF14), and AMs increased expression of the TNFSF14 receptors TNFSFR14 and type I transmembrane lymphotoxin β receptor (LTβR). TNFSF14 signaling via the LTβR was sufficient to cause AM apoptosis. TNFSF14 deficiency or blockade preserved AMs during influenza infection and diminished bacterial burdens and mouse mortality during pneumococcal superinfection. The adoptive transfer of AMs decreased the severity of pneumococcal superinfections, if those AMs lacked the LTβR. Thus, preserving AMs by interrupting TNFRSF14-LTβR interactions can make virus-infected lungs less susceptible to severe bacterial superinfection.