HVEM signaling in pulmonary epithelial cells is required for protection against Streptococcus pneumoniae

Abstract The most common cause of community-acquired pneumonia in the world is Streptococcus pneumoniae (S. pneumoniae). It is a serious and urgent issue to develop new therapies including non-antibiotic treatments for this pathogen. The herpes virus entry mediator (HVEM), a member of the tumor necrosis receptor super family 14 (TNFRSF14), has been reported to provide host innate immune defense in intestinal mucosal barriers against Citrobacter rodentium infection. Here we show using C10-Cre transgenic mice crossed to mice with a floxed Hvemallele that mice with pulmonary bronchiolar non-ciliated Clara cell-specific deletion of HVEM (HvemdelCC10) display higher bacterial burden and increased mortality after S. pneumoniae infection. Injection of an HVEM neutralizing antibody had a similar effect. This indicates that epithelial HVEM is also critical for pulmonary mucosal protection during the infection. In response to S. pneumonia, HVEM-deficiency led to reduced CXCL1 secretion, accompanied by impaired neutrophil recruitment to the lung. Likewise, deletion of part of the cytoplasmic tail of HVEM (HvemdelCT), causing loss of the ability of HVEM to signal, showed a similar susceptibility to S. pneumonia, indicating the importance of the intracellular signaling of HVEM in epithelial cells for the bacterial clearance. Taken together, these results reveal the protective role of HVEM in epithelial cells against S. pneumonia infection and suggest that activated HVEM signaling in epithelial cells could be used for the treatment of S. pneumoniae infection.