Sustained desensitization to bacterial Toll-like receptor ligands after resolutionof respiratory influenza infection

TLDR

Lower respiratory tract infections account for about 35 % of infectious disease deaths, and bacterial pneumonia often follows influenza, with each lung infection potentially altering immunity for months due to lack of cross‑reactive adaptive responses. We show that after influenza or RSV infection, lung sentinel cells become desensitized to TLR ligands for several months, reducing chemokine production and NF‑κB activation in alveolar macrophages, which dampens neutrophil recruitment and is associated with higher bacterial loads during secondary respiratory infections.

Abstract

The World Health Organization estimates that lower respiratory tract infections (excluding tuberculosis) account for ∼35% of all deaths caused by infectious diseases. In many cases, the cause of death may be caused by multiple pathogens, e.g., the life-threatening bacterial pneumonia observed in patients infected with influenza virus. The ability to evolve more efficient immunity on each successive encounter with antigen is the hallmark of the adaptive immune response. However, in the absence of cross-reactive T and B cell epitopes, one lung infection can modify immunity and pathology to the next for extended periods of time. We now report for the first time that this phenomenon is mediated by a sustained desensitization of lung sentinel cells to Toll-like receptor (TLR) ligands; this is an effect that lasts for several months after resolution of influenza or respiratory syncytial virus infection and is associated with reduced chemokine production and NF-κB activation in alveolar macrophages. Although such desensitization may be beneficial in alleviating overall immunopathology, the reduced neutrophil recruitment correlates with heightened bacterial load during secondary respiratory infection. Our data therefore suggests that post-viral desensitization to TLR signals may be one possible contributor to the common secondary bacterial pneumonia associated with pandemic and seasonal influenza infection.