Adenovirus Co-Opts Neutrophilic Inflammation to Enhance Transduction of Epithelial Cells

Human adenoviruses (HAdV) cause a variety of infections in human hosts, from self-limited upper respiratory tract infections in otherwise healthy people to fulminant pneumonia and death in immunocompromised patients. Many HAdV enter polarized epithelial cells by using the primary receptor, the Coxsackievirus and adenovirus receptor (CAR). Recently published data demonstrate that a potent neutrophil (PMN) chemoattractant, interleukin-8 (IL-8), stimulates airway epithelial cells to increase expression of the apical isoform of CAR (CAR(Ex8)), which results in increased epithelial HAdV type 5 (HAdV5) infection. However, the mechanism for PMN-enhanced epithelial HAdV5 transduction remains unclear. In this manuscript, the molecular mechanisms behind PMN mediated enhancement of epithelial HAdV5 transduction are characterized using an MDCK cell line that stably expresses human CAR(Ex8) under a doxycycline inducible promoter (MDCK-CAR(Ex8) cells). Contrary to our hypothesis, PMN exposure does not enhance HAdV5 entry by increasing CAR(Ex8) expression nor through activation of non-specific epithelial endocytic pathways. Instead, PMN serine proteases are responsible for PMN-mediated enhancement of HAdV5 transduction in MDCK-CAR(Ex8) cells. This is evidenced by reduced transduction upon inhibition of PMN serine proteases and increased transduction upon exposure to exogenous human neutrophil elastase (HNE). Furthermore, HNE exposure activates epithelial autophagic flux, which, even when triggered through other mechanisms, results in a similar enhancement of epithelial HAdV5 transduction. Inhibition of F-actin with cytochalasin D partially attenuates PMN mediated enhancement of HAdV transduction. Taken together, these findings suggest that HAdV5 can leverage innate immune responses to establish infections.

Automated summary

Human adenoviruses (HAdV) can cause various infections, and neutrophils enhance viral transmission in epithelial cells. In this study, neutrophil serine proteases were found to be critical for neutrophil-enhanced epithelial cell infection. Additionally, neutrophil elastase could activate autophagy in epithelial cells, leading to increased viral transmission.