# Klebsiella pneumoniae infection induces an S100A8/A9-mediated autocrine loop in human airway epithelium to amplify inflammation

## TL;DR

This study shows how Klebsiella pneumoniae infection triggers a self-amplifying inflammation loop in airway cells through S100A8/A9 proteins.

## Contribution

The discovery of an S100A8/A9-mediated autocrine loop in airway epithelium during K. pneumoniae infection is novel.

## Key findings

- K. pneumoniae infection induces S100A8/A9 transcription and secretion in human bronchial epithelial cells.
- S100A8/A9 activates an autocrine loop that amplifies inflammation and cytokine production in epithelial cells.
- Disrupting this loop reduces neutrophil chemotaxis and inflammation during infection.

## Abstract

Klebsiella pneumoniae pneumonia is marked by an excessive inflammatory response that drives lung injury. The initial stages of infection and the mechanisms driving hyper-inflammation at the airway epithelial barrier are not fully defined. The alarmins S100A8/A9 are potent inflammatory mediators, and studies have indicated their importance in the host response to K. pneumoniae. Here, we show that infection with live K. pneumoniae directly induces the transcription and secretion of the S100A8/A9 heterodimer in a primary human bronchial epithelial (HBE) cell model. Furthermore, the infection sensitizes epithelial cells by upregulating the expression of Toll-like receptor 4, a key receptor that mediates S100A8/A9 signaling. We also established that HBE cells are highly responsive to extracellular S100A8/A9, which stimulates pro-inflammatory cytokine production. Critically, silencing of endogenous S100A9 expression in HBE cells significantly attenuated NF-κB activation and the overall cytokine response to bacterial infection, providing direct evidence for an epithelium-intrinsic autocrine amplification loop. Functionally, disruption of this loop markedly reduced the ability of epithelial cell supernatants to induce neutrophil chemotaxis. These findings reveal a novel autocrine mechanism that positions the airway epithelium not just as a responder, but as an active initiator and amplifier of local inflammation during early K. pneumoniae infection.