Blocking of Birc3/TLR4/Myd88 signaling protects carbapenem-resistant klebsiella pneumoniae in a mouse model of infection.

Background: Klebsiella pneumonia (KP) and carbapenem-resistant Klebsiella pneumonia (CRKP) lung infections significantly increase the morbidity and mortality of pneumonia. Recent studies have shown that baculoviral IAP repeat-containing 3 (Birc3) plays an important role in the prevention and treatment of pneumonia. However, the role of Birc3 in CRKP-induced pneumonia has not been widely reported.

Methods: In vivo, we successfully established a mouse model of pneumonia induced by KP and CRKP. In vitro, we established a macrophage model treated with KP and CRKP. The phagocytosis of macrophages treated with CRKP was measured by Flow cytometry and coated plate counting. STRING and Co-IP assays were used to predict and verify the relationship between Birc3 and toll-like receptor 4 (TLR4) or myeloid differentiation factor 88 (Myd88). HE staining was used to detect the lung pathological changes of anti-Birc3 IgG inhibited CRKP-induced inflammatory cells. The levels of inflammatory factors and proteins were detected by ELISA and Western blot, respectively.

Results: The phagocytic ability of macrophages was reduced, and the cytokine storm was enhanced in CRKP treated Raw264.7 cells. Macrophages treated with CRKP impaired phagocytosis. Birc3 could interact with TLR4 and MyD88. Anti-Birc3 IgG inhibited CRKP-induced inflammatory cell lung infiltration. In addition, mice treated with anti-Birc3 IgG improved the CRKP-induced inflammatory cell lung infiltration, bacterial spread, and cytokine storm by inhibiting the Birc3/TLR4/Myd88 signaling pathway.

Conclusion: The results suggest that Birc3 may serve as a target for the treatment of bacterial infection and lung inflammation in CRKP-induced pneumonia.