Author summary The emergence of hypervirulent Klebsiella pneumoniae (hvKP) poses a significant public health threat due to its capacity to cause severe, often fatal, systemic infections. Of further co...

Klebsiella pneumoniae, a major public health threat, resists antibiotics and can spread from the gut to the bloodstream, causing severe infections. Our study reveals how the immune system uses complement proteins C3 and C4 to block this spread. C3 limits bacterial growth in the gut through two potential mechanisms: (i) coating K. pneumoniae with fragments that signal bacteria-eating phagocytic cells to destroy it and (ii) recruiting more phagocytes into the gut. C3 also helps clear bacteria that escape into the blood. However, when antibiotic-resistant strains overgrow, C3 alone is insufficient. In these cases, C4 becomes critical, likely by enhancing C3’s ability to tag bacteria for elimination. This two-layered defense highlights new immune pathways that could be targeted to prevent bloodstream infections, especially in vulnerable patients or those colonized with drug-resistant bacteria. These insights open doors to innovative strategies against life-threatening Klebsiella infections.

Klebsiella pneumoniae (Kpn) is a Gram-negative opportunistic pathogen and a leading cause of hospital-acquired infections. The gastrointestinal (GI) tract serves as a critical site for Kpn colonizati....