Divergent roles for complement components C3 and C4 in controlling Klebsiella pneumoniae gut colonization and systemic dissemination

Klebsiella pneumoniae is an escalating public health threat driven by the emergence of antibiotic-resistant and hyper-encapsulated strains that spread systemically from the gut. The immune defenses preventing gut colonization and dissemination remain poorly defined. Herein, we uncover distinct and context-dependent roles for complement proteins C3 and C4 in host defense following K. pneumoniae infection. Following gut colonization, C3 and C4 levels rise significantly. In addition to inducing alternative pathway-mediated C3b deposition on K. pneumoniae grown under gut-relevant conditions, C3 is critical for recruiting myeloid cells to the gut, promoting local opsonophagocytosis, and preventing lethal systemic spread. Depletion of systemic C3 reveals mucosal-derived C3 controls K. pneumoniae GI colonization, whereas systemic C3 is essential for limiting fatal dissemination. In contrast, C4 is dispensable for controlling GI colonization, dissemination, and myeloid recruitment under conditions of natural acquisition. However, C4 becomes critical for controlling GI burden and systemic disease following antibiotic-induced dysbiosis and supercolonization with antibiotic-resistant K. pneumoniae . Collectively, these findings reveal a dual-layered immune strategy: C3-driven opsonophagocytosis is critical for controlling colonization and dissemination under baseline conditions, while C4 becomes indispensable following antibiotic-induced supercolonization. This work advances our understanding of complement-dependent mucosal immune protection and identifies potential targets for preventing gut-to-bloodstream transition of this pathogen.