In vivo evolution of a Klebsiella pneumoniae capsule defect promotes complement-mediated opsono-phagocytosis and persistence during recurrent infection

Bain, William; Ahn, Brian; Peñaloza, Hernán F; McElheny, Christi L; Tolman, Nathanial; van der Geest, Rick; Gonzalez-Ferrer, Shekina; Chen, Nathalie; An, Xiaojing; Hosuru, Ria; Tabary, Mohammadreza; Papke, Erin; Kohli, Naina; Farooq, Nauman; Bachman, William; Olonisakin, Tolani F; Xiong, Zeyu; Griffith, Marissa P; Sullivan, Mara; Franks, Jonathan; Mustapha, Mustapha M; Iovleva, Alina; Suber, Tomeka; Shanks, Robert Q; Ferreira, Viviana P; Stolz, Donna B; Van Tyne, Daria; Doi, Yohei; Lee, Janet S

carbapenemase-producing (KPC-Kp) bloodstream infections rarely overwhelm the host but are associated with high mortality. The complement system is a key host defense against bloodstream infection. However, there are varying reports of serum resistance among KPC-Kp isolates. We assessed growth of 59 KPC-Kp clinical isolates in human serum and found increased resistance in 16/59 (27%). We identified five genetically-related bloodstream isolates with varying serum resistance profiles collected from a single patient during an extended hospitalization marked by recurrent KPC-Kp bloodstream infections. We noted a loss-of-function mutation in the capsule biosynthesis gene, , that emerged during infection was associated with decreased polysaccharide capsule content, and resistance to complement-mediated killing. Surprisingly, disruption of increased deposition of complement proteins on the microbial surface compared to the wild-type strain and led to increased complement-mediated opsono-phagocytosis in human whole blood. Disabling opsono-phagocytosis in the airspaces of mice impaired control of the loss-of-function mutant in an acute lung infection model. These findings describe the rise of a capsular mutation that promotes KPC-Kp persistence within the host by enabling co-existence of increased bloodstream fitness and reduced tissue virulence.

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