作者
William Bain,Brian Ahn,Hernán F. Peñaloza,Christi L. McElheny,Nathanial J. Tolman,Rick van der Geest,Shekina Gonzalez-Ferrer,Nathalie Chen,Xiuli An,Ria Hosuru,Mohammadreza Tabary,Erin Papke,Naina Kohli,Nauman Farooq,William Bachman,Tolani F. Olonisakin,Zeyu Xiong,M. Patrick Griffith,Mara Sullivan,Jonathan Franks,Mustapha M. Mustapha,Alina Iovleva,Tomeka Suber,Robert M. Q. Shanks,Viviana P. Ferreira,Donna B. Stolz,Daria Van Tyne,Yohei Doi,Janet Lee
摘要
Abstract Background Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) bloodstream infections are associated with high mortality. We studied clinical bloodstream KPC-Kp isolates to investigate mechanisms of resistance to complement, a key host defense against bloodstream infection. Methods We tested growth of KPC-Kp isolates in human serum. In serial isolates from a single patient, we performed whole genome sequencing and tested for complement resistance and binding by mixing study, direct ELISA, flow cytometry, and electron microscopy. We utilized an isogenic deletion mutant in phagocytosis assays and an acute lung infection model. Results We found serum resistance in 16 of 59 (27%) KPC-Kp clinical bloodstream isolates. In five genetically-related bloodstream isolates from a single patient, we noted a loss-of-function mutation in the capsule biosynthesis gene, wcaJ. Disruption of wcaJ was associated with decreased polysaccharide capsule, resistance to complement-mediated killing, and surprisingly, increased binding of complement proteins. Furthermore, an isogenic wcaJ deletion mutant exhibited increased opsono-phagocytosis in vitro and impaired in vivo control in the lung after airspace macrophage depletion in mice. Conclusions Loss of function in wcaJ led to increased complement resistance, complement binding, and opsono-phagocytosis, which may promote KPC-Kp persistence by enabling co-existence of increased bloodstream fitness and reduced tissue virulence.