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

Bain, W.; Ahn, B.; Penaloza, H.; McElheny, C.; Tolman, N.; van der Geest, R.; Gonzalez-Ferrer, S.; Chen, N.; An, X.; Hosuru, R.; Tabary, M.; Papke, E.; Kohli, N.; Farooq, N.; Bachman, W.; Olonisakin, T.; Xiong, Z.; Griffith, M. P.; Sullivan, M.; Franks, J.; Mustapha, M.; Iovleva, A.; Suber, T.; Shanks, R. M.; Ferreira, V.; Stolz, D. B.; Van Tyne, D.; Doi, Y.; Lee, J.

doi:10.1101/2023.05.31.542722

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bioRxiv · 10.1101/2023.05.31.542722

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

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Abstract

Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (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, wcaJ, that emerged during infection was associated with decreased polysaccharide capsule content, and resistance to complement-mediated killing. Surprisingly, disruption of wcaJ 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 in vivo control of the wcaJ 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/542722v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@155736eorg.highwire.dtl.DTLVardef@10d47c0org.highwire.dtl.DTLVardef@e1ab83org.highwire.dtl.DTLVardef@1c33131_HPS_FORMAT_FIGEXP M_FIG Graphical abstract Created with BioRender.com C_FIG

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Bain, W., Ahn, B., Penaloza, H., McElheny, C., Tolman, N., van der Geest, R., Gonzalez-Ferrer, S., Chen, N., An, X., Hosuru, R., Tabary, M., Papke, E., Kohli, N., Farooq, N., Bachman, W., Olonisakin, T., Xiong, Z., Griffith, M. P., Sullivan, M., Franks, J., Mustapha, M., Iovleva, A., Suber, T., Shanks, R. M., Ferreira, V., Stolz, D. B., Van Tyne, D., Doi, Y., Lee, J.. 2023-06-01. In vivo evolution of a Klebsiella pneumoniae capsule defect promotes complement-mediated opsono-phagocytosis and persistence during recurrent infection. https://doi.org/10.1101/2023.05.31.542722

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