AmpR Increases the Virulence of Carbapenem-Resistant Klebsiella pneumoniae by Regulating the Initial Step of Capsule Synthesis

摘要

Background: Non-hypermucoviscous carbapenem-resistant Klebsiella pneumoniae with enhanced virulence lacking hvKP-specific virulence factors is uncommon, and the virulence mechanisms of this organism are not understood. Methods: Following a retrospective study of carbapenem-resistant K. pneumoniae based on core genome multilocus sequence typing (cgMLST), isolates that caused high mortality were investigated with a genome-wide association study (GWAS), proteome analysis and an animal model. Results: The subclone of sequence type 11 (ST11) K. pneumoniae , which belongs to complex type 3176 (CT3176) and K-locus 47 (KL47), was highlighted due to the high mortality of infected patients. GWAS analysis showed that transcriptional regulatory gene ampR was associated with the CT3176 isolates. In a mouse model, the mortality, bacterial load and pathological changes of mice infected with ampR -carrying isolates were distinct from those infected with ampR -null isolates. The ampR gene that enhances the virulence of the non-hypermucoviscous KL47 strain was unable to enhance the virulence of hypermucoviscous KL1 strain. Proteome analysis showed that the expression of WcaJ in the ampR isolates was significantly higher than that in the ampR ? isolates. Quantification of capsular polysaccharide confirmed that more capsule polysaccharide was produced by ampR and ampR -complementary strains compared to ampR ? strains. It is suggested that the enhancement of the initial stage of capsule synthesis may be the cause of the enhanced virulence of these non-hypermucoviscous ST11 carbapenem-resistant K. pneumoniae isolates. Conclusion: Non-hypermucoviscous ST11 carbapenem-resistant K. pneumoniae with enhanced virulence warrants continued surveillance and investigation.