Abstract
ST258-K. pneumoniae (ST258-KP) strains, the most widespread multidrug-resistant hospital-acquired pathogens, belong to at least two clades differing in a 215 Kb genomic region that includes the cluster of capsule genes. To investigate the effects of the different capsular phenotype on host-pathogen interactions, we studied representatives of ST258-KP clades, KKBO-1 and KK207-1, for their ability to activate monocytes and myeloid dendritic cells from human immune competent hosts. The two ST258-KP strains strongly induced the production of inflammatory cytokines. Significant differences between the strains were found in their ability to induce the production of IL-1β: KK207-1/clade I was much less effective than KKBO-1/clade II in inducing IL-1β production by monocytes and dendritic cells. The activation of NLRP3 inflammasome pathway by live cells and/or purified capsular polysaccharides was studied in monocytes and dendritic cells. We found that glibenclamide, a NLRP3 inhibitor, inhibits more than 90% of the production of mature IL-1β induced by KKBO1 and KK207-1. KK207-1 was always less efficient compared to KKBO-1 in: a) inducing NLRP3 and pro-IL-1β gene and protein expression; b) in inducing caspase-1 activation and pro-IL-1β cleavage. Capsular composition may play a role in the differential inflammatory response induced by the ST258-KP strains since capsular polysaccharides purified from bacterial cells affect NLRP3 and pro-IL-1β gene expression through p38MAPK- and NF-κB-mediated pathways. In each of these functions, capsular polysaccharides from KK207-1 were significantly less efficient compared to those purified from KKBO-1. On the whole, our data suggest that the change in capsular phenotype may help bacterial cells of clade I to partially escape innate immune recognition and IL-1β-mediated inflammation.
Highlights
Carbapenem-resistant Enterobacteriaceae, and especially Klebsiella pneumoniae (KP) producing the KPC-type carbapenemases (KPC-KP), have emerged as an important cause of healthcare-associated infections correlated with high morbidity and mortality [1,2,3]
To assess whether capsular composition of the two ST258-KP strains may affect pathways leading to inflammasome activation and/or cytokine production, we purified capsular polysaccharides from bacterial cells from KKBO-1 and KK207-1 as previously described [22] and studied their ability to affect pathways involved in the production of inflammatory cytokines in monocytes and Myeloid Dendritic Cells (MDC): in particular we studied a) the activation of p38 MAPK and NF-κB
ST258-KP strains were shown to circumvent killing by human neutrophils [15,37] but no differences between strains with cpsBO-4 or cps207-2 were revealed [11] suggesting that capsule switch does not confer to strains of the ST258-KP clades an additional benefit in terms of resistance to neutrophil phagocytosis
Summary
Carbapenem-resistant Enterobacteriaceae, and especially Klebsiella pneumoniae (KP) producing the KPC-type carbapenemases (KPC-KP), have emerged as an important cause of healthcare-associated infections correlated with high morbidity and mortality [1,2,3]. ST258-KP descended from an ST11-like ancestor which acquired a 1.1 Mb genomic region including the cps locus (cpsBO-4) from ST442-like K. pneumoniae via recombination [4,13,14] This clone has been named ST258 clade II/ST258-2 [4,11] or ST258b [14]. It has been reported that the uptake of ST258-KP strains by activated neutrophils in vitro is very low at least compared to Staphylococcus aureus, used as positive control in the assay [15] These data suggest the resistance of ST258-KP strains to neutrophil phagocytosis but they do not correlate the capsular phenotype to this virulence trait [11]
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