Hypervirulent Klebsiella pneumoniae Strains Modulate Human Dendritic Cell Functions and Affect TH1/TH17 Response

Abstract

Hypervirulent Klebsiella pneumoniae (Hv-Kp) strains have emerged as pathogens causing life-threatening, invasive disease even in immunocompetent hosts. Systemic dissemination usually occurs following perturbations of the gut microbiota and is facilitated by Hv-Kp resistance to phagocytosis and complement activity. Hv-Kp are usually associated with K1 or K2 capsular types, produce several iron uptake systems (e.g., aerobactin and salmochelin) and are often but not invariably, capsular material hyper-producers (hypermucoviscous phenotype: HMV). Whether Hv-Kp escape the immune response at mucosal site is unknown. In this work, we studied the effects of Hv-Kp on human dendritic cells (DCs), central players of the IL-23/IL-17 and IL-12/IFN-γ axis at mucosal sites, essential for pathogen clearance. Four Hv-Kp and HMV strains were selected and their activity on DC maturation and cytokine production was compared to that of non-virulent Kp strains with classic or HMV phenotypes. While the maturation process was equally induced by all Kp strains, significant differences between virulent and non-virulent strains were found in the expression of genes for cytokines involved in T-cell activation and differentiation. The non-virulent KP04C62 and the classic Kp, KPC157 induced high expression of TH1 (IL-12p70 and TNFα) and TH17 cytokines (IL-23, IL-1β and IL-6), while Hv-Kp poorly activated these cytokine genes. Moreover, conditioned media from DCs cultured with non-virulent Kp, either classical or hypercapsulated, induced the activation of IL-17 and IFN-γ genes in preactivated CD4+-cells suggesting their TH17/TH1 differentiation. Conditioned media from Hv-Kp poorly activated IL-17 and IFN-γ genes. In summary, our data indicate that Hv-Kp interfere with DC functions and T-cell differentiation and suggest that the escape from the IL-23/IL-17 and IL-12/IFN-γ axes may contribute to pathogen dissemination in immunocompetent hosts.

Differences in molecular characteristics and expression of virulence genes in carbapenem-resistant and sensitive Klebsiella pneumoniae isolates in Ningbo, China

“…The iucABCD gene cluster encodes the aerobactin synthase, and the membrane protein receptor is encoded by the iutA gene. The iroA ( iroBCDN gene cluster) encodes salmochelin ( Paczosa and Mecsas, 2016 ; Palmer and Skaar, 2016 ; Nicolò et al, 2022 ), allowing bacteria to uptake sufficient iron for growth and reproduction. The results of this study showed that the positive rates of the rmpA , peg-344 , and iroB genes in CSKP were 44.1, 42.7, and 45.5%, respectively, significantly higher than in CRKP, while there were no significant differences in the positive rates of the rmpA2 and iucA genes.…”

Pyroptosis, apoptosis, and autophagy are involved in infection induced by two clinical Klebsiella pneumoniae isolates with different virulence

“…There was a report that hvKp strains with thick polysaccharide capsules are able to resist neutrophil phagocytosis and complement-mediated killing ( Nicolò et al., 2022 ). Lin et al.…”

“…In contrast to classical K. pneumoniae (cKp), this strain, especially K1 and K2 serotypes, can cause more severe and metastatic infections such as pyogenic liver abscesses, endophthalmitis, and meningitis even in immunocompetent hosts of any age ( Russo and Marr, 2019 ). The presence of genotypic markers iucA, peg-344, and rmpA can be used, albeit imperfectly, to most accurately distinguish the cKp and hvKp strains as previously reported ( Nicolò et al., 2022 ). There was a high prevalence of hvKp among K. pneumoniae isolates ranging from 31% to 37.8% in China ( Zhang et al., 2016 ).…”

Targeting Th17 cells: a promising strategy to treat oral mucosal inflammatory diseases

“…The external cell signaling regulatory kinase, IL-6, and STAT3 pathways jointly drive IL-17 expression ( 63 ). Another study found that mice lacking IL-17A receptors reduced Th1 immune-dependent infections, such as tuberculosis, but were unable to fight pulmonary Klebsiella pneumoniae infection because these mice had a reduced ability to recruit granulocytes to clear the infection ( 64 , 65 ). The production of IL-17 was also required.…”