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Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection.

ABSTRACT: K. pneumoniae sequence type 258 (Kp ST258) is a major cause of healthcare-associated pneumonia. However, it remains unclear how it causes protracted courses of infection in spite of its expression of immunostimulatory lipopolysaccharide, which should activate a brisk inflammatory response and bacterial clearance. We predicted that the metabolic stress induced by the bacteria in the host cells shapes an immune response that tolerates infection. We combined in situ metabolic imaging and transcriptional analyses to demonstrate that Kp ST258 activates host glutaminolysis and fatty acid oxidation. This response creates an oxidant-rich microenvironment conducive to the accumulation of anti-inflammatory myeloid cells. In this setting, metabolically active Kp ST258 elicits a disease-tolerant immune response. The bacteria, in turn, adapt to airway oxidants by upregulating the type VI secretion system, which is highly conserved across ST258 strains worldwide. Thus, much of the global success of Kp ST258 in hospital settings can be explained by the metabolic activity provoked in the host that promotes disease tolerance.

SUBMITTER: Wong Fok Lung T

PROVIDER: S-EPMC9081115 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection.

Wong Fok Lung Tania T Charytonowicz Daniel D Beaumont Kristin G KG Shah Shivang S SS Sridhar Shwetha H SH Gorrie Claire L CL Mu Andre A Hofstaedter Casey E CE Varisco David D McConville Thomas H TH Drikic Marija M Fowler Brandon B Urso Andreacarola A Shi Wei W Fucich Dario D Annavajhala Medini K MK Khan Ibrahim N IN Oussenko Irina I Francoeur Nancy N Smith Melissa L ML Stockwell Brent R BR Lewis Ian A IA Hachani Abderrahman A Upadhyay Baskota Swikrity S Uhlemann Anne-Catrin AC Ahn Danielle D Ernst Robert K RK Howden Benjamin P BP Sebra Robert R Prince Alice A

Cell metabolism 20220411 5

K. pneumoniae sequence type 258 (Kp ST258) is a major cause of healthcare-associated pneumonia. However, it remains unclear how it causes protracted courses of infection in spite of its expression of immunostimulatory lipopolysaccharide, which should activate a brisk inflammatory response and bacterial clearance. We predicted that the metabolic stress induced by the bacteria in the host cells shapes an immune response that tolerates infection. We combined in situ metabolic imaging and transcript ...[more]

PMID: 35413274

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Project description:Chronic alcohol consumption perturbs the normal intestinal microbial communities (dysbiosis). To investigate the relationship between alcohol-mediated dysbiosis and pulmonary host defense we developed a fecal adoptive transfer model, which allows us to investigate the impact of alcohol-induced gut dysbiosis on host immune response to an infectious challenge at a distal organ, independent of prevailing alcohol use. Male C57BL/6 mice were treated with a cocktail of antibiotics (ampicillin, gentamicin, neomycin, vancomycin, and metronidazole) via daily gavage for two weeks. A separate group of animals was fed a chronic alcohol (or isocaloric dextrose pair-fed controls) liquid diet for 10 days. Microbiota-depleted mice were recolonized with intestinal microbiota from alcohol-fed or pair-fed (control) animals. Following recolonization groups of mice were sacrificed prior to and 48 hrs. post respiratory infection with Klebsiella pneumoniae. Klebsiella lung burden, lung immunology and inflammation, as well as intestinal immunology, inflammation, and barrier damage were examined. Results showed that alcohol-associated susceptibility to K. pneumoniae is, in part, mediated by gut dysbiosis, as alcohol-naïve animals recolonized with a microbiota isolated from alcohol-fed mice had an increased respiratory burden of K. pneumoniae compared to mice recolonized with a control microbiota. The increased susceptibility in alcohol-dysbiosis recolonized animals was associated with an increase in pulmonary inflammatory cytokines, and a decrease in the number of CD4+ and CD8+ T-cells in the lung following Klebsiella infection but an increase in T-cell counts in the intestinal tract following Klebsiella infection, suggesting intestinal T-cell sequestration as a factor in impaired lung host defense. Mice recolonized with an alcohol-dysbiotic microbiota also had increased intestinal damage as measured by increased levels of serum intestinal fatty acid binding protein. Collectively, these results suggest that alterations in the intestinal immune response as a consequence of alcohol-induced dysbiosis contribute to increased host susceptibility to Klebsiella pneumonia.

Dataset Information

Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection.

Publications

Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection.

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