Dataset Information

Tenascin-C Deficiency Is Associated With Reduced Bacterial Outgrowth During Klebsiella pneumoniae-Evoked Pneumosepsis in Mice.

ABSTRACT: Tenascin C (TNC) is an extracellular matrix glycoprotein that recently emerged as an immunomodulator. TNC-deficient (TNC^-/-) mice were reported to have a reduced inflammatory response upon systemic administration of lipopolysaccharide, the toxic component of gram-negative bacteria. Here, we investigated the role of TNC during gram-negative pneumonia derived sepsis. TNC^+/+ and TNC^-/- mice were infected with Klebsiella pneumoniae via the airways and sacrificed 24 and 42 h thereafter for further analysis. Pulmonary TNC protein levels were elevated 42 h after infection in TNC^+/+ mice and remained undetectable in TNC^-/- mice. TNC^-/- mice showed modestly lower bacterial loads in lungs and blood, and a somewhat reduced local-but not systemic-inflammatory response. Moreover, TNC^-/- and TNC^+/+ mice did not differ with regard to neutrophil recruitment, lung pathology or plasma markers of distal organ injury. These results suggest that while TNC shapes the immune response during lipopolysaccharide-induced inflammation, this role may be superseded during pneumosepsis caused by a common gram-negative pathogen.

SUBMITTER: Meijer MT

PROVIDER: S-EPMC7990887 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Tenascin-C Deficiency Is Associated With Reduced Bacterial Outgrowth During Klebsiella pneumoniae-Evoked Pneumosepsis in Mice.

Meijer Mariska T MT de Vos Alex F AF Scicluna Brendon P BP Roelofs Joris J JJ Abou Fayçal Chérine C Orend Gertraud G Uhel Fabrice F van der Poll Tom T

Frontiers in immunology 20210311

Tenascin C (TNC) is an extracellular matrix glycoprotein that recently emerged as an immunomodulator. TNC-deficient (TNC-/-) mice were reported to have a reduced inflammatory response upon systemic administration of lipopolysaccharide, the toxic component of gram-negative bacteria. Here, we investigated the role of TNC during gram-negative pneumonia derived sepsis. TNC+/+ and TNC-/- mice were infected with Klebsiella pneumoniae via the airways and sacrific ...[more]

PMID: 33776992

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Project description:The polysaccharide capsule is an essential virulence factor for Klebsiella pneumoniae in both community-acquired hypervirulent strains as well as health care-associated classical strains that are posing significant challenges due to multidrug resistance. Capsule production is known to be transcriptionally regulated by a number of proteins, but very little is known about how these proteins collectively control capsule production. RmpA and RcsB are two known regulators of capsule gene expression, and RmpA is required for the hypermucoviscous (HMV) phenotype in hypervirulent K. pneumoniae strains. In this report, we confirmed that these regulators performed their anticipated functions in the ATCC 43816 derivative, KPPR1S: rcsB and rmpA mutants are HMV negative and have reduced capsule gene expression. We also identified a novel transcriptional regulator, RmpC, encoded by a gene near rmpA The ΔrmpC strain has reduced capsule gene expression but retains the HMV phenotype. We further showed that a regulatory cascade exists in which KvrA and KvrB, the recently characterized MarR-like regulators, and RcsB contribute to capsule regulation through regulation of the rmpA promoter and through additional mechanisms. In a murine pneumonia model, the regulator mutants have a range of colonization defects, suggesting that they regulate virulence factors in addition to capsule. Further testing of the rmpC and rmpA mutants revealed that they have distinct and overlapping functions and provide evidence that HMV is not dependent on overproduction of capsule. This distinction will facilitate a better understanding of HMV and how it contributes to enhanced virulence of hypervirulent strains.IMPORTANCE Klebsiella pneumoniae continues to be a substantial public health threat due to its ability to cause health care-associated and community-acquired infections combined with its ability to acquire antibiotic resistance. Novel therapeutics are needed to combat this pathogen, and a greater understanding of its virulence factors is required for the development of new drugs. A key virulence factor for K. pneumoniae is the capsule, and community-acquired hypervirulent strains produce a capsule that causes hypermucoidy. We report here a novel capsule regulator, RmpC, and provide evidence that capsule production and the hypermucoviscosity phenotype are distinct processes. Infection studies showing that this and other capsule regulator mutants have a range of phenotypes indicate that additional virulence factors are in their regulons. These results shed new light on the mechanisms controlling capsule production and introduce targets that may prove useful for the development of novel therapeutics for the treatment of this increasingly problematic pathogen.

Project description:Gastric microbiota provides a biological barrier against the invasion of foreign pathogens from the oral cavity, playing a vital role in maintaining gastrointestinal health. Klebsiella spp. of oral origin causes various infections not only in gastrointestinal tract but also in other organs, with Klebsiella pneumoniae serotype K1 resulting in a liver abscess (KLA) through oral inoculation in mice. However, the relationship between gastric microbiota and the extra-gastrointestinal KLA infection is not clear. In our study, a 454 pyrosequencing analysis of the bacterial 16S rRNA gene shows that the composition of gastric mucosal microbiota in mice with or without KLA infection varies greatly after oral inoculation with K. pneumoniae serotype K1 isolate. Interestingly, only several bacteria taxa show a significant change in gastric mucosal microbiota of KLA mice, including the decreased abundance of Bacteroides, Alisptipes and increased abundance of Streptococcus. It is worth noting that the abundance of Klebsiella exhibits an obvious increase in KLA mice, which might be closely related to KLA infection. At the same time, the endogenous antibiotics, defensins, involved in the regulation of the bacterial microbiota also show an increase in stomach and intestine. All these findings indicate that liver abscess caused by K. pneumoniae oral inoculation has a close relationship with gastric microbiota, which might provide important information for future clinical treatment.Gastric microbiota provides a biological barrier against the invasion of foreign pathogens from the oral cavity, playing a vital role in maintaining gastrointestinal health. Klebsiella spp. of oral origin causes various infections not only in gastrointestinal tract but also in other organs, with Klebsiella pneumoniae serotype K1 resulting in a liver abscess (KLA) through oral inoculation in mice. However, the relationship between gastric microbiota and the extra-gastrointestinal KLA infection is not clear. In our study, a 454 pyrosequencing analysis of the bacterial 16S rRNA gene shows that the composition of gastric mucosal microbiota in mice with or without KLA infection varies greatly after oral inoculation with K. pneumoniae serotype K1 isolate. Interestingly, only several bacteria taxa show a significant change in gastric mucosal microbiota of KLA mice, including the decreased abundance of Bacteroides, Alisptipes and increased abundance of Streptococcus. It is worth noting that the abundance of Klebsiella exhibits an obvious increase in KLA mice, which might be closely related to KLA infection. At the same time, the endogenous antibiotics, defensins, involved in the regulation of the bacterial microbiota also show an increase in stomach and intestine. All these findings indicate that liver abscess caused by K. pneumoniae oral inoculation has a close relationship with gastric microbiota, which might provide important information for future clinical treatment.

Dataset Information

Tenascin-C Deficiency Is Associated With Reduced Bacterial Outgrowth During Klebsiella pneumoniae-Evoked Pneumosepsis in Mice.

Publications

Tenascin-C Deficiency Is Associated With Reduced Bacterial Outgrowth During <i>Klebsiella pneumoniae</i>-Evoked Pneumosepsis in Mice.

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