Commensal Bacteroidetes protect against Klebsiella pneumoniae colonization and transmission through IL-36 signalling.
Ontology highlight
ABSTRACT:
SUBMITTER: Sequeira RP
PROVIDER: S-EPMC7610889 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:An important yet poorly understood facet of the life cycle of a successful pathogen is host-to-host transmission. Hospital-acquired infections (HAI) resulting from the transmission of drug-resistant pathogens affect hundreds of millions of patients worldwide. Klebsiella pneumoniae, a Gram-negative bacterium, is notorious for causing HAI, with many of these infections difficult to treat, as K. pneumoniae has become multidrug resistant. Epidemiological studies suggest that K. pneumoniae host-to-host transmission requires close contact and generally occurs through the fecal-oral route. Here, we describe a murine model that can be utilized to study mucosal (oropharynx and gastrointestinal [GI]) colonization, shedding within feces, and transmission of K. pneumoniae through the fecal-oral route. Using an oral route of inoculation, and fecal shedding as a marker for GI colonization, we showed that K. pneumoniae can asymptomatically colonize the GI tract in immunocompetent mice and modifies the host GI microbiota. Colonization density within the GI tract and levels of shedding in the feces differed among the clinical isolates tested. A hypervirulent K. pneumoniae isolate was able to translocate from the GI tract and cause hepatic infection that mimicked the route of human infection. Expression of the capsule was required for colonization and, in turn, robust shedding. Furthermore, K. pneumoniae carrier mice were able to transmit to uninfected cohabitating mice. Lastly, treatment with antibiotics led to changes in the host microbiota and development of a transient supershedder phenotype, which enhanced transmission efficiency. Thus, this model can be used to determine the contribution of host and bacterial factors toward K. pneumoniae dissemination.
| S-EPMC7573435 | biostudies-literature
Project description:Sequence type 36 (ST36) Klebsiella pneumoniae is distributed worldwide. We found an ST36 K. pneumoniae clinical isolate that was carbapenem resistant, carried blaKPC-2, had mucoid regulator gene rmpA, and exhibited high virulence. The finding suggests the emergence of carbapenem-resistant hypervirulent K. pneumoniae of ST36, and surveillance of carbapenem-resistant hypervirulent K. pneumoniae is required.
| S-EPMC6021629 | biostudies-literature
Project description:The bacterial pathogen Streptococcus pneumoniae colonizes the nasopharynx prior to causing disease, necessitating successful competition with the resident microflora. Cytokines of the IL-17 family are important in host defence against this pathogen but their effect on the nasopharyngeal microbiome is unknown. Here we analyse the influence of IL-17 on the composition and interactions of the nasopharyngeal microbiome before and after pneumococcal colonization.Using a murine model and 16S rRNA profiling, we found that a lack of IL-17 signalling led to profound alterations in the nasal but not lung microbiome characterized by decreased diversity and richness, increases in Proteobacteria and reduction in Bacteroidetes, Actinobacteria and Acidobacteria. Following experimental pneumococcal nasal inoculation, animals lacking IL-17 family signalling showed increased pneumococcal colonization, though both wild type and knockout animals showed as significant disruption of nasal microbiome composition, with increases in the proportion of Proteobacteria, even in animals that did not have persistent colonization. Sparse correlation analysis of the composition of the microbiome at various time points after infection showed strong positive interactions within the Firmicutes and Proteobacteria, but strong antagonism between members of these two phyla.These results show the powerful influence of IL-17 signalling on the composition of the nasal microbiome before and after pneumococcal colonization, and apparent lack of interspecific competition between pneumococci and other Firmicutes. IL-17 driven changes in nasal microbiome composition may thus be an important factor in successful resistance to pneumococcal colonization and potentially could be manipulated to augment host defence against this pathogen.
| S-EPMC5651609 | biostudies-literature
Project description:Enterobacteriaceae are among the first colonizers of neonate intestine. Members of this family, such as Escherichia and Klebsiella, are considered pathobionts and as such are capable of inducing local and systemic disease under specific colonization circumstances. Interplay between developing microbiota and pathogenic function of pathobionts are poorly understood. In this study, we investigate the functional interaction between various colonization patterns on an early colonizer, K. pneumoniae. K. pneumoniae 51-5 was isolated from stool of a healthy, premature infant, and found to contain the genotoxin island pks associated with development of colorectal cancer. Using intestinal epithelial cells, macrophages, and primary splenocytes, we demonstrate K. pneumoniae 51-5 upregulates expression of proinflammatory genes in vitro. Gnotobiotic experiments in Il10-/- mice demonstrate the neonate isolate induces intestinal inflammation in vivo, with increased expression of proinflammatory genes. Regulation of microbiota assembly revealed K. pneumoniae 51-5 accelerates onset of inflammation in Il10-/- mice, most significantly when microbiota is naturally acquired. Furthermore, K. pneumoniae 51-5 induces DNA damage and cell cycle arrest. Interestingly, K. pneumoniae 51-5 induced tumors in ApcMin/+; Il10-/- mice was not significantly affected by absence of colibactin activating enzyme, ClbP. These findings demonstrate pathogenicity of infant K. pneumoniae isolate is sensitive to microbial colonization status.
| S-EPMC6399262 | biostudies-literature
Project description:Biofilm-dispersal is a key determinant for further dissemination of biofilm-embedded bacteria. Recent evidence indicates that biofilm-dispersed bacteria have transcriptional features different from those of both biofilm and planktonic bacteria. In this study, the in vitro and in vivo phenotypic properties of Klebsiella pneumoniae cells spontaneously dispersed from biofilm were compared with those of planktonic and sessile cells. Biofilm-dispersed cells, whose growth rate was the same as that of exponential planktonic bacteria but significantly higher than those of sessile and stationary planktonic forms, colonized both abiotic and biotic surfaces more efficiently than their planktonic counterparts regardless of their initial adhesion capabilities. Microscopy studies suggested that dispersed bacteria initiate formation of microcolonies more rapidly than planktonic bacteria. In addition, dispersed cells have both a higher engulfment rate and better survival/multiplication inside macrophages than planktonic cells and sessile cells. In an in vivo murine pneumonia model, the bacterial load in mice lungs infected with biofilm-dispersed bacteria was similar at 6, 24 and 48 h after infection to that of mice lungs infected with planktonic or sessile bacteria. However, biofilm-dispersed and sessile bacteria trend to elicit innate immune response in lungs to a lesser extent than planktonic bacteria. Collectively, the findings from this study suggest that the greater ability of K. pneumoniae biofilm-dispersed cells to efficiently achieve surface colonization and to subvert the host immune response confers them substantial advantages in the first steps of the infection process over planktonic bacteria.
| S-EPMC6760147 | biostudies-literature
Project description:Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36? and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity. We provide molecular and translational evidence that EGFRi/MEKi in concert with the skin commensal bacterium Cutibacterium acnes act synergistically to induce IL-36? in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36? expression was the combined result of C. acnes-induced NF-?B activation and EGFRi/MEKi-mediated expression of the transcription factor Krüppel-like factor 4 (KLF4), due to the presence of both NF-?B and KLF4 binding sites in the human IL-36? gene promoter. EGFRi/MEKi increased KLF4 expression by blockade of the EGFR/MEK/ERK pathway. These results provide an insight into understanding the pathological mechanism of the acneiform skin toxicities induced by EGFRi/MEKi and identify IL-36? and the transcription factor KLF4 as potential therapeutic targets.
| S-EPMC7269569 | biostudies-literature
Project description:Interleukin-22 (IL-22) is highly induced in response to infections with a variety of pathogens, and its main functions are considered to be tissue repair and host defense at mucosal surfaces. Here we showed that IL-22 has a unique role during infection in that its expression suppressed the intestinal microbiota and enhanced the colonization of a pathogen. IL-22 induced the expression of antimicrobial proteins, including lipocalin-2 and calprotectin, which sequester essential metal ions from microbes. Because Salmonella enterica ser. Typhimurium can overcome metal ion starvation mediated by lipocalin-2 and calprotectin via alternative pathways, IL-22 boosted its colonization of the inflamed intestine by suppressing commensal Enterobacteriaceae, which are susceptible to the antimicrobial proteins. Thus, IL-22 tipped the balance between pathogenic and commensal bacteria in favor of a pathogen. Taken together, IL-22 induction can be exploited by pathogens to suppress the growth of their closest competitors, thereby enhancing pathogen colonization of mucosal surfaces.
| S-EPMC3964146 | biostudies-literature
Project description:UNLABELLED:Carbapenem-resistant Klebsiella pneumoniae strains are formidable hospital pathogens that pose a serious threat to patients around the globe due to a rising incidence in health care facilities, high mortality rates associated with infection, and potential to spread antibiotic resistance to other bacterial species, such as Escherichia coli Over 6 months in 2011, 17 patients at the National Institutes of Health (NIH) Clinical Center became colonized with a highly virulent, transmissible carbapenem-resistant strain of K. pneumoniae Our real-time genomic sequencing tracked patient-to-patient routes of transmission and informed epidemiologists' actions to monitor and control this outbreak. Two of these patients remained colonized with carbapenemase-producing organisms for at least 2 to 4 years, providing the opportunity to undertake a focused genomic study of long-term colonization with antibiotic-resistant bacteria. Whole-genome sequencing studies shed light on the underlying complex microbial colonization, including mixed or evolving bacterial populations and gain or loss of plasmids. Isolates from NIH patient 15 showed complex plasmid rearrangements, leaving the chromosome and the blaKPC-carrying plasmid intact but rearranging the two other plasmids of this outbreak strain. NIH patient 16 has shown continuous colonization with blaKPC-positive organisms across multiple time points spanning 2011 to 2015. Genomic studies defined a complex pattern of succession and plasmid transmission across two different K. pneumoniae sequence types and an E. coli isolate. These findings demonstrate the utility of genomic methods for understanding strain succession, genome plasticity, and long-term carriage of antibiotic-resistant organisms. IMPORTANCE:In 2011, the NIH Clinical Center had a nosocomial outbreak involving 19 patients who became colonized or infected with blaKPC-positive Klebsiella pneumoniae Patients who have intestinal colonization with blaKPC-positive K. pneumoniae are at risk for developing infections that are difficult or nearly impossible to treat with existing antibiotic options. Two of those patients remained colonized with blaKPC-positive Klebsiella pneumoniae for over a year, leading to the initiation of a detailed genomic analysis exploring mixed colonization, plasmid recombination, and plasmid diversification. Whole-genome sequence analysis identified a variety of changes, both subtle and large, in the blaKPC-positive organisms. Long-term colonization of patients with blaKPC-positive Klebsiella pneumoniae creates new opportunities for horizontal gene transfer of plasmids encoding antibiotic resistance genes and poses complications for the delivery of health care.
| S-EPMC4937214 | biostudies-literature
Project description:Carbapenem-resistant (CR) sequence type 258 (ST258) Klebsiella pneumoniae has become an urgent health care threat, causing an increasing number of high-mortality infections. Its resistance to numerous antibiotics and threat to immunocompromised patients necessitate finding new therapies to combat these infections. Previous successes in the laboratory, as well as the conservation of capsular polysaccharide (CPS) among the members of the ST258 clone, suggest that monoclonal antibody (MAb) therapy targeting the outer polysaccharide capsule of K. pneumoniae could serve as a valuable treatment alternative for afflicted patients. Here, we isolated several IgG antibodies from mice inoculated with a mixture of CR K. pneumoniae CPS conjugated to anthrax protective antigen. Two of these MAbs, 17H12 and 8F12, bind whole and oligosaccharide epitopes of the CPS of clade 2 ST258 CR K. pneumoniae, which is responsible for the most virulent CR K. pneumoniae infections in the United States. These antibodies were shown to agglutinate all clade 2 strains and were also shown to promote extracellular processes killing these bacteria, including biofilm inhibition, complement deposition, and deployment of neutrophil extracellular traps. Additionally, they promoted opsonophagocytosis and intracellular killing of CR K. pneumoniae by human-derived neutrophils and cultured murine macrophages. Finally, when mice were intratracheally infected with preopsonized clade 2 CR K. pneumoniae, these MAbs reduced bacterial dissemination to organs. Our data suggest that broadly reactive anticapsular antibodies and vaccines against clade 2 ST258 CR K. pneumoniae are possible. Such MAbs and vaccines would benefit those susceptible populations at risk of infection with this group of multidrug-resistant bacteria.IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae is an enteric bacterium that has been responsible for an increasing number of deadly outbreaks and hospital-acquired infections. The pathogen's resistance to numerous antibiotics, including new drugs, leaves few therapeutic options available for infected patients, who often are too sick to fight the infection themselves. Immunotherapy utilizing monoclonal antibodies has been successful in other medical fields, and antibodies targeting the outer polysaccharide capsule of these bacteria could be a valuable treatment alternative. This study presents two anticapsular antibodies, 17H12 and 8F12, that were found to be protective against the most virulent carbapenem-resistant K. pneumoniae clinical strains. These antibodies are shown to promote the killing of these strains through several extracellular and intracellular processes and prevent the spread of infection in mice from the lungs to distal organs. Thus, they could ultimately treat or protect patients infected or at risk of infection by this multidrug-resistant bacterium.
| S-EPMC5885035 | biostudies-literature
Project description:Treatment of pneumococcal infections is limited by antibiotic resistance and exacerbation of disease by bacterial lysis releasing pneumolysin toxin and other inflammatory factors. We identified a novel peptide in the Klebsiella pneumoniae secretome, which enters Streptococcus pneumoniae via its AmiA-AliA/AliB permease. Subsequent downregulation of genes for amino acid biosynthesis and peptide uptake was associated with reduction of pneumococcal growth in defined medium and human cerebrospinal fluid, irregular cell shape, decreased chain length and decreased genetic transformation. The bacteriostatic effect was specific to S. pneumoniae and Streptococcus pseudopneumoniae with no effect on Streptococcus mitis, Haemophilus influenzae, Staphylococcus aureus or K. pneumoniae. Peptide sequence and length were crucial to growth suppression. The peptide reduced pneumococcal adherence to primary human airway epithelial cell cultures and colonization of rat nasopharynx, without toxicity. We also analysed the effect of peptide on the proteome of S. pneumoniae. We found alteration of the proteome by the peptide with some proteins turned on or off in line with the transcriptomic changes. We therefore identified a peptide with potential as a therapeutic for pneumococcal diseases suppressing growth of multiple clinical isolates, including antibiotic resistant strains, while avoiding bacterial lysis and dysbiosis.
2024-04-08 | PXD050408 | Pride