A plasmid locus associated with Klebsiella clinical infections encodes a microbiome-dependent gut fitness factor
| Autor: | Caitlyn L. Holmes, Nicole Sunshine, Yehudit Bergman, Patricia J. Simner, Michael C. Schatz, Vincent B. Young, Jay Vornhagen, Srividya Ramakrishnan, Michael A. Bachman, Robert Hein, Yunfan Fan, Winston Timp, Christine M. Bassis, Sophia Mason |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Bacterial Diseases
Male Operon Klebsiella pneumoniae Molecular biology Gene Sequencing Bacteremia Gut flora Biochemistry Mice Plasmid Sequencing techniques Medical Conditions Antibiotics Nucleic Acids Klebsiella Medicine and Health Sciences DNA sequencing Biology (General) Genetics 0303 health sciences biology Virulence Antimicrobials food and beverages Drugs Genomics Animal Models 3. Good health Intestines Infectious Diseases Ribosomal RNA Experimental Organism Systems Medical Microbiology Organ Specificity Host-Pathogen Interactions Female Research Article Plasmids Cell biology Cellular structures and organelles QH301-705.5 Immunology Kanamycin Resistance Locus (genetics) Mouse Models Microbial Genomics Research and Analysis Methods Microbiology beta-Lactamases 03 medical and health sciences Model Organisms Bacterial Proteins Virology Microbial Control Animals Microbiome Operons Non-coding RNA Gene 030304 developmental biology Pharmacology Bacteria 030306 microbiology Gut Bacteria Organisms Biology and Life Sciences DNA RC581-607 biology.organism_classification Klebsiella Infections Gastrointestinal Microbiome Mice Inbred C57BL Molecular biology techniques Genetic Loci Animal Studies RNA Parasitology Genetic Fitness Immunologic diseases. Allergy human activities Ribosomes Genome Bacterial |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 17, Iss 4, p e1009537 (2021) |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Klebsiella pneumoniae (Kp) is an important cause of healthcare-associated infections, which increases patient morbidity, mortality, and hospitalization costs. Gut colonization by Kp is consistently associated with subsequent Kp disease, and patients are predominantly infected with their colonizing strain. Our previous comparative genomics study, between disease-causing and asymptomatically colonizing Kp isolates, identified a plasmid-encoded tellurite (TeO3-2)-resistance (ter) operon as strongly associated with infection. However, TeO3-2 is extremely rare and toxic to humans. Thus, we used a multidisciplinary approach to determine the biological link between ter and Kp infection. First, we used a genomic and bioinformatic approach to extensively characterize Kp plasmids encoding the ter locus. These plasmids displayed substantial variation in plasmid incompatibility type and gene content. Moreover, the ter operon was genetically independent of other plasmid-encoded virulence and antibiotic resistance loci, both in our original patient cohort and in a large set (n = 88) of publicly available ter operon-encoding Kp plasmids, indicating that the ter operon is likely playing a direct, but yet undescribed role in Kp disease. Next, we employed multiple mouse models of infection and colonization to show that 1) the ter operon is dispensable during bacteremia, 2) the ter operon enhances fitness in the gut, 3) this phenotype is dependent on the colony of origin of mice, and 4) antibiotic disruption of the gut microbiota eliminates the requirement for ter. Furthermore, using 16S rRNA gene sequencing, we show that the ter operon enhances Kp fitness in the gut in the presence of specific indigenous microbiota, including those predicted to produce short chain fatty acids. Finally, administration of exogenous short-chain fatty acids in our mouse model of colonization was sufficient to reduce fitness of a ter mutant. These findings indicate that the ter operon, strongly associated with human infection, encodes factors that resist stress induced by the indigenous gut microbiota during colonization. This work represents a substantial advancement in our molecular understanding of Kp pathogenesis and gut colonization, directly relevant to Kp disease in healthcare settings. Author summary The bacterial pathogen Klebsiella pneumoniae is of substantial public health concern due to its ability to cause serious antibiotic-resistant infections. These infections frequently occur in healthcare settings, especially in patients with detectable gut colonization by K. pneumoniae. Importantly, infectious K. pneumoniae strains are often detected in the gut of patients with K. pneumoniae disease, indicating that the gut is a reservoir of infectious K. pneumoniae. Our previous work interrogating the genetic underpinnings of K. pneumoniae disease in colonized patients identified a strong association between K. pneumoniae infection and the presence of an enigmatic genetic locus known as the ter operon. We found that this operon is not needed for pneumonia and bacteremia, and therefore, we explored the importance of the ter operon in the gut. K. pneumoniae lacking ter function was at a disadvantage in the gut, thus explaining the connection between the ter operon and infection in hospitalized patients. Interestingly, the advantage conferred by the ter operon in the gut was associated with the presence of specific indigenous gut microbiota and the presence of short-chain fatty acids, which are metabolized by the host and gut microbiota. This work demonstrates that the ter operon is a microbiome-dependent gut fitness factor and suggests that indigenous gut bacteria may limit colonization by infectious K. pneumoniae. |
| Databáze: | OpenAIRE |
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