Dataset Information

Interleukin-10 Produced by Myeloid-Derived Suppressor Cells Provides Protection to Carbapenem-Resistant Klebsiella pneumoniae Sequence Type 258 by Enhancing Its Clearance in the Airways.

ABSTRACT: Carbapenem-resistant Klebsiella pneumoniae sequence type 258 (CRKP-ST258) can cause chronic infections in lungs and airways, with repeated episodes of bacteremia. In this report we addressed whether the recruitment of myeloid cells producing the anti-inflammatory cytokine interleukin-10 (IL-10) modulates the clearance of CKRP-ST258 in the lungs and establishes bacterial persistence. Our data demonstrate that during pneumonia caused by a clinical isolate of CRKP-ST258 (KP35) there is an early recruitment of monocyte-myeloid-derived suppressor cells (M-MDSCs) and neutrophils that actively produce IL-10. However, M-MDSCs were the cells that sustained the production of IL-10 over the time of infection evaluated. Using mice unable to produce IL-10 (IL-10^-/-), we observed that the production of this cytokine during the infection caused by KP35 is important to control bacterial burden, to prevent lung damage, to modulate cytokine production, and to improve host survival. Importantly, intranasal transfer of bone marrow-derived M-MDSCs from mice able to produce IL-10 at 1 day prior to infection improved the ability of IL-10^-/- mice to clear KP35 in the lungs, decreasing their mortality. Altogether, our data demonstrate that IL-10 produced by M-MDSCs is required for bacterial clearance, reduction of lung tissue damage, and host survival during KP35 pneumonia.

SUBMITTER: Penaloza HF

PROVIDER: S-EPMC6479034 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Interleukin-10 Produced by Myeloid-Derived Suppressor Cells Provides Protection to Carbapenem-Resistant <i>Klebsiella pneumoniae</i> Sequence Type 258 by Enhancing Its Clearance in the Airways.

Peñaloza Hernán F HF Noguera Loreani P LP Ahn Danielle D Vallejos Omar P OP Castellanos Raquel M RM Vazquez Yaneisi Y Salazar-Echegarai Francisco J FJ González Liliana L Suazo Isidora I Pardo-Roa Catalina C Salazar Geraldyne A GA Prince Alice A Bueno Susan M SM

Infection and immunity 20190301 5

Carbapenem-resistant <i>Klebsiella pneumoniae</i> sequence type 258 (CRKP-ST258) can cause chronic infections in lungs and airways, with repeated episodes of bacteremia. In this report we addressed whether the recruitment of myeloid cells producing the anti-inflammatory cytokine interleukin-10 (IL-10) modulates the clearance of CKRP-ST258 in the lungs and establishes bacterial persistence. Our data demonstrate that during pneumonia caused by a clinical isolate of CRKP-ST258 (KP35) there is an ea ...[more]

PMID: 30804104

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Project description:Klebsiella pneumoniae is rapidly acquiring resistance to all known antibiotics, including carbapenems. Multilocus sequence type ST258 (sequence type 258), carrying a gene encoding the K. pneumoniae carbapenemase (blaKPC) on a transmissible plasmid, is the most prevalent carbapenem-resistant Enterobacteriaceae (CRE) in the United States and has disseminated worldwide. Previously, whole-genome sequencing identified core genome single nucleotide variants that divide ST258 into two distinct clades, ST258a and ST258b. Furthermore, a subset of ST258b strains have a 347-base deletion within the enterobactin (Ent) exporter gene entS Despite the predicted inability of these strains to secrete the siderophore Ent, this clade is prevalent among clinical isolates, indicating that a full-length entS gene is not necessary for infection. To compare the transcriptional responses of ST258 subtypes to iron limitation, we performed transcriptome sequencing (RNA-Seq) in minimal medium alone or supplemented with iron or human serum and measured gene expression patterns. Iron limitation induced differential expression of distinct iron acquisition pathways when comparing ST258a and ST258b strains, including the upregulation of the hemin transport operon in entS partial deletion isolates. To measure how K. pneumoniae strains vary in iron chelation and siderophore production, we performed in vitro chrome azurol S (CAS) and Arnow assays as well as mass spectrometry. We determined that both ST258a and ST258b strains grow under iron-depleted conditions, can utilize hemin for growth, and secrete Ent, despite the partial entS deletion in a subset of ST258b strains. All carbapenem-resistant (CR) K. pneumoniae strains tested were susceptible to growth inhibition by the Ent-sequestering innate immune protein lipocalin 2.IMPORTANCE Carbapenem-resistant Enterobacteriaceae, including K. pneumoniae, are a major health care concern worldwide because they cause a wide range of infection and are resistant to all or nearly all antibiotics. To cause infection, these bacteria must acquire iron, and a major mechanism of acquiring iron is by secreting a molecule called enterobactin that strips iron from host proteins. However, a subset of carbapenem-resistant K. pneumoniae strains that lack a portion of the entS gene that is required for enterobactin secretion was recently discovered. To understand how these mutant strains obtain iron, we studied their transcriptional responses, bacterial growth, and enterobactin secretion under iron-limited conditions. We found that strains both with mutated and intact entS genes grow under iron-limiting conditions, secrete enterobactin, and utilize an alternate iron source, hemin, for growth. Our data indicate that carbapenem-resistant K. pneumoniae can use varied methods for iron uptake during infection.

Project description:Carbapenem-resistantKlebsiella pneumoniae(CR-Kp) is significant threat to public health worldwide. The primary reservoir for CR-Kp is the intestinal tract, where the bacterium is usually present at low density, but can bloom following antibiotic treatment, mostly in hospital settings. The impact of disturbances in the intestinal environment on the fitness, survival, expansion, and drug susceptibility of this pathogen is not well-understood. Nevertheless, gaining such knowledge could lead to innovative intervention strategies for addressing colonization and infection. Here, we adopted anin vivomodel to examine the transcriptional adaptation of a CR-Kp clinical isolate to immune activation in the intestine. We report that as early as 6 hours following host treatment with anti-CD3 antibody, CR-Kp underwent rapid transcriptional changes including downregulation of genes involved in sugar utilization and amino acid biosynthesis, and upregulation of genes involved in amino acid uptake and catabolism, antibiotic resistance, and stress response. In agreement with these findings, the concentration of oxidative species and amino acids was increased in the mouse intestine following treatment. Genes encoding for proteins containing the domain of unknown function (DUF) 1471 were particularly upregulated, however their deletion did not impair CR-Kp fitness in vivoupon immune activation. Transcription factor enrichment analysis identified the global regulator cAMP-Receptor Protein CRP as a potential orchestrator of the observed transcriptional signature. In keeping with the recognized role of CRP in regulating utilization of alternative carbon sources, CRP deletion in CR-Kp resulted in strongly impaired gut colonization, but this effect was not amplified by immune activation. Thus, following intestinal colonization, which occurs in a CRP-dependent manner, CR-Kp can rapidly respond to immune cues by implementing a well-defined and complex transcriptional program whose direct relevance towards bacterial fitness remains cryptic. Further analyses utilizing this model may identify key factors to tackle the intestinal stage of CR-Kp colonization.

Dataset Information

Interleukin-10 Produced by Myeloid-Derived Suppressor Cells Provides Protection to Carbapenem-Resistant Klebsiella pneumoniae Sequence Type 258 by Enhancing Its Clearance in the Airways.

Publications

Interleukin-10 Produced by Myeloid-Derived Suppressor Cells Provides Protection to Carbapenem-Resistant <i>Klebsiella pneumoniae</i> Sequence Type 258 by Enhancing Its Clearance in the Airways.

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