Acquired resistance to innate immune clearance promotes Klebsiella pneumoniae ST258 pulmonary infection
Danielle Ahn, Hernán Peñaloza, Zheng Wang, Matthew Wickersham, Dane Parker, Purvi Patel, Antonius Koller, Emily I. Chen, Susan M. Bueno, Anne-Catrin Uhlemann, Alice Prince
Danielle Ahn, Hernán Peñaloza, Zheng Wang, Matthew Wickersham, Dane Parker, Purvi Patel, Antonius Koller, Emily I. Chen, Susan M. Bueno, Anne-Catrin Uhlemann, Alice Prince
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Research Article Infectious disease Pulmonology

Acquired resistance to innate immune clearance promotes Klebsiella pneumoniae ST258 pulmonary infection

Abstract

Adaptive changes in the genome of a locally predominant clinical isolate of the multidrug-resistant Klebsiella pneumoniae ST258 (KP35) were identified and help to explain the selection of this strain as a successful pulmonary pathogen. The acquisition of 4 new ortholog groups, including an arginine transporter, enabled KP35 to outcompete related ST258 strains lacking these genes. KP35 infection elicited a monocytic response, dominated by Ly6Chi monocytic myeloid-derived suppressor cells that lacked phagocytic capabilities, expressed IL-10, arginase, and antiinflammatory surface markers. In comparison with other K. pneumoniae strains, KP35 induced global changes in the phagocytic response identified with proteomics, including evasion of Ca2+ and calpain activation necessary for phagocytic killing, confirmed in functional studies with neutrophils. This comprehensive analysis of an ST258 K. pneumoniae isolate reveals ongoing genetic adaptation to host microenvironments and innate immune clearance mechanisms that complements its repertoire of antimicrobial resistance genes and facilitates persistence in the lung.

Authors

Danielle Ahn, Hernán Peñaloza, Zheng Wang, Matthew Wickersham, Dane Parker, Purvi Patel, Antonius Koller, Emily I. Chen, Susan M. Bueno, Anne-Catrin Uhlemann, Alice Prince

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Figure 4

Resistance of KP35 to myeloid-derived suppressor cell (MDSC) and neutrophil killing.

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Resistance of KP35 to myeloid-derived suppressor cell (MDSC) and neutrop...
Bacterial survival of KP35 (red) and KPPR1 (blue) (MOI of 1) in the presence of: (A) MDSCs derived from bone marrow monocytes (BM/MDSCs), polarized ex vivo (n = 6) with (B) MDSC survival over the course of infection, and (C) freshly isolated neutrophils (NEUTs) from BM (n = 4) with (D) neutrophil survival. *P < 0.05 compared with NEUTs with KP35. (E and F) Inhibition of neutrophil killing of KPPR1 or KP35 (MOI of 1) by supernatant (SUP) harvested from BM/MDSCs stimulated with KP35 or KPPR1 (MOI of 10) or a media control (MED), n = 9. **P < 0.05 compared with KPPR1 infection with KPPR1 or KP35 infected SUP. There was no change in cell viability over time (B, D, and F). Graphs are compiled from 2 (A–D) or 3 independent experiments (E and F). For all graphs, each data point is the mean value ± SEM. *P < 0.05 by 2-way ANOVA. For all analyses, Bonferroni’s correction for multiple comparisons was performed.