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Acquired resistance to innate immune clearance promotes Klebsiella pneumoniae ST258 pulmonary infection
Danielle Ahn, … , Anne-Catrin Uhlemann, Alice Prince
Danielle Ahn, … , Anne-Catrin Uhlemann, Alice Prince
Published October 20, 2016
Citation Information: JCI Insight. 2016;1(17):e89704. https://doi.org/10.1172/jci.insight.89704.
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Research Article Infectious disease Pulmonology

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

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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 1

Kinetics of KP35 infection and host response.

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Kinetics of KP35 infection and host response.
(A) Antimicrobial suscepti...
(A) Antimicrobial susceptibility of the K. pneumoniae strains isolated from the airway and bloodstream of a patient over a 3-month hospitalization. B, blood; T, tracheal aspirate. Red = resistant, Yellow = intermediate, or Green = sensitive minimum inhibitory concentration for the given isolate for the corresponding antibiotic. (B) Kinetics of KP35 clearance from bronchoalveolar lavage fluid (BALF), lung homogenate, and spleen following intranasal inoculation of 1 × 108 to 2 × 108 CFU in WT mice over the course of a 4-day infection. # = the lower limit of detection. Horizontal lines represent median values and each data point represents an individual mouse. n = 6 per time point. All data were compiled from 2 independent experiments. n = 5–6 per time point. *P < 0.05, compared with CFU at 4 hours of infection, Kruskal-Wallis test, 1-way ANOVA, Dunn’s correction for multiple comparisons. (C) Weight loss over the course of infection, data points represent mean values ± SEM. n = 5–6 per time point. (D) Bacterial load enumerated from selected compartments after 7 days of infection. # = the lower limit of detection. Horizontal lines represent median values and each data point represents an individual mouse. n = 4–6 per compartment. (E) CT imaging demonstrates diffuse bronchopneumonia 48 hours following KP35 infection. Representative axial images obtained with the Quantum FX CT Scanner in 3-μm slices are shown. (F) Histopathology of KP35 pneumonia demonstrating peribronchial consolidation and cellular infiltrates in H&E-stained sections of lung, PBS control, and KP35 infection at 48 and 96 hours. (G) Trichrome staining of KP35-infected lung sections demonstrating patchy disruption of the alveolar architecture and discrete areas of collagen deposition. Scale bars (F and G): 100 μm.

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