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. 2015 Sep;83(9):3418-27.
doi: 10.1128/IAI.00678-15. Epub 2015 Jun 8.

Distinct Contributions of Neutrophils and CCR2+ Monocytes to Pulmonary Clearance of Different Klebsiella pneumoniae Strains

Huizhong Xiong  1 , Rebecca A Carter  1 , Ingrid M Leiner  1 , Yi-Wei Tang  2 , Liang Chen  3 , Barry N Kreiswirth  3 , Eric G Pamer  4
Affiliations

VSports手机版 - Distinct Contributions of Neutrophils and CCR2+ Monocytes to Pulmonary Clearance of Different Klebsiella pneumoniae Strains

Huizhong Xiong et al. Infect Immun. 2015 Sep.

Abstract

Klebsiella pneumoniae is a common respiratory pathogen, with some strains having developed broad resistance to clinically available antibiotics. Humans can become infected with many different K. pneumoniae strains that vary in genetic background, antibiotic susceptibility, capsule composition, and mucoid phenotype. Genome comparisons have revealed differences between K. pneumoniae strains, but the impact of genomic variability on immune-mediated clearance of pneumonia remains unclear. Experimental studies of pneumonia in mice have used the rodent-adapted 43816 strain of K. pneumoniae and demonstrated that neutrophils are essential for optimal host defense. It remains unclear, however, whether CCR2(+) monocytes contribute to K. pneumoniae clearance from the lung. We selectively depleted neutrophils, CCR2(+) monocytes, or both from immunocompetent mice and determined susceptibility to infection by the 43816 strain and 4 newly isolated clinical K. pneumoniae strains VSports手机版. The clinical K. pneumoniae strains, including one carbapenem-resistant ST258 strain, are less virulent than 43816. Optimal clearance of each of the 5 strains required either neutrophils or CCR2(+) monocytes. Selective neutrophil depletion markedly worsened infection with K. pneumoniae strain 43816 and three clinical isolates but did not increase susceptibility of mice to infection with the carbapenem-resistant K. pneumoniae ST258 strain. Depletion of CCR2(+) monocytes delayed recovery from infection with each of the 5 K. pneumoniae strains, revealing a contribution of these cells to bacterial clearance from the lung. Our findings demonstrate strain-dependent variation in the contributions of neutrophils and CCR2(+) monocytes to clearance of K. pneumoniae pulmonary infection. .

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"V体育官网入口" Figures

FIG 1
FIG 1
LD50s of different K. pneumoniae strains upon intratracheal inoculation of mice. WT C57BL/6 mice were inoculated intratracheally (i.t.) with increasing doses of each isolate. The survival rates were determined on day 7 postinfection, and the LD50s were calculated.
FIG 2
FIG 2
Time course of bacterial clearance in the lung. WT animals were inoculated i.t. with different strains at a dose of 0.1 LD50. At the designated time points, the mice were sacrificed. The lungs were perfused, homogenized, and plated following serial dilution to determine the bacterial burden, which was plotted as CFU.
FIG 3
FIG 3
Neutrophil and CCR2+ monocyte recruitment to the lung. (A) Representative flow cytometry plots showing Ly6C+ CD11b+ monocytes and histograms of TNF-α expression by activated monocytes in the lung at 24 h following infection. WT animals were inoculated i.t. with different K. pneumoniae strains at a dose of 0.1 LD50. The lung was homogenized, and the cellular infiltrates were stained and analyzed by flow cytometry. Uninf, uninfected. (B) Representative flow cytometry plots showing Ly6G+ CD11b+ neutrophils and their TNF-α expression from the same experiments. (C) Quantification of neutrophil and monocyte numbers in the lung at 24 and 48 h following infection (n = 4 per group).
FIG 4
FIG 4
H&E staining of infected lungs at 24 h following infection. Magnification, ×63. Scale bar, 50 μm. Blue arrows, type I pneumocytes; black arrows, type II pneumocytes; green arrow, alveolar macrophage; orange arrows, infiltrating leukocytes.
FIG 5
FIG 5
Effects of cell depletion on bacterial clearance. Animals undergoing cell depletion were inoculated i.t. with Kp-MH189 (A), Kp-MH1867 (B), Kp-MH225 (C), Kp-MH258 (D), or 43816 (E) at a dose of 0.1 LD50. At 24 h following infection, lung homogenates were plated, and the relative changes in CFU were determined by comparison to the isotype control (n = 5 for each group). Statistical analysis was carried out by comparing the absolute values of CFU of each treatment to those of the isotype control.
FIG 6
FIG 6
Weight changes following infection and cell depletion. (A) Schematic of the experiment. (B to F) The animals undergoing cell depletion were challenged with Kp-MH189 (B), Kp-MH1867 (C), Kp-MH225 (D), Kp-MH258 (E), or 43816 (F) at a dose of 0.1 LD50. The relative weight changes of mice were determined by comparison to the initial weight on day 0 (100). Each symbol represents one treatment group. Each death, the day it occurred, and its group are indicated as symbols at the top of each graph (n = 5 for each group).
FIG 7
FIG 7
Survival rates following infection and cell depletion. Mice undergoing cell depletion were inoculated with Kp-MH189 (A), Kp-MH1867 (B), Kp-MH225 (C), Kp-MH258 (D), or 43816 (E) at a dose of 0.1 LD50. The survival rates on day 7 following infection were plotted (n = 5 for each group).
FIG 8
FIG 8
Bacterial burden in the surviving animals from the experiment for Fig. 6 were euthanized on day 7, lung homogenates were plated, and CFU were quantified. N.A, the whole group of mice died before day 7 so it was not possible to assess the CFU at the endpoint.
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