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Bacterial Infections

Brucella neotomae Recapitulates Attributes of Zoonotic Human Disease in a Murine Infection Model

Yoon-Suk Kang, Daniel A. Brown, James E. Kirby
Craig R. Roy, Editor
Yoon-Suk Kang
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
bHarvard Medical School, Boston, Massachusetts, USA
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Daniel A. Brown
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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James E. Kirby
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
bHarvard Medical School, Boston, Massachusetts, USA
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Craig R. Roy
Yale University School of Medicine
Roles: Editor
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DOI: 10.1128/IAI.00255-18
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    FIG 1

    Virulence of B. neotomae in BALB/c mice. (A) Two groups of eight mice each were infected i.p. with a low dose (106 CFU) or a high dose (108 CFU) of B. neotomae. Survival was monitored for 2 weeks. (B) Representative image of liver 14 days after high-dose infection in a surviving mouse. The arrows indicate white-tinged granulomas or microabscesses on the liver surface.

  • FIG 2
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    FIG 2

    VirB T4SS contributes to pathogenesis. (A to C) Bacterial CFU in liver, spleen, and thymus. (D and E) B. neotomae genome copies in liver and spleen. The data shown are the medians and interquartile ranges for five mice per group. #, significant difference between wild-type and ΔvirB4 bacterial infections using Dunn’s posttest. There were no statistically significant differences for either CFU or genome copies between wild-type and complemented virB4 (virB4c) infections at any time point. (F) Liver and spleen weights during infection. The data shown are medians and interquartile ranges for five mice per group. #, significant difference between both wild-type and virB4c infections and uninfected controls. Liver and spleen weights were not statistically different between ΔvirB4 strain-infected mice and uninfected control mice at any time point. (G) Representative spleens from infections with wild-type (T4SS+) or ΔvirB4 (T4SS−) strains. Significant splenic enlargement was noted 7 and 14 days following wild-type bacterial infection. Scale bar = 1 cm. (H) Small-animal imaging following infection with bacterial strains with a luciferase operon reporter. The color bar is scaled to a minimum and maximum of 2.0 × 104 and 1.5 × 106 p/s/cm2/sr, respectively. Two of three mice per infecting strain with maximal signal are shown. Bacterial inocula in all experiments were 107 per mouse by intraperitoneal injection.

  • FIG 3
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    FIG 3

    Histopathology of B. neotomae infection. (A and B) Granulomatous inflammation (arrows) 3 days (A) and necrotizing granuloma (arrow) 7 days (B) postinfection with wild-type B. neotomae. (C) Splenic white-pulp expansion 7 days postinfection with wild-type organisms (w, white pulp; r, red pulp; h, histiocytes). (D) In contrast, white-pulp expansion was not evident following ΔvirB4 bacterial infection. (E and F) Splenic infarct gross pathology (E) and associated microscopic pathology with evidence of tissue necrosis (F) 14 days postinfection with wild-type organisms. (G) (Top) Immunofluorescence microscopy demonstrating intracellular clusters of B. neotomae organisms within hepatic granulomas 3 days postinfection with the wild-type strain. (Left) Fluorescent image of bacteria expressing tdTomato fluorescent reporter. (Right) Merged bright-field and gray-scale images. (Bottom) In contrast, only very rare organisms were observed following infection with the ΔvirB4 strain, generally as single organisms or very small clusters (arrows), likely within Kupffer cells lining sinusoidal spaces. Bars = 5 µm.

  • FIG 4
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    FIG 4

    Transmission electron microscopy images of hepatic infection. (A) Hepatic granuloma 3 days postinfection, composed of concentric histiocytes. (B) A central histiocyte appears necrotic and contains a replicative phagosome, inside of which are multiple bacteria. (C to E) B. neotomae bacteria replicating inside membrane-bound phagosomes (arrowheads) 7 days postinfection (C) and also found in multilaminar phagosomes (D, arrows) suggestive of autophagosomes or autophagolysosomes in close association with rough endoplasmic reticulum (E, arrows).

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    FIG 5

    Cytokine gene expression. Cytokine and Toll-like receptor mRNA gene expression was determined in liver and spleen at the indicated times postinfection by reverse transcriptase qPCR. Expression was normalized to actin gene expression within each sample to control for efficiency of mRNA extraction. The data points are plotted relative to the median gene expression from uninfected mice and represent the medians and interquartile ranges of values from five mice per group. w, significant difference between wild-type bacterial infection and a mock-infected control; c, significant difference between virB4c infection and an uninfected control; b, significant difference between ΔvirB4 bacterial infection and an uninfected control.

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Brucella neotomae Recapitulates Attributes of Zoonotic Human Disease in a Murine Infection Model
Yoon-Suk Kang, Daniel A. Brown, James E. Kirby
Infection and Immunity Dec 2018, 87 (1) e00255-18; DOI: 10.1128/IAI.00255-18

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Brucella neotomae Recapitulates Attributes of Zoonotic Human Disease in a Murine Infection Model
Yoon-Suk Kang, Daniel A. Brown, James E. Kirby
Infection and Immunity Dec 2018, 87 (1) e00255-18; DOI: 10.1128/IAI.00255-18
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KEYWORDS

Brucella
Brucella neotomae
brucellosis
bioluminescent imaging
murine model
pathogenesis
pathology
type IV secretion system
undulant fever

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