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doi: 10.1371/journal.pone.0043207. Epub 2012 Aug 15.

Development and characterization of a caprine aerosol infection model of melioidosis

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Development and characterization of a caprine aerosol infection model of melioidosis

Carl Soffler et al. PLoS One. 2012.

Abstract

Infection with Burkholderia pseudomallei causes the disease melioidosis, which often presents as a serious suppurative infection that is typically fatal without intensive treatment and is a significant emerging infectious disease in Southeast Asia. Despite intensive research there is still much that remains unknown about melioidosis pathogenesis. New animal models of melioidosis are needed to examine novel aspects of pathogenesis as well as for the evaluation of novel therapeutics. The objective of the work presented here was to develop a subacute to chronic caprine model of melioidosis and to characterize the progression of disease with respect to clinical presentation, hematology, clinical microbiology, thoracic radiography, and gross and microscopic pathology. Disease was produced in all animals following an intratracheal aerosol of 10(4) CFU delivered, with variable clinical manifestations indicative of subacute and chronic disease. Bronchointerstitial pneumonia was apparent microscopically by day 2 and radiographically and grossly apparent by day 7 post infection (PI). Early lesions of bronchopneumonia soon progressed to more severe bronchointerstitial pneumonia with pyogranuloma formation. Extrapulmonary dissemination appeared to be a function of pyogranuloma invasion of pulmonary vasculature, which peaked around day 7 PI. Histopathology indicated that leukocytoclastic vasculitis was the central step in dissemination of B. pseudomallei from the lungs as well as in the establishment of new lesions. While higher doses of organism in goats can produce acute fatal disease, the dose investigated and resulting disease had many similarities to human melioidosis and may warrant further development to provide a model for the study of both natural and bioterrorism associated disease.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Temperatures from selected goats.
Peaks in temperature are seen on days 1 and 2 and between days 6 and 9. Based on the temporospatial distribution of gross lesions, these peaks are likely associated with bacteremic dissemination events even though bacteremia was not detected with blood culture. BpG15 (square), BpG21 (circle), BpG22 (triangle), BpG27 (diamond).
Figure 2
Figure 2. Granulocyte counts from selected goats.
During the first half of the study, the granulocyte count appears to mirror the temperature trends seen in Figure 1. BpG15 (square), BpG21 (circle), BpG22 (triangle), BpG27 (diamond), RR High (dash-dot)/Low (dot-dot): reference range limits of normal caprine granulocyte count.
Figure 3
Figure 3. Thoracic and extirpated lung radiographs of goats infected with an intratracheal aerosol of
A) Goat 15, day 7, left lateral thorax with a mild bronchointerstitial pattern restricted to the caudal lung lobes. B) Goat 16, day 7, left lateral thorax with moderate to severe bronchointerstitial infiltrates with numerous ill-defined variably sized nodules in all lung lobes with the caudal lung lobes more affected. C) Goat 22, day 21, right lateral thorax with small nodules seen in all lung lobes and mild-moderate bronchointerstitial infiltrates diffusely. D) Goat 22, day 21, extirpated lungs, numerous nodules in all lung lobes, which are much more distinct than in the in vivo radiographs.
Figure 4
Figure 4. Gross and histologic lesions of caprine melioidosis.
A) Lung, multiple discrete subpleural targetoid pyogranulomas with tan purulent centers and consolidated hyperemic rims; B) a splenic subcapsular pyogranuloma bulging over the splenic surface with regional capsulitis and injected vessels; C) bronchiolar epithelium showing apical surface deciliation, segmental necrosis of the pseudostratified ciliated epithelium, neutrophil transcytosis, and luminal aggregates of neutrophils suspended in inflammatory edema; D) pulmonary septal thickening secondary to neutrophil infiltration; E) sever necrosuppurative/ulcerative tracheitis with neutrophil transcytosis and a mucosal abscess (inset); F) linear renal pyogranuloma extending from the cortex down into the medulla obliterating large areas of renal parenchyma. 4C–4F hematoxylin and eosin staining.
Figure 5
Figure 5. Caprine melioidosis vasculitides in multiple organs.
A) pulmonary pyogranuloma encroaching on large interlobular vein, resulting in a segmental leukocytoclastic vasculitis – unaffected endothelium is present on the contralateral side of the vessel; B) pulmonary vasculitis in a medium-sized artery demonstrating a clear separation of the tunica intima from the tunica media by neutrophils and macrophages with segmental intimal proliferation; C) splenic capsular vasculitis with perivascular neutrophilic infiltrate; D) vasocentric renal pyogranuloma showing neutrophil infiltration into the subintima and adventitia with endothelial proliferation and fibrinoid necrosis of a small renal vessel E) focal vasculitis and early pyogranuloma formation at the corticomedullary junction of the adrenal gland; F) leukocytoclastic arteritis in the testicle with an adjacent area of testicular degeneration showing diminished stratification of spermatogenic cells and interstitial suppurative orchitis. 5A–5F, hematoxylin and eosin staining.

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