title: Low-dose exposure of C57BL/6 mice to burkholderia pseudomallei mimics chronic human melioidosis.
abstract: Burkholderia pseudomallei is the etiological agent of human melioidosis, a disease with a broad spectrum of clinical manifestations ranging from fatal septicemia to chronic localized infection or asymptomatic latent infection. Most clinical and immunological studies to date have focused on the acute disease process; however, little is known about pathology and immune response in chronic melioidosis. Here, we have developed a murine model of chronic disease by challenging C57BL/6 mice intranasally with a low dose of B. pseudomallei and monitoring them up to 100 days postinfection. Bacterial burdens were heterogeneous in different animals at all time points, consistent with the spectrum of clinical severity observed in humans. Proinflammatory cytokines such as gamma interferon (IFN-γ), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) were induced during chronic infection, and histopathological analysis showed features in common with human melioidosis. Interestingly, many of these features were similar to those induced by Mycobacterium tuberculosis in humans, such as development of a collagen cord that encapsulates the lesions, the presence of multinucleated giant cells, and granulomas with a caseous necrotic center, which may explain why chronic melioidosis is often misdiagnosed as tuberculosis. Our model now provides a relevant and practical tool to define the immunological features of chronic melioidosis and aid in the development of more effective treatment of this disease in humans.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Conejero
authors.forename: Natasha
authors.initials: N
authors.lastname: Patel
authors.forename: Melanie
authors.initials: M
authors.lastname: de Reynal
authors.forename: Sara
authors.initials: S
authors.lastname: Oberdorf
authors.forename: Joanne
authors.initials: J
authors.lastname: Prior
authors.forename: Philip L
authors.initials: PL
authors.lastname: Felgner
authors.forename: Richard W
authors.initials: RW
authors.lastname: Titball
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Salguero
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bancroft
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D016957:Burkholderia pseudomallei / Q000472:pathogenicity*; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015726:Giant Cells / Q000473:pathology; D006099:Granuloma / Q000209:etiology / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008554:Melioidosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D015850:Interleukin-6; D007371:Interferon-gamma; D003094:Collagen