title: The Blood Transcriptome of Experimental Melioidosis Reflects Disease Severity and Shows Considerable Similarity with the Human Disease.
abstract: Melioidosis, a severe human disease caused by the bacterium Burkholderia pseudomallei, has a wide spectrum of clinical manifestations ranging from acute septicemia to chronic localized illness or latent infection. Murine models have been widely used to study the pathogenesis of infection and to evaluate novel therapies or vaccines, but how faithfully they recapitulate the biology of human melioidosis at a molecular level is not known. In this study, mice were intranasally infected with either high or low doses of B. pseudomallei to generate either acute, chronic, or latent infection and host blood and tissue transcriptional profiles were generated. Acute infection was accompanied by a homogeneous signature associated with induction of multiple innate immune response pathways, such as IL-10, TREM1, and IFN signaling, largely found in both blood and tissue. The transcriptional profile in blood reflected the heterogeneity of chronic infection and quantitatively reflected the severity of disease. Genes associated with fibrosis and tissue remodeling, including matrix metalloproteases and collagen, were upregulated in chronically infected mice with severe disease. Transcriptional signatures of both acute and chronic melioidosis revealed upregulation of iNOS in tissue, consistent with the expression of IFN-γ, but also Arginase-1, a functional antagonist of the iNOS pathway, and was confirmed by immunohistochemistry. Comparison of these mouse blood datasets by pathway and modular analysis with the blood transcriptional signature of patients with melioidosis showed that many genes were similarly perturbed, including Arginase-1, IL-10, TREM1, and IFN signaling, revealing the common immune response occurring in both mice and humans.
authors: Immunology and Infection Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
authors: Laura
authors: L
authors: Conejero
authors: The Francis Crick Institute, Mill Hill Laboratory, (formerly MRC National Institute for Medical Research), London, UK.
authors: Krzysztof
authors: K
authors: Potempa
authors: The Francis Crick Institute, Mill Hill Laboratory, (formerly MRC National Institute for Medical Research), London, UK.
authors: Christine M
authors: CM
authors: Graham
authors: Immunology and Infection Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
authors: Natasha
authors: N
authors: Spink
authors: The Francis Crick Institute, Mill Hill Laboratory, (formerly MRC National Institute for Medical Research), London, UK.
authors: Simon
authors: S
authors: Blankley
authors: School of Veterinary Medicine, University of Surrey, Guildford, UK.
authors: Francisco J
authors: FJ
authors: Salguero
authors: The Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Thailand.
authors: Rungnapa
authors: R
authors: Pankla-Sranujit
authors: The Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Thailand.
authors: Prasong
authors: P
authors: Khaenam
authors: The Jackson Laboratory, Farmington, CT, USA.
authors: Jacques F
authors: JF
authors: Banchereau
authors: Baylor Institute for Immunology Research, Thousand Oaks, Dallas, Texas, USA.
authors: Virginia
authors: V
authors: Pascual
authors: Damien Chaussabel, PhD, Director, Systems Biology Department, Sidra Medical and Research Center, Sidra Medical and Research Center, Al Nasr Tower, AL Corniche Street, Qatar Foundation ∣ PO Box 26999 ∣ Doha, Qatar.
authors: Damien
authors: D
authors: Chaussabel
authors: The Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Thailand.
authors: Ganjana
authors: G
authors: Lertmemongkolchai
authors: The Francis Crick Institute, Mill Hill Laboratory, (formerly MRC National Institute for Medical Research), London, UK.|NHLI, St. Mary's Hospital, Imperial College, London, UK.
authors: Anne
authors: A
authors: O'Garra
authors: Immunology and Infection Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
authors: Gregory J
authors: GJ
authors: Bancroft
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000097:blood; D016957:Burkholderia pseudomallei / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008554:Melioidosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000097:blood / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D059467:Transcriptome / Q000235:genetics; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: C556062:IL10 protein, mouse; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D016753:Interleukin-10; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C481673:Arg2 protein, mouse; D001119:Arginase