title: Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.
abstract: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1β, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18Rα on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.
authors.affiliation: Centre of Excellence for Research in AIDS, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia;
authors.forename: Hong Yien
authors.initials: HY
authors.lastname: Tan
authors.affiliation: Centre of Excellence for Research in AIDS, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia;
authors.forename: Yean Kong
authors.initials: YK
authors.lastname: Yong
authors.affiliation: Centre of Excellence for Research in AIDS, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; Tropical Infectious Diseases Research and Education Center, Department of Medical Microbiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia;
authors.forename: Esaki M
authors.initials: EM
authors.lastname: Shankar
authors.affiliation: Centre for Biomedical Research, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria 3004, Australia;
authors.forename: Geza
authors.initials: G
authors.lastname: Paukovics
authors.affiliation: Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden;
authors.forename: Rada
authors.initials: R
authors.lastname: Ellegård
authors.affiliation: Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden;
authors.forename: Marie
authors.identifier: 0000-0002-4524-0177
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Centre of Excellence for Research in AIDS, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; Infectious Disease Unit, Department of Medicine, University of Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia;
authors.forename: Adeeba
authors.initials: A
authors.lastname: Kamarulzaman
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia 6009, Australia; Department of Clinical Immunology, Royal Perth Hospital, Perth, Western Australia 6000, Australia; crowe@burnet.edu.au martyn.french@uwa.edu.au.
authors.forename: Martyn A
authors.identifier: 0000-0002-4644-1982
authors.initials: MA
authors.lastname: French
authors.affiliation: Centre for Biomedical Research, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria 3004, Australia; Infectious Diseases Unit, Alfred Hospital, Melbourne, Victoria 3004, Australia; and Department of Infectious Diseases, Monash University, Melbourne, Victoria 3004, Australia crowe@burnet.edu.au martyn.french@uwa.edu.au.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Crowe
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death; D000066673:Cell Self Renewal / Q000276:immunology*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood; D013577:Syndrome; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy / Q000276:immunology*
chemical_list: C410167:AIM2 protein, human; D044966:Anti-Retroviral Agents; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009569:Nitric Oxide; D020170:Caspase 1