title: xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation.
abstract: The physiological functions of macrophage, which plays a central role in the pathogenesis of tuberculosis, depend on its redox state. System xc-, a cystine-glutamate transporter, which consists of xCT and CD98, influences many ROS-dependent pathways by regulating the production of the antioxidant glutathione. xCT's ability to alter this critical host redox balance by increasing the glutathione synthesis aspect of phagocyte physiology suggested that it might influence tuberculosis pathogenesis. In this study, we found that the xCT expression was increased in peripheral blood monocyte of active tuberculosis. xCT expression in macrophage was induced by Mycobacterium tuberculosis (Mtb) through TLR2/Akt- and p38-dependent signaling pathway. Importantly, xCT deficiency conferred protection against tuberculosis, as xCT knock out mice displayed increased Mtb load and reduced pulmonary pathology in lung compared to wild type mice. xCT disruption enhanced the mycobateriacidal activity of macrophage through increasing the mycothiol oxidation. Importantly, chemical inhibition of xCT with sulfasalazine, a specific xCT inhibitor that is already approved by the FDA for treatment of inflammatory bowel disease, produces similar protective effects in vivo and in vitro, indicating xCT might be a novel and useful target for host-directed TB treatment strategy.
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.|Shenzhen Key Laboratory of Infection and Immunity, Shenzhen University School of Medicine, Shenzhen, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.|Shenzhen Key Laboratory of Infection and Immunity, Shenzhen University School of Medicine, Shenzhen, China.
authors.forename: Qianting
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.|Shenzhen Key Laboratory of Infection and Immunity, Shenzhen University School of Medicine, Shenzhen, China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Zhejiang University, Hangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.|Department of Immunology, Bengbu Medical College, Bengbu, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Subhalaxmi
authors.initials: S
authors.lastname: Nambi
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.|Shenzhen Key Laboratory of Infection and Immunity, Shenzhen University School of Medicine, Shenzhen, China.
authors.forename: Wenfei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.|Shenzhen Key Laboratory of Infection and Immunity, Shenzhen University School of Medicine, Shenzhen, China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Bengbu Medical College, Bengbu, China.
authors.forename: Junying
authors.initials: J
authors.lastname: Wu
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Guofang
authors.initials: G
authors.lastname: Deng
authors.affiliation: Shenzhen Key Laboratory of Infection and Immunity, Shenzhen University School of Medicine, Shenzhen, China.
authors.forename: Qunyi
authors.initials: Q
authors.lastname: Deng
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Centre for Tuberculosis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Liu
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.
authors.forename: Boping
authors.initials: B
authors.lastname: Zhou
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Centre for Tuberculosis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Department of Infectious Diseases and Immunology, Sydney Medical School, the University of Sydney, Sydney, NSW, Australia.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sassetti
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Zhejiang University, Hangzhou, China.
authors.forename: Fudi
authors.initials: F
authors.lastname: Wang
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.|Shenzhen Key Laboratory of Infection and Immunity, Shenzhen University School of Medicine, Shenzhen, China.|Centre for Tuberculosis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Chen
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors / Q000097:blood* / Q000276:immunology; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004198:Disease Susceptibility; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D012460:Sulfasalazine / Q000494:pharmacology; D014376:Tuberculosis / Q000097:blood* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
chemical_list: D027182:Amino Acid Transport System y+; D000890:Anti-Infective Agents; C118895:SLC7A11 protein, human; C492255:Slc7a11 protein, mouse; D012460:Sulfasalazine
keywords: immune; inflammatory; macrophage; tuberculosis; xCT