title: HspX knock-out in Mycobacterium tuberculosis leads to shorter antibiotic treatment and lower relapse rate in a mouse model--a potential novel therapeutic target.
abstract: Effective global tuberculosis control is hindered by the need for prolonged chemotherapy which leads to poor patient compliance. Therefore novel drug targets that shorten the duration of chemotherapy and reduce disease relapse rates are highly desirable. We have previously shown that HspX, an alpha-crystallin-like protein, is associated with growth suppression of Mycobacterium tuberculosis in mouse models. We determined to evaluate hspX as a novel target for controlling M. tuberculosis growth in combination with traditional antibiotic therapy in the Cornell mouse model. The hspX deletion mutant (ΔhspX) was used as a model of potential hspX inhibition. Normal BALB/c mice were infected with ΔhspX or the wild type (WT) strain. Three weeks after infection, the mice were treated with rifampicin, isoniazid and pyrazinamide for 14 weeks followed by 8 weeks of hydrocortisone. The effect of chemotherapy was measured by organ bacterial counts and the relapse rate. Antibiotic treatment of mice infected with ΔhspX resulted in faster visceral clearance; organs were disease free 8 weeks post-treatment for ΔhspX infection compared to 14 weeks for the WT strain. Disease relapse rate was significantly lower in ΔhspX infection (60.7%) compared to WT infection (92.6%). HspX may be a promising therapeutic target in combination with traditional antibiotic therapy to shorten the length of treatment and reduce disease relapse.
authors.affiliation: Institute of Infection and Immunity, St George's, University of London, United Kingdom. Electronic address: ymhu@sgul.ac.uk.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Hu
authors.affiliation: University of Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Preventive Medicine, School of Medicine, Autonoma University of Madrid, Madrid, Spain.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Menendez
authors.affiliation: Department of Preventive Medicine, School of Medicine, Autonoma University of Madrid, Madrid, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Garcia
authors.affiliation: School of Medicine, University of St Andrews, United Kingdom.
authors.forename: Katarina
authors.initials: K
authors.lastname: Oravcova
authors.affiliation: School of Medicine, University of St Andrews, United Kingdom.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gillespie
authors.affiliation: Institutes of Global Health & Translational Medicine, University of Liverpool, United Kingdom.
authors.forename: Gerry R
authors.initials: GR
authors.lastname: Davies
authors.affiliation: Institute of Infection and Immunity, St George's, University of London, United Kingdom.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Mitchison
authors.affiliation: Institute of Infection and Immunity, St George's, University of London, United Kingdom.
authors.forename: Anthony R M
authors.initials: AR
authors.lastname: Coates
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D055786:Gene Knockout Techniques; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000235:genetics; D012008:Recurrence; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*; D014400:Tuberculosis, Splenic / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C118127:HspX protein, Mycobacterium tuberculosis; D007166:Immunosuppressive Agents; C021650:hydrocortisone acetate; D006854:Hydrocortisone
keywords: Mouse model; Mycobacterium tuberculosis; Treatment; hspX knock-out mutant