title: Improved control of tuberculosis and activation of macrophages in mice lacking protein kinase R.
abstract: Host factors that microbial pathogens exploit for their propagation are potential targets for therapeuic countermeasures. No host enzyme has been identified whose genetic absence benefits the intact mammalian host in vivo during infection with Mycobacterium tuberculosis (Mtb), the leading cause of death from bacterial infection. Here, we report that the dsRNA-dependent protein kinase (PKR) is such an enzyme. PKR-deficient mice contained fewer viable Mtb and showed less pulmonary pathology than wild type mice. We identified two potential mechanisms for the protective effect of PKR deficiency: increased apoptosis of macrophages in response to Mtb and enhanced activation of macrophages in response to IFN-gamma. The restraining effect of PKR on macrophage activation was explained by its mediation of a previously unrecognized ability of IFN-gamma to induce low levels of the macrophage deactivating factor interleukin 10 (IL10). These observations suggest that PKR inhibitors may prove useful as an adjunctive treatment for tuberculosis.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Kangyun
authors.initials: K
authors.lastname: Wu
authors.forename: Jovanka
authors.initials: J
authors.lastname: Koo
authors.forename: Xiuju
authors.initials: X
authors.lastname: Jiang
authors.forename: Ran
authors.initials: R
authors.lastname: Chen
authors.forename: Stanley N
authors.initials: SN
authors.lastname: Cohen
authors.forename: Carl
authors.initials: C
authors.lastname: Nathan
mesh_terms: D000818:Animals; D017209:Apoptosis; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D009169:Mycobacterium tuberculosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy* / Q000517:prevention & control; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency*
chemical_list: D047428:Protein Kinase Inhibitors; D016753:Interleukin-10; D007371:Interferon-gamma; D019892:eIF-2 Kinase