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.
Highlights
In an era when the spread of antibiotic resistance has outpaced the introduction of new anti-infectives, attention has turned to the possibility of directing adjunctive anti-infective therapy against temporarily dispensable targets in the host [1]
We discovered that PKR-deficient macrophages underwent more apoptosis than wild type macrophages when infected with Mycobacterium tuberculosis (Mtb) in vivo and in vitro, and produced more isoform of nitric oxide synthase (iNOS) and TNF-alpha in response to IFNgamma
Impact of PKR Deficiency on Tuberculosis To determine the impact of PKR deficiency on tuberculosis, we compared the bacterial burden in Mtb-infected wild type and PKR-deficient mice up to 168 days after low-dose infection by aerosol (Figure 1A)
Summary
In an era when the spread of antibiotic resistance has outpaced the introduction of new anti-infectives, attention has turned to the possibility of directing adjunctive anti-infective therapy against temporarily dispensable targets in the host [1]. If a drug does not act on the pathogen, the pathogen cannot become resistant based on the usual mechanisms: impaired drug uptake or retention, reduced drug activation, increased drug inactivation, or the mutation, over-expression or bypass of the target. This notion has lent increased interest to studying the biology of host-pathogen relationships by identifying cellular (host) genes exploited by pathogens (CGEPs) [2,3]. The first CGEPs for a mycobacterium were identified when an RNAi screen confirmed the importance of phagocytic recognition and uptake machinery for M. fortuitum infection of a cell line from drosophila [4]. RNAi screens against all known kinases and phosphatases in a mouse macrophage cell line [6] and against all genes in a human macrophage cell line [7] identified numerous candidate CGEPs for Mtb
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