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.

Cell death and autophagy in tuberculosis

“…These data suggest that the host-protective role of macrophage apoptosis in TB may be restricted in time and tissue compartment, following the induction of adaptive immunity and in the period when bacterial burden in the lung is normally held at a plateau level in wild-type mice infected with wild-type Mtb . That notion is supported by data from aerosol infection of protein kinase R (PKR) −/− mice [75]. These mice exhibit increased macrophage apoptosis during TB and have lower lung CFU than wild-type mice at 70 days post-infection but not at 21 days.…”

Advancing host-directed therapy for tuberculosis

“…However, deletion of PKR in mice results in improved control of intracellular M. tuberculosis infection, as well as increased macrophage apoptosis, enhanced expression of tumour necrosis factor (TNF) and inducible nitric oxide synthase in response to IFNγ, and reduced production of the immunosuppressive cytokine interleukin-10 (IL-10) 36 . Although there are currently no small-molecule PKR inhibitors, this enzyme is a potential tuberculosis HDT target.…”

Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

“…The Alox5 2/2 mice are also more resistant to Mtb infection (Bafica et al 2005;Divangahi et al 2010). Finally, mice deficient in the protein kinase R (Pkr) gene are more resistant to Mtb infections, and this correlates with higher levels of apoptosis in infected macrophages (Wu et al 2012).…”