Evidence for dispensability of protein kinase R in host control of tuberculosis

Genetic deficiency of protein kinase R (PKR) in mice was reported to enhance macrophage activation in vitro in response to interferon‐γ (IFNγ) and to reduce the burden of Mycobacterium tuberculosis (Mtb) in vivo (Wu et al. PloS One. 2012 7 :e30512). Consistent with this, treatment of wild‐type (WT) macrophages in vitro with a novel PKR inhibitor (Bryk et al., Bioorg. Med. Chem. Lett. 2011 21 :4108–4114) also enhanced IFN‐γ–dependent macrophage activation (Wu et al. PloS One. 2012 7 :e30512). Here we show that co‐treatment with IFN‐γ and a new PKR inhibitor identified herein to be highly but not completely selective likewise induced macrophages to produce more reactive nitrogen intermediates (RNI) and tumor necrosis factor alpha (TNF‐α) and less interleukin 10 (IL‐10) than seen with IFN‐γ alone. Unexpectedly, however, this new PKR inhibitor had a comparable effect on PKR‐deficient macrophages. Retrospective investigation revealed that the PKR‐deficient mice in (Wu et al. PloS One. 2012 7 :e30512) had not been backcrossed. On comparing genetically matched PKR‐deficient and WT mice, we saw no impact of PKR deficiency on macrophage activation in vitro or during the course of Mtb infection in vivo. In addition, although 129S1/SvImJ macrophage responses to IFN‐γ were greater than those of C57BL/6J macrophages, PKR was not required to mediate the IFN‐γ–dependent production of IL‐10, RNI or TNF‐α in either strain. Together the data cast doubt on PKR as a potential therapeutic target for tuberculosis.