Editors' ChoiceInfectious Disease

Deterring zoster

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Science Translational Medicine  30 Aug 2017:
Vol. 9, Issue 405, eaao4217
DOI: 10.1126/scitranslmed.aao4217


Germline mutations in RNA polymerase III cause susceptibility to life-threatening varicella zoster infection.

Cytosolic virus sensors detect pathogen-associated molecular patterns (PAMPs), including viral RNA and DNA. Activation of downstream signaling molecules leads to induction of the type I interferon (IFN) response and up-regulation of antiviral IFN-stimulated genes that limit virus infection and spread. Failure to activate this antiviral response can be catastrophic for the infected host, as occurs when rare mutations in virus sensors lead to life-threatening infection.

In a recent issue of The Journal of Clinical Investigation, Ogunjimi et al. sought to determine why otherwise healthy children can sometimes develop life-threatening varicella zoster (VZV) infections involving the central nervous system or the lung. Upon analysis of the exome sequences of 21 children with extremely rare, life-threatening VZV infections, the authors found that four had rare mutations in RNA polymerase 3A (POLR3A) or RNA polymerase 3C (POLR3C), or both. Since these genes are involved in the cytosolic detection of viral DNA, the authors studied the response of patient cells to RNA and DNA PAMPs. They found that peripheral blood mononuclear cells from these patients exhibited a defective type I IFN response to AT-rich DNA from the VZV genome and that transcomplementation of cells with wild-type POLR3A and POLR3C alleles restored the antiviral response in patient cells.

Since some patients had mutations in more than one gene (POLR3A and POLR3C), it is difficult to precisely determine the relative contributions of each mutation, or to say with certainty whether one mutation may be sufficient to confer risk. Nevertheless, this study by Ogunjimi et al. is the first demonstration that a viral DNA sensor can prevent life-threatening viral infection in humans.

Aside from POLR3A/POLR3C, the cGAS-STING pathway also can detect viral DNA. However, the findings here suggest that an intact cGAS-STING pathway fails to limit VZV infection in these patients. Why the POLR3A/POLR3C genes are so specifically important for VZV infection is unclear, but it could be explained by unique AT-rich features of VZV genome that are preferentially detected by POLR3A/POLR3C. Alternatively, susceptibility to VZV might be due to distinct contributions of DNA-sensing pathways in specific cell types or VZV-mediated antagonism of alternative DNA-sensing pathways, which might leave POLR3A/POLR3C as a last line of defense.

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