Editors' ChoiceInfectious Disease

How to straighten out that which bends up

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Science Translational Medicine  29 Mar 2017:
Vol. 9, Issue 383, eaan0773
DOI: 10.1126/scitranslmed.aan0773

Abstract

Chikungunya virus requires host granzyme A to drive joint inflammation.

Chikungunya virus (CHIKV) infection is characterized by high fevers, followed by severe, debilitating joint pain. Although viremia and fevers typically resolve over the first week of infection, the rheumatic manifestations can last for months. In fact, chikungunya means “that which bends up” in the Kimakonde language, in reference to patients’ contorted postures. In the last decade, CHIKV has spread globally, infecting millions. Joint manifestations are common, and some individuals will go on to develop chronic, destructive joint disease that mimics rheumatoid arthritis. With no vaccine or specific treatments available, the health and economic consequences are substantial.

Now, Wilson and colleagues demonstrate that granzyme A plays a key role in the rheumatic complications of CHIKV. The investigators began their quest to identify new players in CHIKV arthritis by performing transcriptional profiling of lymph nodes and hind feet from infected mice. As had been described in people, there was a pronounced type I interferon response, which persisted in the inflamed feet of the mice even after viremia had subsided. What stood out to the authors was the prominent induction of granzymes A, B, and K. These are serine proteases secreted by NK cells and cytotoxic T cells, cells known to infiltrate CHIKV-infected tissue. Remarkably, the authors found that granzyme A knock-out mice were dramatically protected from joint inflammation, demonstrating that granzyme A is not simply a biomarker of disease but actually drives disease pathogenesis. Granzyme A deficiency had no effect on the level of the virus but substantially reduced the infiltration of NK cells and T cells into infected feet. Key remaining questions are how granzyme A promotes inflammation and whether it is also a driver in noninfectious arthritis.

Additional findings suggest that granzyme A inhibition could be translated into new therapies for CHIKV. Granzyme A was also elevated in serum of nonhuman primates and symptomatic patients infected with CHIKV. In mice, a granzyme A inhibitor, Serpin b6b, ameliorated joint inflammation when it was administered at the time of peak viremia. Thus, intervention with granzyme A inhibitors as soon as patients develop fevers could potentially avert subsequent joint disease and straighten out “that which bends up.”

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