Arginine deficiency is involved in thrombocytopenia and immunosuppression in severe fever with thrombocytopenia syndrome

Xiao Kun Li, Qing Bin Lu, Wei Wei Chen, Wen Xu, Rong Liu, Shao Fei Zhang, Juan Du, Hao Li, Ke Yao, Di Zhai, Pan He Zhang, Bo Xing, Ning Cui, Zhen Dong Yang, Chun Yuan, Xiao Ai Zhang, Zhe Xu, Wu Chun Cao, Zeping Hu, Wei Liu

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) caused by a recently identified bunyavirus, SFTSV, is an emerging infectious disease with extensive geographical distribution and high mortality. Progressive viral replication and severe thrombocytopenia are key features of SFTSV infection and fatal outcome, whereas the underlying mechanisms are unknown. We revealed arginine deficiency in SFTS cases by performing metabolomics analysis on two independent patient cohorts, suggesting that arginine metabolism by nitric oxide synthase and arginase is a key pathway in SFTSV infection and consequential death. Arginine deficiency was associated with decreased intraplatelet nitric oxide (Plt-NO) concentration, platelet activation, and thrombocytopenia. An expansion of arginase-expressing granulocytic myeloid-derived suppressor cells was observed, which was related to T cell CD3-z chain down-regulation and virus clearance disturbance, implicating a role of arginase activity and arginine depletion in the impaired anti-SFTSV T cell function. Moreover, a comprehensive measurement of arginine bioavailability, global arginine bioavailability ratio, was shown to be a good prognostic marker for fatal prediction in early infection. A randomized controlled trial demonstrated that arginine administration was correlated with enhanced Plt-NO concentration, suppressed platelet activation, and elevated CD3-z chain expression and eventually associated with an accelerated virus clearance and thrombocytopenia recovery. Together, our findings revealed the arginine catabolism pathway-associated regulation of platelet homeostasis and T cell dysregulation after SFTSV infection, which not only provided a functional mechanism underlying SFTS pathogenesis but also offered an alternative therapy choice for SFTS.

Original languageEnglish (US)
Article numbereaat4162
JournalScience Translational Medicine
Volume10
Issue number459
DOIs
StatePublished - Sep 19 2018
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Li, X. K., Lu, Q. B., Chen, W. W., Xu, W., Liu, R., Zhang, S. F., Du, J., Li, H., Yao, K., Zhai, D., Zhang, P. H., Xing, B., Cui, N., Yang, Z. D., Yuan, C., Zhang, X. A., Xu, Z., Cao, W. C., Hu, Z., & Liu, W. (2018). Arginine deficiency is involved in thrombocytopenia and immunosuppression in severe fever with thrombocytopenia syndrome. Science Translational Medicine, 10(459), [eaat4162]. https://doi.org/10.1126/scitranslmed.aat4162