TY - JOUR
T1 - Arginine deficiency is involved in thrombocytopenia and immunosuppression in severe fever with thrombocytopenia syndrome
AU - Li, Xiao Kun
AU - Lu, Qing Bin
AU - Chen, Wei Wei
AU - Xu, Wen
AU - Liu, Rong
AU - Zhang, Shao Fei
AU - Du, Juan
AU - Li, Hao
AU - Yao, Ke
AU - Zhai, Di
AU - Zhang, Pan He
AU - Xing, Bo
AU - Cui, Ning
AU - Yang, Zhen Dong
AU - Yuan, Chun
AU - Zhang, Xiao Ai
AU - Xu, Zhe
AU - Cao, Wu Chun
AU - Hu, Zeping
AU - Liu, Wei
N1 - Publisher Copyright:
Copyright © 2018 The Authors, some rights reserved.
PY - 2018/9/19
Y1 - 2018/9/19
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aat4162
DO - 10.1126/scitranslmed.aat4162
M3 - Article
C2 - 30232226
AN - SCOPUS:85053529101
SN - 1946-6234
VL - 10
JO - Science translational medicine
JF - Science translational medicine
IS - 459
M1 - eaat4162
ER -