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

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-ζ 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-ζ 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.

Neutrophil Diversity in Health and Disease

“…The latter two types are usually defined as 'suppressive neutrophils' and, unlike LDNs/PMN-MDSCs that often contain immature elements [54,57,66], they are homogeneously composed of populations of mature activated cells [8,54] (Figure 2 and Box 1). Typical LDNs/PMN-MDSCs are observed in septic patients, as well as in those with fungal (e.g., Aspergillus fumigatus and C. albicans) and viral (e.g., bunyavirus and hepatitis C and B virus) infections [54,[67][68][69][70]; they have been shown to inhibit proliferation and interferon γ (IFN-γ) production by CD4 + and CD8 + T cells in vitro via ROS or arginase 1 (ARG1) production [54,[67][68][69][70]. However, their phenotype and functions are less well characterized than those of LDNs/PMN-MDSCs in pregnancy and cancer.…”

Emerging Applications of Metabolomics in Clinical Pharmacology

“…developed a targeted metabolomics method monitoring ~200 metabolites using a triple quadrupole mass spectrometer coupled to a high‐performance liquid chromatograph. This method has been widely adopted for mechanistic studies of cancer and infectious diseases targeting cell metabolism . In particular, the method is ultrasensitive and can detect ~60 metabolites from only 10,000 hematopoietic stem cells, which enables metabolomics profiling of rare cell populations .…”

“…Using a similar strategy, Hu et al . performed metabolic profiling of the serum samples from healthy subjects and patients infected with severe fever with thrombocytopenia syndrome (SFTS) virus.…”

“…This method has been widely adopted for mechanistic studies of cancer and infectious diseases targeting cell metabolism. [27][28][29][30] In particular, the method is ultrasensitive and can detect ~60 metabolites from only 10,000 hematopoietic stem cells, which enables metabolomics profiling of rare cell populations. 28 Recent studies have also utilized high resolution MS instruments such as Orbitrap and time-of-flight (TOF) for targeted metabolite quantification.…”

“…This work provided a potentially new strategy for targeted treatment of a subpopulation of SCLC. Using a similar strategy, Hu et al 30 performed metabolic profiling of the serum samples from healthy subjects and patients infected with severe fever with thrombocytopenia syndrome (SFTS) virus. This study aimed to understand the mechanisms underlying the clinical features, including progressive viral replication and severe thrombocytopenia, and identify a potential therapeutic target for a disease with high mortality but no specific therapeutics.…”