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Peripheral serotonin causes dengue-induced thrombocytopenia through 5HT2 receptors

Mohamad Fadhli Bin Masri, Chinmay Kumar Mantri, Abhay P.S. Rathore and Ashley L. St. John

Key points

  • We identified peripheral serotonin derived from mast cells to be required for dengue virus-induced thrombocytopenia.

  • Therapeutic targeting of platelet 5HT2 receptors reversed platelet activation, aggregation, splenic platelet uptake and thrombocytopenia.

Abstract

Dengue virus (DENV) is the most prevalent vector-borne viral pathogen, infecting millions of patients annually. Thrombocytopenia, a reduction in circulating platelet counts, is the most consistent sign of DENV-induced disease, independent of disease severity. However, the mechanisms leading to DENV-induced thrombocytopenia are unknown. Here, we show that thrombocytopenia is caused by serotonin, derived from mast cells (MCs), which are immune cells that are present in the perivascular space and a major peripheral source of serotonin. We show that during DENV infection, MCs release serotonin, which prompts platelet activation, aggregation and enhanced phagocytosis, dependent on 5HT2A receptors. MC-deficiency in mice or pharmacological inhibition of MCs reversed thrombocytopenia. Furthermore, reconstitution of MC-deficient mice with wild-type MCs, but not MCs lacking serotonin synthesis due to deficiency in the enzyme tryptophan hydroxylase-1 (TPH1), restored the thrombocytopenic phenotype. Exogenous serotonin was also sufficient to overcome the effects of drugs that inhibit platelet activation in vitro and to restore thrombocytopenia in DENV-infected MC-deficient mice. Therapeutic targeting of 5HT2A receptors during DENV infection effectively prevented thrombocytopenia in mice. Similarly, serotonin derived from DENV-activated human MCs led to increased human platelet activation. Thus MC-derived serotonin is a previously unidentified mechanism of DENV-induced thrombocytopenia and a potential therapeutic target.

  • Submitted August 15, 2018.
  • Accepted February 6, 2019.