THESIS DEFENSE — PUBLIC SEMINAR: MAST CELL SEROTONIN PROMOTES THROMBOCYTOPENIA DURING DENGUE VIRUS INFECTION

Start Date & Time: 
Wednesday, 10 October, 2018 - 09:30
End Date & Time: 
Wednesday, 10 October, 2018 - 10:30
Venue: 

Meeting Room 7C, Level 7, Duke-NUS

Speaker Details: 

MOHAMAD FADHLI BIN MASRI
IBM PhD PROGRAM (INTAKE 2014)

Synopsis: 

Dengue fever is currently the most prevalent vector-borne viral disease and is caused by dengue virus (DENV). Thrombocytopenia, a reduction in platelet counts, is a consistent sign of DENV-induced disease, independent of disease severity. However, the mechanisms leading to DENV-induced thrombocytopenia are not well understood. Mast cells (MCs), immune cells present in the perivascular space, have been implicated in dengue pathogenesis, though their involvement in thrombocytopenia remains unknown. To understand the contribution of MCs to DENV-induced thrombocytopenia, we infected various mouse models with DENV. Through genetic and pharmacological approaches, we showed that MCs promote thrombocytopenia through increasing platelet activation, aggregation and uptake by splenic macrophages. Furthermore, reconstitution of MC-deficient mice with wild-type MCs, but not MCs lacking serotonin synthesis, resulted in thrombocytopenia. We showed that during DENV infection, MCs release serotonin which promotes thrombocytopenia, dependent on platelet 5HT2A receptors. Targeting 5HT2A receptors during DENV infection prevented thrombocytopenia in mice. We validated our findings by showing that MC serotonin and DENV caused increased activation of human platelets. Our findings have identified that the interaction between MCs and platelets, dependent on the release of serotonin from MCs, contributes to thrombocytopenia during DENV infection, highlighting a potential therapeutic target of disease.

Thesis Advisor: Asst. Prof. Ashley St. John