Mackman to lead 4-year $1.5-million award study into role of clotting protease and receptor in the innate immune response to viral infections

UNC receives $1.5-million grant to study the role of a clotting protease and receptor in the innate immune response to viral infections. Nigel Mackman, PhD, Distinguished Professor of Medicine, and joint Professor of Pharmacology, is the principal investigator of a 4-year $1.5-million award from the National Heart Lung and Blood Institute. This grant will determine the role of thrombin activation of protease-activated receptor 1 in the innate immune response to viral infections.

Mackman to lead 4-year $1.5-million award study into role of clotting protease and receptor in the innate immune response to viral infections click to enlarge Dr. Nigel Mackman

UNC receives $1.5-million grant to study the role of a clotting protease and receptor in the innate immune response to viral infections. Nigel Mackman, PhD, Distinguished Professor of Medicine,and joint Professor of Pharmacology, is the principal investigator of a 4-year, $1.5-million award from the National Heart, Lung, and Blood Institute. This grant will determine the role of thrombin activation of protease-activated receptor 1 in the innate immune response to viral infections. 

Viral infections cause considerable morbidity and mortality worldwide. The clotting system is activated as part of the host response to viral infection. However, excessive activation of coagulation can contribute to pathology associated with viral infections. For instance, after infection with hemorrhagic fever viruses, such as Ebola, consumption of clotting factors leads to secondary hemorrhage.  In contrast, HIV patients have a chronic activation of coagulation that increases cardiovascular disease.

The Mackman team found that mice deficient in the thrombin receptor called protease-activated receptor-1 (PAR-1) were more susceptible to infection with either Coxsackievirus B3 virus or influenza A/H1N1 virus. Similar results were observed in mice deficient in tissue factor or mice anticoagulated with the thrombin inhibitor dabigatran. They demonstrated that the tissue factor-thrombin-PAR-1 pathway enhanced TLR3-dependent expression of interferon beta, which plays a central role in coordinating the innate immune response to viral infections. Understanding how the clotting system and PAR-1 contributes to the host defense to viral infection may allow the identification of individuals with increased susceptibility to infection and may lead to the development of an agent to enhance antiviral pathways.