Deciphering the Role of Macrophage Subsets and Macrophage-Derived Factors During Arthrogenic Alphaviral Infection

Abstract

The current situation of global warming has a serious impact on the control of arthropod-borne infectious diseases. Climate change has led to an increase in conducive breeding habitats for mosquitoes. This change in climate has contributed to the widespread distribution of mosquito-transmitted arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV). RRV is currently endemic to Australia and Papua New Guinea, while CHIKV causes global outbreaks. The recent CHIKV outbreak in the Americas has taken the world by surprise and has affected more than 1 million individuals as of early 2015. To date, there are no specific therapeutics strategies available for the treatment of alphaviral diseases, largely due to the ill-defined innate immune responses elicited by these viruses. This thesis describes new insights into the alphavirus-elicited immune response at the cellular and molecular levels using in vitro, in vivo and ex vivo experimental approaches. In these studies, we identified the differential role of macrophages in modulating the RRV disease progression through an atypical IL-10-dependent M1/M2 polarisation of inflammatory monocytes. RRV-induced differentiation of M1 macrophages triggered the pathogenic inflammatory processes giving rise to the onset of disease, while M2 macrophages were shown to play a protective role.