From cells over organisms to populations - Characterization of outcomes of emerging alphavirus infections

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Alphaviruses cause severe acute and chronic disease in humans, including long-term debilitating arthralgia in the case of the epidemiologically most relevant alphavirus Chikungunya virus (CHIKV) that has by now spread across four continents, affecting millions of individuals. In Latin America, CHIKV meets two broadly distributed, likely expanding, antigenically related autochthonous alphaviruses, namely Mayaro (MAYV) and Una virus (UNAV). Because of the recent CHIKV introduction, Latin America is a unique setting to understand the fundamental properties underlying alphaviral spread and pathogenesis before adaptation to different vertebrate and invertebrate hosts complicates genomic and serologic analyses. Recently, matrix-remodeling-associated protein 8 (MXRA8) and four-and-a-half LIM domain protein 1 (FHL1) have emerged as key co-factors of alphavirus entry and RNA replication, enhancing our understanding of alphavirus-host interactions. However, the alphaviral immune interplay is poorly understood, challenging imminent alphavirus vaccination programmes. The COALITION project joins 2 German and 2 French PIs that are uniquely positioned to investigate alphavirus immunity by unique preliminary work into alphavirus diagnostics, animal models, cellular immunity, host factors, and access to relevant biological materials. COALITION will investigate alphavirus immune interplay and epidemiology at unprecedented breadth in a single project, on the level of individual cells, of whole organisms and of populations. On the level of cells, COALITION will decipher in vitro and ex vivo the characteristics of monospecific and dual alphaviral infections, analyze the cellular state and cell-intrinsic innate immune responses, deepen the identification of host factors of CHIKV, MAYV and UNAV infection and study the impact of homotypic and heterotypic antibodies on infection. On the level of whole organisms, COALITION will assess immune enhancement in patients acutely infected with CHIKV and adequate controls by exhaustively analyzing their alphaviral immune background and within cynomolgus macaque infection models that allow controlled assessments of the extent of heterotypic immune enhancement and cross-protection, tissue virus spread/diversity between CHIKV, MAYV and UNAV. On the population level, community protective immunity potentially preventing CHIKV emergence will be assessed by continent-wide differential seroprevalence studies, geospatial modelling and phylogeographic reconstructions. Machine learning algorithms validated by uniquely robust serological data will be used to project the future spread of MAYV and CHIKV across Latin America. The results of COALITION will profoundly enhance the understanding of alphaviral pathogenesis and spread and immediately impact vaccine programmes against these emerging threats for human health, contributing to avoid unexpected lack of vaccine safety such as recently observed with a dengue vaccine.