Abstract
Understanding the fundamental mechanisms of arbovirus transmission and pathogenesis is essential to develop strategies for treatment and prevention. We previously took an invivo evolution-based approach and identified the chikungunya virus E1 glycoprotein residue 80 to play a critical role in viral transmission and pathogenesis. In this study, we address the genetic conservation and function of position 80 and demonstrate that this residue is a key determinant in alphavirus infectivity and dissemination through modulation of viral fusion and cholesterol dependence. In addition, in studying the evolution of position 80, we identified a network of glycoprotein residues, including epidemic determinants, that regulate virus dissemination and infectivity. These studies underscore the importance of taking evolution-based approaches to not only identify key viral determinants driving arbovirus transmission and pathogenesis but also to uncover fundamental aspects of arbovirus biology.
Highlights
Viral evolution is a key driving force for arbovirus emergence and in turn can be used to study how arboviruses are transmitted and cause disease
We identified two mutations in the E1 glycoprotein (V80I and A129V) that are important for chikungunya virus (CHIKV) transmission and pathogenesis
Residue 80 in the Chikungunya Virus E1 Glycoprotein Tolerates Aliphatic Amino Acids and Is Genetically Constrained in a Host-Specific Manner To investigate the role of residue E1-80 in the CHIKV replication cycle, we began by addressing the mutational tolerance of this position (Figure 1A)
Summary
Viral evolution is a key driving force for arbovirus emergence and in turn can be used to study how arboviruses are transmitted and cause disease. E1 and the attachment protein E2 are arranged to form 80 trimeric spikes constituted of trimers of E1-E2 heterodimers (Kielian and Rey, 2006). These protein complexes mediate CHIKV internalization by receptor-mediated endocytosis and fusion within the early endosome (Hoornweg et al, 2016), where low endosomal pH triggers E1-E2 dissociation, E1 fusion loop insertion into the target membrane, and membrane fusion (Kielian and Rey, 2006)
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