Metabolic reprogramming of methylthioadenosine-dependent sulfur recycling is a major driver of CHIKV infection

Viral replication is strongly dependent on host cell metabolites as primary sources of essential building blocks and due to the involvement of metabolites in the regulation of essential reactions. As chikungunya virus (CHIKV) is one of the emerging pathogens, we chose this virus to generate a metabolic profile of infected host cells. We detected that in particular 5ʹ-methylthioadenosine (MTA) concentrations were increased in infected cells. Additional studies showed that this increase was accompanied by increased methionine adenosyltransferase-2a (MAT2A) expression. In sulfur-depleted media, exogenously added MTA restored CHIKV replication more efficiently than its precursor S-adenosylmethionine (SAM), while inhibitions of MAT2A or of de novo cysteine (Cys) biosynthesis reduced viral infectivity. Moreover, infection with CHIKV upregulated the expression of the U34-tRNA methyltransferase ALKBH8 and deletion of ALKBH8 led to a reduction of virus replication, recapitulating Met-Cys deprivation effects. In line with the essential role of methyl donors (SAM) we proved the nanomolar potency of the S-adenosylhomocysteine hydrolase inhibitors DzNep and Adox for CHIKV replication. Thus, our results uncovered the relationship between metabolism and secondary regulatory effects for CHIKV replication.