Chikungunya virus (CHIKV) is an important reemerging human pathogen transmitted by mosquitoes. The virus causes an acute febrile illness,
chikungunya fever, which is characterized by
headache,
rash, and debilitating (poly)
arthralgia that can reside for months to years after
infection. Currently, effective
antiviral therapies and
vaccines are lacking. Due to the high morbidity and economic burden in the countries affected by CHIKV, there is a strong need for new strategies to inhibit CHIKV replication. The serotonergic drug
5-nonyloxytryptamine (5-NT) was previously identified as a potential host-directed inhibitor for CHIKV
infection. In this study, we determined the mechanism of action by which the
serotonin receptor agonist 5-NT controls CHIKV
infection. Using time-of-addition and entry bypass assays, we found that 5-NT predominantly inhibits CHIKV in the early phases of the replication cycle, at a step prior to
RNA translation and genome replication. Intriguingly, however, no effect was seen during virus-cell binding, internalization, membrane fusion and genomic
RNA (gRNA) release into the cell cytosol. In addition, we show that the
serotonin receptor antagonist methiothepin mesylate (MM) also has
antiviral properties toward CHIKV and specifically interferes with the cell entry process and/or membrane fusion. Taken together, pharmacological targeting of
5-HT receptors may represent a potent way to limit viral spread and disease severity.IMPORTANCE The rapid spread of
mosquito-borne viral diseases in humans puts a huge economic burden on developing countries. For many of these
infections, including those caused by chikungunya virus (CHIKV), there are no specific treatment possibilities to alleviate disease symptoms. Understanding the virus-host interactions that are involved in the viral replication cycle is imperative for the rational design of therapeutic strategies. In this study, we discovered an
antiviral compound, elucidated its mechanism of action, and propose
serotonergic drugs as potential host-directed
antivirals for CHIKV.