Serotonergic Drugs Inhibit Chikungunya Virus Infection at Different Stages of the Cell Entry Pathway

Abstract

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.

Can selective serotonin reuptake inhibitors have a neuroprotective effect during COVID-19?

“…Additionally, buspirone, a serotonin-receptor agonist, was able to decrease T-CD8 cell count and increase CD4/CD8 ratios in HIV-infected patients ( Eugen-Olsen et al, 2000 ). Inhibition of chikungunya ( Bouma et al, 2020 ), reovirus ( Mainou et al, 2015 ), and parainfluenza ( Rabbani and Barik, 2017 ) infection has also been shown to be mediated by this monoamine. However, 5-HT immunomodulatory actions may be virus and/or receptor-dependent, as exemplified by JC virus infection, where virus internalization is stimulated by serotonin 5-HT 2A receptors ( Assetta et al, 2013 ; O'Hara and Atwood, 2008 ).…”

Drug repurposing of selective serotonin reuptake inhibitors: Could these drugs help fight COVID-19 and save lives?

“…Also, 5-HT decreases HIV infection in human macrophages by downregulating the expression of C-C chemokine receptor type 5 (CCR5), an essential co-receptor for HIV entry, and reduces proviral DNA synthesis (51%), probably through serotonin 5-HT1A receptor [44]. Furthermore, the infectivity of reovirus and chikungunya were found to be reduced in the presence of a specific 5-HT1B/5-HT1D receptor agonist [45,46]. Peripheral 5-HT is also able to modulate several mechanisms of different viral infections through its receptors.…”

Antivirals against the Chikungunya Virus

“…Interestingly, also the 5-HT antagonist methiothepin mesylate (MM, Figure 5 ) was able to inhibit 97 ± 1.0% of the CHIKV replication at 10 µM. A time-of-addition study suggested two different modes of actions: for 5-NT, the inhibition of the uncoating and for MM, the internalisation and membrane hemifusion step [ 133 ].…”