Miltefosine reduces coxsackievirus B3 lethality of mice with enhanced STAT3 activation
Chun Yu Zhang1, Cheng-Huei Hung2, Yi-Ling Hsiao2
1Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Abstract:
Coxsackievirus B3 (CVB3), one serotype of enteroviruses, can induce fatal myocarditis and hepatitis in neonates, but both treatment and vaccine are unavailable. Few reports tested antivirals to reduce CVB3. Several antivirals were developed against other enterovirus serotypes, but these antivirals failed in clinical trials due to side effects and drug resistance. Repurposing of clinical drugs targeting cellular factors, which enhance viral replication, may be another option. Parasite and cancer studies showed that the cellular protein kinase B (Akt) decreases interferon (IFN), apoptosis, and interleukin (IL)-6-induced STAT3 responses, which suppress CVB3 replication. Furthermore, miltefosine, the Akt inhibitor used in the clinic for parasite infections, enhances IL-6, IFN, and apoptosis responses in treated patients, suggesting that miltefosine could be the potential antiviral for CVB3. This study was therefore designated to test the antiviral effects of miltefosine against CVB3 in vitro and especially, in mice, as few studies test miltefosine in vitro, but not in vivo. In vitro results showed that miltefosine inhibited viral replication with enhanced activation of the cellular transcription factor, STAT3, which is reported to reduce CVB3 both in vitro and in mice. Notably, STAT3 knockdown abolished the anti-CVB3 activity of miltefosine in vitro. Mouse studies demonstrated that miltefosine pretreatment reduced CVB3 lethality of mice with decreased virus loads, organ damage, and apoptosis, but enhanced STAT3 activation. Miltefosine could be prophylaxis for CVB3 by targeting Akt to enhance STAT3 activation in the mechanism, which is independent of IFN responses and hardly reported in pathogen infections.
Insights
Miltefosine, an Akt inhibitor, shows promise as an antiviral for Coxsackievirus B3 (CVB3) by enhancing STAT3 activation. This study demonstrates its effectiveness in vitro and in mice, reducing viral lethality and organ damage.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Coxsackievirus B3 (CVB3) causes fatal neonatal myocarditis and hepatitis, with no available treatments or vaccines.
- Existing antiviral strategies against enteroviruses have faced challenges with side effects and drug resistance.
- Targeting host cellular factors that support viral replication offers a potential therapeutic avenue.
Purpose of the Study:
- To investigate the antiviral effects of miltefosine, a clinical drug and Akt inhibitor, against CVB3 infection.
- To evaluate miltefosine's efficacy in vitro and in a murine model of CVB3 infection.
- To elucidate the mechanism of action, focusing on STAT3 activation.
Main Methods:
- In vitro assays to assess miltefosine's effect on CVB3 replication and STAT3 activation.
- In vivo studies using a mouse model of CVB3 infection, evaluating survival, viral load, organ damage, and apoptosis.
- STAT3 knockdown experiments to confirm its role in miltefosine's antiviral activity.
Main Results:
- Miltefosine significantly inhibited CVB3 replication in vitro, accompanied by enhanced STAT3 activation.
- STAT3 knockdown abrogated the antiviral effect of miltefosine in vitro.
- In vivo, miltefosine pretreatment reduced CVB3-induced lethality, viral loads, organ damage, and apoptosis in mice.
- Miltefosine treatment led to increased STAT3 activation in the infected mice.
Conclusions:
- Miltefosine demonstrates significant antiviral activity against CVB3 through the enhancement of STAT3 activation.
- This mechanism, targeting Akt and boosting STAT3, appears independent of interferon responses.
- Miltefosine holds potential as a prophylactic agent against CVB3, offering a novel therapeutic strategy.
