Synergism between the tyrosine kinase inhibitor sunitinib and Anti-TNF antibody protects against lethal dengue infection

Abstract

Dengue virus (DENV) currently circulates in more than 100 countries and causes an estimated 390 million infections per year. While most cases manifest as a self-resolving fever, ∼1.5% of infections develop into a more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), which causes ∼20,000 deaths annually. The underlying pathological feature of DHF/DSS, also known as Severe Dengue, is an acute increase in vascular permeability leading to hypovolemia and shock. Angiogenic factors and cytokines, such as vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF), have been implicated in the increased vascular permeability, suggesting a potential therapeutic strategy for Severe Dengue. Here, we employed a mouse model of antibody-dependent enhancement of DENV infection, which recapitulates the fatal capillary leakage and shock of human Severe Dengue, to investigate the effects of approved VEGF- and TNF-targeting drugs. DENV infection caused a significant increase in serum VEGF levels within 2 days and resulted in ∼80% mortality within 8 days of infection. Treatment of mice with sunitinib, a VEGF receptor tyrosine kinase inhibitor, once (day 2) or twice (days 1 and 2) post-infection reduced mortality by 50-80% compared with untreated mice. Notably, sunitinib treatment decreased serum TNF levels, white blood cell counts, and hematocrit levels relative to untreated mice, but had only marginal effects on tissue viral burden. Combination therapy with anti-TNF antibody and sunitinib significantly reduced vascular leakage and synergized to provide superior protection from lethal DENV infection compared with either agent alone. These data suggest that a two-pronged anti-angiogenic and anti-inflammatory approach may be useful for the rapid treatment of DHF/DSS.

Repurposing of Kinase Inhibitors for Treatment of COVID-19

“…Sunitinib, believed to primarily work through PDGFR-mediated signaling, was also shown to suppress cytokine storm in a mouse model (137). Finally, sunitinib was shown to synergize with an anti-TNF antibody against lethal dengue infection (138).…”

Three kinds of treatment with Homoharringtonine, Hydroxychloroquine or shRNA and their combination against coronavirus PEDV in vitro

“…A combination of RNAi and a virus receptor trap exerts additive antiviral activity in coxsackievirus B3-induced myocarditis in mice [26]. Likewise, anti-TNF antibody administered with Sunitinib significantly reduces vascular leakage and synergizes to provide superior protection from lethal DENV infection compared with either agent alone in vivo [27]. Combination therapies targeting viruses at different stages of their infection cycle are a common strategy to improve the efficiency of the antiviral treatment, and the combination of multitarget preparations is expected to be less cytotoxic [28].…”

Three kinds of treatment with Homoharringtonine, Hydroxychloroquine or shRNA and their combination against coronavirus PEDV in intro

“…IFN-β in combination with ribavirin act highly synergistically on production of infectious virus titres and may be highly effective not only as prophylactic agent but also for the treatment of already infected SARS patients [25]. A combination of RNAi and a virus receptor trap exerts additive antiviral activity in coxsackievirus B3-induced myocarditis in mice [26]. Likewise, anti-TNF antibody administered with Sunitinib signi cantly reduces vascular leakage and synergizes to provide superior protection from lethal DENV infection compared with either agent alone in vivo [27].…”