Early control of viral load by favipiravir promotes survival to Ebola virus challenge and prevents cytokine storm in non-human primates

Abstract

Ebola virus has been responsible for two major epidemics over the last several years and there has been a strong effort to find potential treatments that can improve the disease outcome. Antiviral favipiravir was thus tested on non-human primates infected with Ebola virus. Half of the treated animals survived the Ebola virus challenge, whereas the infection was fully lethal for the untreated ones. Moreover, the treated animals that did not survive died later than the controls. We evaluated the hematological, virological, biochemical, and immunological parameters of the animals and performed proteomic analysis at various timepoints of the disease. The viral load strongly correlated with dysregulation of the biological functions involved in pathogenesis, notably the inflammatory response, hemostatic functions, and response to stress. Thus, the management of viral replication in Ebola virus disease is of crucial importance in preventing the immunopathogenic disorders and septic-like shock syndrome generally observed in Ebola virus-infected patients.

Single Dose of a VSV-Based Vaccine Rapidly Protects Macaques From Marburg Virus Disease

“…Moreover, control animals generated an excessive inflammatory response punctuated by substantial upregulation of genes encoding cytokines and chemokines and those important for neutrophil activation and function. This is in line with previous reports of neutrophilia and cytokine storm following lethal challenge with both EBOV and MARV (8,12,16,27,(37)(38)(39)(40). Finally, robust induction of genes that play a role in wound healing was also detected in control animals, indicative of the coagulopathy that accompanies EVD and MVD (37,39,40).…”

Evaluation of favipiravir in the treatment of COVID-19 based on the real-world

“…However, NK cells may be a double-edged sword in the treatment of COVID-19, as it is one of the culprits in the development of cytokine storm syndrome, one of the most common causes of death in a new crown pneumonia [ 57 , 58 ]. In a recently published study, Reynard et al applied FVP to treat Ebola virus in non-human primates and concluded that the reduction of viral load by FVP in early treatment is associated with a reduction in the release of related cytokines including NK cells, greatly reducing the incidence of developing cytokine storms, thereby reducing disease severity [ 59 ]. Interestingly, Ferri et al reported a significant rate of SARS-CoV-2 infection in patients with autoimmune systemic diseases compared to the general population, but these patients tended to have relatively benign outcomes after diagnosis of COVID-19, possibly because such patients are themselves taking immunosuppressive agents (e.g.…”

Early Sertoli cell gene expression regulates pathogenesis in response to Ebola virus

“…A lack of immune response followed by overexpression later during infection has been linked to fatality in previous animal model and human studies 61 . High viral loads early during infection followed by sustained upregulation of immune signaling activity in Leydig cells is reminiscent of the so-called cytokine storm that has been reported in fatal cases of EVD, in which case the more moderate response observed in Sertoli cells may go some way to explaining their continued survival 62,63 . The Sertoli cells maintain an immune privileged niche in part through anti-inflammatory signaling, and this may explain our observations in the current study as well as the asymptomatic nature of persistent testicular EBOV infections 3,22 .…”

“…In this case, extended upregulation of the Hemostasis pathway may be a response mounted by Leydig and Sertoli cells in opposition to downregulation induced by EBOV. If this is the case, then hemorrhaging during EVD may be caused by an overly robust response by host cells, similar to the cytokine storm 62,63 .…”