Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection byivermectin.

Guilherme Dias De Melo,Marc Lecuit,Sylvain Levallois,Agnès Marchio,Françoise Lazarini,Thomas Cokelaer,Hervé Bourhy,Pierre‐Marie Lledo,Pascal Pineau,Jean‐Pierre Changeux,Etienne Kornobis,Lauriane Kergoat,David Hardy,Florence Larrous,Lena Feige

doi:10.15252/emmm.202114122

Abstract

The devastating pandemic due to SARS‐CoV‐2 and the emergence of antigenic variants that jeopardize the efficacy of current vaccines create an urgent need for a comprehensive understanding of the pathophysiology of COVID‐19, including the contribution of inflammation to disease. It also warrants for the search of immunomodulatory drugs that could improve disease outcome. Here, we show that standard doses of ivermectin (IVM), an anti‐parasitic drug with potential immunomodulatory activities through the cholinergic anti‐inflammatory pathway, prevent clinical deterioration, reduce olfactory deficit, and limit the inflammation of the upper and lower respiratory tracts in SARS‐CoV‐2‐infected hamsters. Whereas it has no effect on viral load in the airways of infected animals, transcriptomic analyses of infected lungs reveal that IVM dampens type I interferon responses and modulates several other inflammatory pathways. In particular, IVM dramatically reduces the Il‐6/Il‐10 ratio in lung tissue and promotes macrophage M2 polarization, which might account for the more favorable clinical presentation of IVM‐treated animals. Altogether, this study supports the use of immunomodulatory drugs such as IVM, to improve the clinical condition of SARS‐CoV‐2‐infected patients.

Highlights

Coronaviruses cause respiratory disease in a wide variety of hosts
COVID-19 clinical outcome is attenuated by ivermectin In order to study the effects of IVM chemical therapy on clinical outcome, we assessed body weight, clinical score and olfactory performance daily for 4 days post-infection
The results presented are consistent with a role of type I and III IFN responses in the pathogenesis of SARS-CoV-2-associated lung disease in hamsters

Summary

Introduction

During the ongoing pandemic of SARS-CoV-2 causing coronavirus disease 19 (COVID-19), clinical signs other than respiratory symptoms have been linked to infection, frequently associated with neurological symptoms such as anosmia and ageusia. These features have been related to an over-responsiveness of patients’ immune system to SARS-CoV-2 (Bhaskar et al, 2020, Han et al, 2020, Qiu et al, 2020). IVM has been shown to exert an immunomodulatory effect in humans and animals (Heidary & Gharebaghi, 2020, Sajid et al, 2006) under conditions that are known to involve the -7 nAChR (Pavlov & Tracey, 2012), even though its underlying mechanisms are yet to be established (Laing et al, 2017). In vitro inhibition of SARS-CoV-2 replication by IVM in Vero/hSLAM cells has been reported (Caly et al, 2020), albeit at much higher concentrations (50- to 100-fold) than those clinically attainable in humans (150-400 μg/kg) (Bray et al, 2020, Chaccour et al, 2020, Guzzo et al, 2002)

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