Attenuation of clinical and immunological outcomes during SARS‐CoV‐2 infection by ivermectin

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.

Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients

“…Along with an increasing number of clinical trials assessing the clinical benefit of IVM for patients with COVID-19 [45], alternate immunological mechanisms have been proposed [35]. IVM has shown immunomodulatory and anti-inflammatory properties in mouse models of different diseases [46,47] as well as in SARS-CoV-2-infected hamsters [48]. Along the same line, statins have prominent in vivo effects on endothelial cell biology and it has been discussed whether they would be able to act on vascular dysfunction associated with COVID-19 [49].…”

The mechanisms of action of ivermectin against SARS-CoV-2—an extensive review

“…A study by Zhang et al demonstrated that ivermectin suppressed IL-6 and TNFα production, two major components of the detrimental cytokine storm induced by SARS-CoV-2 and “dramatically reduced” IL-6/IL-10 ratio modulating infection outcomes [ 47 , 60 ].…”

“…No olfactory deficit was observed in ivermectin treated females (0/6), while 33.3% (2/6) of saline-treated females presented with hyposmia/anosmia (Fisher’s exact test p = 0.455). Ivermectin dramatically reduced the IL-6/IL-10 ratio in lung tissue, which likely accounts for the more favorable clinical presentation in treated animals [ 60 ]. Loss of smell has been reported as one of the common symptoms in COVID-19 [ 66 ].…”

“…Ivermectin inhibits STAT-3 Matsuyama et al 2020 [ 44 ] The PD-L1 receptors present on the endothelial cells are activated by STAT-3 causing T cell lymphopenia. IVM inhibits STAT-3 through direct inhibition Matsuyama et al 2020 [ 44 ] Level 12: Action on P21 activated kinase 1 (PAK1) IVM suppresses the Akt/mTOR signaling and promotes ubiquitin-mediated degradation of PAK1 hence compromising STAT-3 activity and decreasing IL-6 production Dou et al 2016 [ 59 ] Level 13: Action on Interleukin-6 (IL-6) levels IVM suppressed IL-6 and TNFα production Zhang et al 2008 [ 47 ] IVM “dramatically reduced” IL-6/IL-10 ratio modulating infection outcomes De Melo et al 2020 [ 60 ] Level 14: Action on allosteric modulation of P2X4 receptor Positive allosteric modulation of P2X 4 by IVM enhances ATP-mediated secretion of CXCL5 Layhadi et al 2018 [ 63 ] Level 15: Action on high mobility group box 1 (HMGB1) Ivermectin inhibits HMGB1 Juarez et al 2018 [ 65 ] Level 16: Action as an immunomodulator on lung tissue and olfaction No olfactory deficit was observed in IVM-treated females; IVM dramatically reduced the IL-6/IL-10 ratio in lung De Melo et al 2020 [ 60 ] Level 17: Action as an anti-inflammatory Anti-inflammatory action of IVM was explained as inhibition of cytokine production by lipopolysaccharide challenged macrophages, blockade of activation of NF-kB, and the stress-activated MAP kinases JNK and p38, and inhibition of TLR4 signaling Zhang et al 2008 [ 47 ] Ci et al 2009 [ 67 ] Yan et al 2011 [ 68 ] …”

Ivermectin Does Not Protect against SARS-CoV-2 Infection in the Syrian Hamster Model

“…In an in vivo model of mouse hepatitis virus, a type 2 family RNA coronavirus similar to SARS-CoV-2, ivermectin reduced the viral load and protected mice from disease [ 8 ]. In Syrian hamsters infected with SARS-CoV-2, treatment with ivermectin did not result in a direct antiviral activity, but rather apparently showed some immunomodulatory effects, improved lung pathology and clinical presentations [ 9 ]. Ivermectin is being assessed as a treatment for COVID-19 in a large number of clinical trials, with no clear evidence of its clinical benefit so far [ 10 ].…”