Ivermectin reduces coronavirus infection in vivo: a mouse experimental model

[-] Haitchpeasauce | 1 points | Nov 03 2020 13:18:06

Came across this in the COVID19 sub.

Abstract

SARS-CoV2 is a single strand RNA virus member of the type 2 coronavirus family, responsible for causing COVID-19 disease in humans. The objective of this study was to test the ivermectin drug in a murine model of coronavirus infection using a type 2 family RNA coronavirus similar to SARS-CoV2, the mouse hepatitis virus (MHV). BALB/cJ female mice were infected with 6,000 PFU of MHV-A59 (Group Infected; n=20) and immediately treated with one single dose of 500 ug/kg of ivermectin (Group Infected + IVM; n=20), or were not infected and treated with PBS (Control group; n=16). Five days after infection/treatment, mice were euthanized to obtain different tissues to check general health status and infection levels. Overall results demonstrated that viral infection induces the typical MHV disease in infected animals, with livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while ivermectin administration showed a better health status with lower viral load (23,192 AU; p<0.05) and few livers with histopathological damage (p<0.05), not showing statistical differences with control mice (P=NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in treated mice compared to infected animals. In conclusion, ivermectin seems to be effective to diminish MHV viral load and disease in mice, being a useful model for further understanding new therapies against coronavirus diseases.

An excerpt from the introduction:

However, experimental conditions with SARS-CoV2 are not easily available in research laboratories due to biosecurity reasons, thus having in vivo preclinical data is not always easy. Mouse hepatitis virus (MHV) is a similar single strand RNA coronavirus (Fan et al., 2020) affecting different mouse organs (Weiss and Leibowitz, 2011), also highly contagious with natural transmission occurring by respiratory or oral routes, showing high morbidity and low mortality rate, with no vaccine or treatment available, whose control requires to sacrifice the entire laboratory mice colony when an infection occurs. It has been proposed that MHV could be an interesting model to test new therapies for COVID 19 in animal models, since it has been recently demonstrated that the mechanism of infection has some similarities with SARS-CoV-2 (Körner et al., 2020). After entry into the host cell, both coronaviruses require a similar nuclear transport system mediated by the importin a/ß1 heterodimer (Timani et al., 2005; Wulan et al., 2015), making this system an interesting target for the development of candidate therapies against the viral infection.

The dose used is in the safe therapeutic range, and was found to significantly reduced viral load and liver inflammation.

Using a mouse virus similar to SARS-CoV-2. Some might say that a mouse isn't a human and a mouse virus isn't SARS-CoV-2 and they would be right, but MHV uses a similar importin α/β nuclear transport system. It may indicate the Ivermectin molecule binds in a generalised way to importin α making it less likely for many kinds of virus to escape this mechanism.

This study is supportive that the virus nucleoprotein is being transported into the nucleus and disrupting many cell functions needed to fight the infection, leading to worse outcomes. Taken with other studies, it supports the theory that the Interferon JAK-STAT signalling pathway is being disrupted.

Granted, importin α/β transport is the mechanism the study author highlights, there may be other explanations for efficacy.

Mice were immediately euthanized by cervical dislocation to dissect liver and spleen for weight recording, histological and qPCR analysis. At necropsy, liver appearance was blindly scored (0 to 3) by an independent trained technician considering the main pathologicpattern of MHV infection (Macphee et al., 1985; Perlman, 1998)

Poor mice, thank you for contributing to our fight against COVID-19 and our understanding of the natural world.

[-] TrumpLyftAlles | 2 points | Nov 04 2020 15:09:05

This study is supportive that the virus nucleoprotein is being transported into the nucleus and disrupting many cell functions needed to fight the infection

I didn't see this in the parts of the study you posted. Is this your belief, and consider the study supportive of that? Is there other supportive evidence? (I don't know much about the nucleoprotein and don't have an opinion.)

After entry into the host cell, both coronaviruses require a similar nuclear transport system mediated by the importin a/ß1 heterodimer.

Which two viruses? It confusing because the studies after the quote are pre-covid19.

Interferon JAK-STAT signalling pathway

Something else I don't know about. Hey, they say the first step to wisdom is knowing that you're ignorant!

Thanks for posting this, and your analysis (especially).

[-] Haitchpeasauce | 1 points | Nov 04 2020 15:55:23

Whenever we talk about viruses and Importin, we are referring to it utilising this transport mechanism to deliver its disruptive protein package into the nucleus.

Both viruses, as in MHV and SARS-CoV-2, are coronaviruses that use importin, and the paper says mice importin is similar to ours. Similar enough that it seems Ivermectin works in mice too. It is promising for further drug studies in mice.

My lay understanding of JAK-STAT is:

Interferon signalling proteins outide the cell bind to the cell membrane
Causing JAK enzyme to activate another protein called STAT present within the cell cytoplasm
This connects with importin α which in turn connect with importin β
Importin β is needed to transport STAT through the nuclear pore complex into the nucleus which
STAT triggers a bunch of antiviral genes that would attack viral replication in the cell, as well as stimulate more interferon production which will warn nearby cells there is an infection and to prepare accordingly.

The above omits a bunch of stuff but that's the pathway.

So SARS-CoV-2 is theorised to take advantage of importin, disrupt interferon production, block further STAT transport, disrupt antiviral genes. It messes with cells so it can replicate undisturbed and without causing symptoms in the host.

[-] TrumpLyftAlles | 1 points | Nov 04 2020 15:58:42

Thanks for the explanation(s)! There's a STAT video that I haven't watched, and a Methods of Action video too. Time to do that.