Veterinary medicine at the forefront in the fight against COVID-19
Coronaviruses are generally zoonotic, and certainly not news in animal health circles. Therapies shown to inhibit replication of viruses having animal hosts could hold promise for treating the novel coronavirus in people.
Coronaviruses, so named for their knobby surface projections that create a crown-like appearance,1-3 were first identified in the 1930s but are thought to have originated more than 10,000 years ago.4,5 They and their associated illnesses have been observed in cattle, horses, cats, dogs, swine, rabbits, rodents and bats, among others.6,7
In humans, seven coronavirus strains have been identified, as have their bat and rodent reservoirs, and their intermediate hosts, including cattle, camels and civets.8-16 Most of these strains cause nothing more than the common cold in people, but three—severe acute respiratory syndrome (SARS),17 Middle East respiratory syndrome (MERS)18 and SARS-CoV-2—have proven more daunting.
As the professionals with the most thorough understanding of One Health, veterinarians around the world have been working hard on COVID-19 diagnostic, prevention and treatment measures. Here’s a look at some of the work being done.
At Cornell University College of Veterinary Medicine, a group of researchers have shunted their work to focus on SARS-CoV-2. Virology professor and coronavirus expert Gary Whittaker, PhD, who has done extensive research on MERS, is investigating the SARS-CoV- 2 spike protein and its mechanisms for fusing with the host cell.19 He hopes to apply his findings to drug and vaccine development. The team also includes investigators who are working on diagnostic tests for SARS-CoV-2.
Louisiana State University
Researchers at Louisiana State University School of Veterinary Medicine are working to develop a COVID-19 vaccine, slated to begin animal trials soon. The group, which includes investigators who study bovine coronaviruses, is collaborating with researchers at Tulane University, one of the first facilities to obtain samples of SARS-CoV-2 from the Centers for Disease Control and Prevention.
University of California, Davis
The coronavirus that afflicts cats and causes deadly feline infectious peritonitis (FIP) has long been a subject of research at the University of California, Davis, School of Veterinary Medicine. Investigators at the school have used an antiviral drug shown to block virus replication in monkeys and mice as a springboard for developing a protocol to treat FIP in cats experimentally infected with feline enteric coronavirus.20
"It’s the virus-infected cells that are producing all of these nasty cytokines that are causing this inflammation,” explains Niels Pedersen, DVM, PhD, who has been studying feline coronavirus for the past five decades, “so if you can stop the replication cold in its tracks, you're going to immediately stop the cytokines from being produced."
Treatment has been largely successful in feline studies, which gives Pedersen hope for the nearly identical remdesivir, now in clinical trials for the treatment of SARS-CoV-2. “If it can be done in cats, why can't it be done in humans?" he says.
Other global research
The concept of drug repurposing might also be applied to the parasiticide ivermectin, an FDA-approved anti-parasitic agent for animals and humans that, in recent years, has been shown to have antiviral activity in vitro by interfering with virus replication.21-25 In vitro studies have demonstrated that ivermectin interferes with replication of many viruses, including human immunodeficiency virus 1,22 West Nile virus,23 dengue virus,22,24 Venezuelan encephalitis virus,25 simian virus,22,26 pseudorabies27 and influenza.21
A recent study,28 published in the journal Antiviral Research, demonstrates that ivermectin impedes SARS-CoV-2 in vitro.* Previous reports on similar coronaviruses describe the role of specific proteins in viral transport into the host nucleus, suggesting that ivermectin’s nuclear transport inhibitory activity may be effective against SARS-CoV-2.
Cells infected with SARS-CoV-2 were treated two hours post infection with a single dose of ivermectin at serial dilutions. At 24 hours, the addition of 5 µM ivermectin produced a 99.8% reduction in cell-associated viral RNA, which increased to 99.98% at 48 hours; this equated to an approximately 5,000-fold reduction of viral RNA compared with control samples. No cell toxicity was observed at this concentration.
The study’s Australian investigators, from Monash University and the Peter Doherty Institute for Infection and Immunity, hypothesize that ivermectin inhibits the IMPα/β1-mediated nuclear import of viral proteins, but they hope to confirm this mechanism in the case of SARS-CoV-2. The identification of the specific SARS-CoV-2 and/or host component(s) impacted is an important focus their future work.
This research sets the stage for development of an effective antiviral drug that, if given to patients early in infection, could reduce SARS-CoV-2 viral load, block disease progression and limit person-to-person transmission.
The answers to the COVID-19 pandemic will be shaped like medications and vaccines. And surely, they will be colored by extensive data established by the veterinary community.
*Editor’s note: The FDA has issued a public warning stating that people should not self-medicate with ivermectin in an effort to treat or prevent COVID-19. The warning reads, in part: “FDA is concerned about the health of consumers who may self-medicate by taking ivermectin products intended for animals, thinking they can be a substitute for ivermectin intended for humans. People should never take animal drugs, as the FDA has only evaluated their safety and effectiveness in the particular animal species for which they are labeled. These animal drugs can cause serious harm in people. People should not take any form of ivermectin unless it has been prescribed to them by a licensed health care provider and is obtained through a legitimate source.” For the full FDA letter, click here.
- Almeida JD, Berry DM, Cunningham CH, et al. Virology: coronaviruses. Nature. 1968;220(5168):650.
- Sturman LS, Holmes KV. The molecular biology of coronaviruses. Adv Virus Res 1983;28:35-112.
- McIntosh K, Arber W, Haas R, et al. The molecular biology of coronaviruses. Curr Top Microbiol Immunol 1974.
- Wertheim JO, Chu DK, Peiris JS. The molecular biology of coronaviruses. J Virol 87(12):7039-7045.
- Fehr AR, Perlman S, Maier HJ, et al. The molecular biology of coronaviruses. Methods Mol Biol 2015;1282:1-23.
- Corman VM, Muth D, Niemeyer D, et al. Hosts and sources of endemic human coronaviruses. Adv Virus Res 2018;100:163-188.
- Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 2019;17(3):181-192.
- Forni, D, Cagliani, R, Clerici, M, et al. Evolution of human coronavirus genomes. Trends Microbiol 2019;25(1):35-48.
- Huynh J, Li S, Yount B, et al. Evidence supporting a zoonotic origin of human coronavirus strain NL63. J Virol 2012;86(23):12816-12825.
- Lau, SK, Woo P, Li KS, et al. Discovery of a novel coronavirus, China Rattus Coronavirus HKU24, from Norway rats supports the murine origin of betacoronavirus 1 and has implications for the ancestor of betacoronavirus lineage A. J Virol 204;89(6):3076-3092.
- Fan Y, Zhao K, Shi ZL, et al. Bat coronaviruses in China. Viruses. 2019;11(3):210.
- Bande F, Arshad SS, Bejo MH, et al. Progress and challenges toward the development of vaccines against avian infectious bronchitis. J Immunol Res 2015:42484.
- Murray J. What's new with ferret FIP-like disease? Small Animal Channel website (archived). https://web.archive.org/web/20140424203951/http:/www.smallanimalchannel.com/ferrets/ferret-health/whats-new-with-ferret-fiplike-disease.aspx. Published April 16, 2014. Accessed April 15, 2020.
- Weiss SR, Navas-Martin S. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol Mol Biol Rev 2015;69(4):635-664.
- Zhou P, Fan H, Lan T, et al. Fatal swine acute diarrhoea syndrome caused by an HKU2-related coronavirus of bat origin. Nature. 2018;556(7700):255-258.
- Doucleef M. The molecular biology of coronaviruses. NPR website (archived): https://web.archive.org/web/20120927043755/http:/www.npr.org/blogs/health/2012/09/25/161770135/scientists-go-deep-on-genes-of-sars-like-virus. Published September 26, 2012. Accessed April 15, 2020.
- Falco M. New SARS-like virus poses medical mystery. CNN Health website (archived): https://web.archive.org/web/20131101042029/http:/thechart.blogs.cnn.com/2012/09/24/new-sars-like-virus-poses-medical-mystery/?hpt=he_c2. Published September 24, 2012. Accessed April 15, 2020
- Middle East respiratory syndrome coronavirus (MERS-CoV). PLoS Pathog 2019;7(6):e1002090.
- Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc Natl Acad Sci U S A 2014;111(42):15214-15219.
- Pedersen NC, Perron M, Bannasch M, et al. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg2019;21(4):271-281.
- Gotz V, Magar L, Dornfield D, et al. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep2016;6:23138.
- Wagstaff KM, Sivakumaran H, Heaton SM, et al.Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J 2012;443(3):851-856.
- Yang SNY, Atkinson SC, Wang C, et al.The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antiviral Res 2020;177:104760.
- Tay MY, Fraser JE, Chan WK, et al.Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res 2013;99(3):301-306.
- Lundberg L, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan equine encephalitis virus replication. Antiviral Res 2013;100(3):662-672.
- Wagstaff KM, Rawlinson SR, Hearps AC, et al.An AlphaScreen-based assay for high-throughput screening for specific inhibitors of nuclear import. J Biomolec Screen 2011;16(2):192-200.
- Lv C, Wenkai L, Wang B,et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res 2018;159:55-62.
- Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020;in press. Available at https://www.sciencedirect.com/science/article/pii/S0166354220302011