key: cord-1054393-b1860o5f
authors: Ellis, John A.
title: COVID-19: Is It Raining (on) Cats and Dogs?
date: 2020-09-03
journal: Adv Small Anim Med Surg
DOI: 10.1016/j.asams.2020.08.001
sha: 2f79498e77097270bfec8e5d503b233b471c4297
doc_id: 1054393
cord_uid: b1860o5f

nan

John A. Ellis DVM, PhD, DACVP, DACVM ProfEssor, DEPArtMEnt of VEtErinAry MiCrobiology WEstErn CollEgE of VEtErinAry MEDiCinE UniVErsity of sAskAtChEWAn "One Health" has been the buzzword in Veterinary Colleges for more than a decade. Indeed, COVID-19 and its agent, SARS coronavirus-2 (SARSCoV-2), are exemplary of the homily that all life on the planet is interconnected. This, of course, is the essence of One Health, a primary tenet of which is zoonotic infection. But, as important in understanding and dealing with COVID-19 and averting panic for and about furry friends and a wholesale surrender of pets to pounds, is the concept that species differences matter; interspecies extrapolations have limitations. This of course is the essence, and indeed, the raison d'etre of Veterinary Medicine; the reason you do not reward your dog with bonbons. The purpose of this discussion is to briefly review the complex biology of coronaviruses in the context of COVID-19 and cats and dogs. Let us consider why the devil is in the details.

In human medicine, before COVID-19, coronaviruses were mostly the stuff of common colds, the episodic and exotic SARS and MERS aside. In contrast, in veterinary medicine, regardless of which "side of the bag," small or large, one practices out of, coronaviruses have long been considered significant pathogens; nothing to just sneeze at. Some of these viruses, e.g., canine coronaviruses (CCoV) or bovine coronavirus (BCoV), are epitheliotropic and cause primarily diarrhea and/or respiratory disease. Others, such as mouse hepatitis virus (MHV) or feline infectious peritonitis virus (FIPV) and now, SARSCoV-2, are polytropic, infecting a broader range of cells and causing multisystemic diseases.

In thinking about coronaviruses, or for that matter single-stranded RNA viruses in general, the first simple concept to jettison is "species." Even though these viruses have species names, such as SARS-CoV-2, CCoV, feline coronavirus (FCoV), or MHV, each exists as a population of viruses, or a "quasi-species." In other words, even an average sneeze or puddle of diarrhea can contain a very heterogeneous swarm of genetic variants that are called different "strains" if they have demonstrable phenotypic differences, such as behavioral differences in infectiousness, target cell tropism, or virulence. The recent report of "D" and potentially more transmissible "G" strains of SARSCoV-2 are exemplary of this. What enables this existential dilemma is an error-prone replication scheme "managed" by a fickle enzyme, the RNA-dependent-RNA polymerase. Even though coronaviruses have a proof-reading mechanism that other RNA viruses do not have that eliminates some errors, the viruses still undergo genetic drift via point mutations, and importantly, are very prone to recombination. Recombination occurs when a cell is infected with two different strains of the same coronavirus, two different coronaviruses, or even a coronavirus and another type of virus. Then mixing and matching of the subgenomic "nests" of RNAs or other viral genomic bits can result in the emergence of a very different virus. So, coronaviruses can rapidly evolve in real time, especially if put under immunological pressure in a host. What results is survival of the fittest variants, such as finches in the Galapagos Islands.

If the frequency of call-in questions to televised townhalls on COVID-19 is any reflection, there is considerable interest and concern amongst the general public regarding the possibility of SARSCoV-2 infections in household pets, primarily cats and dogs. Arguably, this was incited in the initial stages of the pandemic by the case of a geriatric Pomeranian in Hong Kong www.advancesinsmallanimal.com volume 33, issue 9 • september 2020 i n s M A l l A n i M A l M E D i C i n E A n D s U r g E r y

with "underlying health conditions." The owner had COVID-19, and although never showing any signs of COVID-19, this unfortunate dog tested variably positive for SARSCoV-2 by PCR on several occasions while under a more than 2-week outof-home quarantine. The poor animal died just 2 days after returning home, and the owner declined a necropsy. Predictably, this raised the specter of "canine COVID-19," despite little supporting evidence of the cause of death, beyond of course excessive and undoubtedly stressful, "attention" by unfamiliar human primates. Additionally, there was the more dramatic case of the eight Siberian tigers at the Bronx zoo that tested PCR-positive for SARSCoV-2 and had variable respiratory signs that could have been compatible with COVID-19. In both instances, evidence points to human-to-"animal" transmission. All of this begs the question of what determines in which hosts a specific virus will find a happy home? In other words, what are the determinants of host specificity?

Think of a virus infection as a chess game with moves inside and outside of a host cell. The first move involves a viral surface protein, the ligand, interacting with a host cell surface molecule, the receptor. With enveloped viruses, such as coronaviruses, these ligands are usually envelope glycoproteins. In the case of coronaviruses, the spike or S protein serves this function. Conversely, cellular receptors are either molecules that perform a specific function for the cell, such as the now famous angiotensin-converting enzyme-2 (ACE-2), the primary receptor for the SARSCoVs, or carbohydrate moieties that are attached via various linkages to the glycans comprising a host cell membrane. The latter stick out above the surface of the cell and have no particular job. Sialic acid is one of these, which acts as a receptor for several viruses, including some of the coronaviruses, e.g., CCoV.

The non-covalent bond that forms between a virus and a cell depends on a complementarity of the shape and charge of the ligand and receptor, as determined by the respective amino acid or carbohy-drate compositions. The receptor binding domain (RBD) of the SARSCoV-2 S protein fits like a hand in glove with the ACE-2 molecule in humans. Seemingly minor differences in amino acids in the RBD, resulting in species or individual differences in the biochemistry of ACE-2, can affect the binding affinity, even among primate species. This can make the interaction with the RBD more like a hand in a mitten; more like what apparently happens in SARSCoV-2 infections in cats and ferrets, with now documented differences in composition of the ACE-2 receptor. In dogs, there is even a greater disparity in the amino acid composition of the ACE-2 compared to humans, making for an even looser fit with the SARSCoV-2 -a bigger, looser mitten.

Once SARSCoV-2 has been internalized by a cell, the game changes, and the 16 non-structural proteins (NSPs) of the virus come into play. The cell moves to block replication with an innate immune response -a response to pathogen-associated molecular patterns (PAMPs) or "danger signals." In the case of SARSCoV-2, negative and double-stranded RNA which are not normally found in vertebrate cells are a couple of the instigators of innate immunity. The result is the production of type-1 interferons that inhibit viral replication. Not to be checkmated, successful viruses such as SARSCoV-2 then move to block this response through the action of one or more of their NSPs. Other NSPs affect the efficacy of viral replication, the cellular inflammatory response, or inflammasome, and apoptosis, or programmed cell death. The specific "pieces" and moves related to these processes are less well investigated in the newly recognized SARSCoV-2.

To summarize, species differences can come into play in almost every move of the virus-cell game and ultimately determine the "winner." They can affect the affinity of binding of the S protein and relatedly transmissibility. And even if a virus binds to a target cell, it does not mean that productive replication and resultant disease will occur. That depends on moves among the viral NSP "pieces" and the "pieces" of the internal cellular machinery; a knight is not always positioned to take the queen.

Aside from a handful of case reports relying usually only on PCR test results as "data," currently there is very little known about the natural history of SARSCoV-2 in cats and dogs. Also, there are sparse data deriving from experimental infections. In the most extensive study to date, following direct intranasal inoculation of 10 5 plaqueforming units of cultured SARSCoV-2, a much higher dose than is likely to be encountered naturally, DSH cats (and ferrets) shed virus and had lesions in the respiratory tract with immunohistochemical evidence of viral "attachment" to epithelial cells, whereas five similarly infected beagles did not. There was evidence of airborne spread from infected to naïve cats, but no clinical signs were reported in any of the species infected. Meanwhile, in the United States alone, millions of dogs and cats live essentially as members of the family, including being the recipients of hugs and kisses. This is common in millions of households which some hundreds of thousands have COVID-19 cases. Therefore, some comfort can be taken in the nearly complete absence of reports of COVID-19-like illnesses in the furry companions of human COVID-19 patients. Admittedly, this is limited armchair "epidemiology," but perhaps telling none-the-less, and furthermore, it offers insight into species differences in susceptibility to the strains of SARSCoV-2 currently circulating in humans.

In conclusion, if nothing else, the COVID-19 and SARSCoV-2 experience in humans and the related concerns regarding the possibility of SARSCoV-2 infection in family pets should emphasize the importance of obtaining an etiologic diagnosis whenever possible. Beyond being simply good medicine, it can be an effective tool in managing an epidemic. Notwithstanding the availability of sensitive, specific, fast, and relatively inexpensive PCR tests for respiratory and enteric pathogens in cats and dogs, now including SARSCoV-2, there has been a tendency, especially in the case of respiratory cases, to not use them -"it's probably just a virus infection, it will get better." Thankfully, the current strains of SARSCoV-2 are apparently not particularly "fit" in cats (and ferrets) and even less so in dogs. Along with this "unfitness" goes an apparently insignificant role in interspecies transmission; you are unlikely to catch SARSCoV-2 from your pet, at least as a result of a productive infection in the animal. Fur as fomite, while certainly a biological possibility, is also most likely insignificant overall, given the increasing acknowledgment of the importance of aerosol/airborne transmission of the virus. However, history and the biology of coronaviral infections indicate that we should expect the unexpected with these successful dangerous microbes. Applying the knowledge of comparative medicine and the tools at our disposal is central to providing calming client education and also to averting being caught out in the rain should SARSCoV-2 evolve to be a significant clinical infection in cats, and maybe even dogs.

Emerging coronaviruses: Genome structure, replication, and pathogensis

Comparative ACE2 variation and primate COVID-19 risk

Susceptibility of ferrets, cats, dogs and other domesticated animals to SARS-coronavirus 2