From Bats to Mink: Past, Current and Future Roles of Animals in Covid-19

75%: this percentage has become essential to introduce the majority of articles and summary publications on the origins of the current pandemic; this is the proportion of emerging human diseases that are said to be “of animal origin”. Thus, nearly three out of four infectious diseases that strike humanity are linked to zoonoses, transmissible from animals to humans and vice versa. Revenge of the animal kingdom on man or the Brownian effect of a coevolution, what is really the zoonotic dimension of this new virus?

Sf the animal origin of SARS-CoV-2 now seems obvious, humans continue to search for the precise name of the "culprits" in the genetic code of the coronavirus. The starting point is now localized to the order of bats where one of the 1400 species of bats, Rhinolophus affinis, seems to be the host of a very similar virus (> 96% genetic identity), but however still devoid of direct zoonotic abilities.

Bat Rhinolophus smithersi.
Taylor, Stoffberg, Monadjem, Schoeman, Bayliss & Cotterill, CC BY

The hypothesis of the intermediate host remains open, because the trail of the pangolin seems less and less likely. If there is an intermediate host, it is essential to find it, not to provide solutions to the crisis we are experiencing, but rather to prevent the next one. The place and time are the two keys to infectious emergence and its prevention. One of the scenarios considered is that of the current existence of one or more pools of viruses pre-adapted to humans, persisting in one or more animal populations, and which remain hidden from us for the moment.

Animal receptivity? Different degrees of reading ...

In six months, there are now more than a hundred scientific publications that focus on the sensitivity of different animal species to this virus. But before discussing the methods and the results obtained, it is very instructive to understand their objectives; in fact, the first reason researchers have to look into this subject is to find an ideal and reliable experimental model. To understand the mechanisms used by this powerful virus in humans, then to find and test the therapeutic or immunological responses, researchers need “non-human” models. However, for once, rodents are lacking: rats and mice are not sensitive to SARS-CoV-2, unless they are "humanized" with the help of genetic modifications.

The “usual” non-human primates (mainly macaques) are sensitive to it, but seem to present less severe forms than humans and their experimental management is always more delicate. New world primates such as marmosets (easier to breed), seem much less sensitive than their old world cousins. So, if cats and ferrets have appeared in the publications, it is not so much to know whether they play an epidemiological role in the current crisis (which seems less and less likely), but it is above all to find a suitable research model, a choice dictated by the teachings of SARS-CoV-1, which had already shown its preferential tropism for certain carnivores such as the palm civet in the early 2000s.

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In fact, the conclusions that can be read on the sensitivity of the cat experimentally infected with very high doses of virus deposited directly in the respiratory tract are hardly applicable to the same cat in its urban ecosystem, even if it is surrounded by humans. infected. It is therefore easier to understand why experimental studies objectify excretion, or even transmission between animals, while analyzes of urban populations of our domestic companions struggle to find a few positive animals, apparently excreting little virus and in a short time. Experimental model and tank do not rhyme, fortunately for humans.

Models and predictions: the computer versus the living

Beyond the objectives, let's take a look at the methods. About half of the publications wishing to explore the receptivity of animals to the new coronavirus do so from the angle of the molecular analysis of the infamous “ACE2” membrane receptor. "Angiotensin Converter Enzyme 2" (ACE2) is a protein present both in free form, but also attached to the surface of many mammalian cells. This is a binding site for the SARS-CoV-2 virus, which has a region called “Region Binding Domain” (RBD) on one of its surface glycoproteins “S” (for “Spike” ) coinciding with the ACE2 of the cell to be infected.

The “Key-Lock” image often used to popularize this step is reflected in reality by a true three-dimensional agreement between certain amino acid sequences of the ACE2 of the host and those of the RBD part of the viral “S” . This harmony is formidably perfect in humans and it is one of the factors of the "success" of this virus in our species. However, this ACE2 enzyme exists in all vertebrates. Researchers have fairly comprehensive databases to compare its sequences across all taxa.

The big idea of ​​the moment is therefore to try to predict the affinity of a species for this coronavirus according to the composition of its ACE2 protein: identification of "key" amino acids, 3D reconstruction, atomic compositions, everything has been scrutinized, in different sieves according to the research teams. We thus obtain gradients of scores, lists of “aptitudes”, pyramids and other spirals of species where, unsurprisingly, the majority of non-human primates are theoretically very “well” placed, and where we then find other potentially very sensitive species more unexpectedly such as some cetaceans, the great anteater, deer, etc. for which the molecular prediction gives high probabilities of infection. This type of study also confirms the poor affinity of laboratory rodents, as well as reptiles, amphibians and birds. Which may seem comforting to us since it limits the number of hosts and therefore of possible reservoirs in the animal kingdom.

This theoretical work is attractive, especially since it is quick to implement and does not require any animal experimentation, no field investigation. You don't have to rub the virus to download a database. He's sometimes supplemented by an approach vitro, where we infect animal cells and not the animals themselves. More expensive, this approach remains respectful of the 3R rule (reduce, refine, replace) aimed at limiting the use of direct animal testing. But when you read the protocols in detail, you realize the subtleties of the methods that make the study deviate even more from reality. in vivo : instead of infecting the cell of animal X with human SARS-CoV-2 viruses, we infect a chimeric cell modified by another virus, then forcing it to express the ACE2 receptor of animal X. Then we the bombardment of viral synthetic proteins "S" (without virus) to determine the attachment rate ...

Certainly, but do the teachings of computer science and cell culture stand the test of nature? Not really. Reducing the complexity of the viral infection just when it attaches to the host cell, on the grounds that it is a mandatory and limiting step, does not always work well.

Dance some studies, we can read for example that the ferret or the mink have probabilities considered to be “low” or “very low” of connection to the receiver. Many experimental studies on the ferret and the cases of farms of tens of thousands of American mink in Europe (Spain, Denmark, the Netherlands) prove on the contrary that proximity to a positive human allows the animal to be infected and clinical signs , viral shedding and transmission to other congeners. Likewise, the Egyptian fruit bat was experimentally infected when predictions made its receptivity unlikely, like many other fruit bats.

Among the wild felids, there has only been a pandemic for 10 months four tigers, three lions, for an puma and recently a new tiger positive (all cured); all suspected cases in wild tigers have been ruled out. Zoo animals have been infected by positive healers in the absence of barrier measures, and yet these species have an “intermediate” position in the probability gradient of studies. in silico, inferior for example to the scores of reindeer or bison.

So, what place for the animal?

The problem that seems to emerge through all the microscopes aimed at the ACE2 receptor in mammals is this: it can work. It seems that the virus can theoretically bind to this enzyme in a very large panel of mammalian species, including those that humans have voluntarily multiplied around them, such as domestic animals (carnivores, but also bovids).

Another category of publication has been emerging in recent months, those of catastrophic scenarios on the silent creation of animal reservoirs: and if the virus mutates and contaminates cattle, for the moment very insensitive ? What if the aquatic fauna became contaminated by exposure to our wastewater rich in viral particles?

So far, infections in natura and experimental studies seem rather reassuring on the fact that the infection in animals is not as immediate as between humans, with much more moderate (or even absent) clinical signs and excretions that are low in doses and short in time.

The particular case of mink

Today, only the case of American mink farms implies a significant circulation and persistence of the virus between animals, as well as a suspicion of passage exceptional from animals to humans. The human reaction is then not original: in the name of the risk, animals are slaughtered in the Netherlands, Spain ... Now that more than 3 million of these mustelids have been killed due to Covid-19.

Even Denmark, which had advocated a less radical approach this summer, finds itself overwhelmed and in comes to these extreme measures. The mink do not die of the virus (their mortality is of the order of 3 per 1000), but by the hand of the man.

Industrial mink farming is therefore the only proven, anthropogenic current case in which active and rapid inter-animal circulation is suspected. Since November, this is also the only case where it has been detected that this prolonged survival of the virus could have led to the appearance of mutations (on the famous “S” protein). This makes some people fear that this type of mutations has consequences on the effectiveness of vaccines under development. Danish Prime Minister Puts Frederiksen announced during a press conference: to limit the risk, all of Denmark's mink will be sacrificed this month.

A precautionary principle that will increase the disastrous bill for these mustelids to 20 million euthanasies. The figure is strong and, by the way, suddenly makes the European citizen aware that 63% of the world production of fur of this species comes from the European Union.

Zoonosis or "retro-zoonosis"?

Apart from the cases of mink in breeding, the concept of zoonosis is now undermined by the absence of proof of regular passage from the animal to the man, and is then more precise in that of "retro-zoonosis", scenario where man becomes the infecting reservoir for the animal. It could then become an additional risk weighing on endangered animal populations that it was trying to protect, such as gorillas, orangutans, or black-footed ferrets.

The roles are reversed and man adds the risk of infection to the already well-stocked arsenal he held to harm animal biodiversity. This is not the first time that humans have transmitted one of their coronaviruses: in 2016, ecotourism around chimpanzees in Taï National Park in Côte d'Ivoire was at the origin of the transmission of HCoV-OC43, a coronavirus very common in cold syndrome, to a population of chimpanzees, in which the clinical signs were fortunately as mild as for their human cousins.

Despite the weight of these crossed risks, the animal still manages to leave the only epidemiological circle to assist humans in their battle against this pandemic and they continue to be able to help them:

  • The dog thus learns to detect Covid-19 patients as it does with tuberculosis, Parkinson's disease or certain cancers. A team ofPennsylvania Veterinary University and another from Maisons-Alfort National Veterinary School are currently training dogs for this detection, Helsinki airport already uses them in the terminals. It remains to be seen how to avoid contamination of the dog itself during these olfactory investigations.
  • Bats reveal novel inflammatory modulation mechanisms. With the same weapons as our immune system (interferon, antibodies, etc.), they manage to keep only a few viral copies without being sick, avoiding invasion and cell death. Their immunity carefully circumvents the trap of the cytokine storm, which is often fatal to mankind.
  • After "humanization", man causes the mouse to recalibrate its immune system to produce antibodies against this virus which does not normally affect it. Among more than 200 different antibodies produced, a candidate which blocks on the target was selected to integrate a therapeutic cocktail, because of its effectiveness in blocking the “RBD” region of the virus, preventing it from binding to the host cell. One of the famous hosts who already benefits from this murine aid is none other that the current tenant of the White House.
  • Even more unexpectedly, a camelid (the Lama) demonstrates the capacities of its humoral immune system to produce formidable antibodies against this famous viral “S” glycoprotein. Already objectified during vaccine trials on SARS-Cov-1 and MERS, this production of antibodies (called "VHH") captures the attention of researchers, because they seem capable of really neutralizing betacoronaviruses, and their small size molecular makes them good candidates for local applications as close as possible to viral entry routes (eg nasal spray).

If this pandemic is often an opportunity to question the patterns of interaction between humans and animals, pointing the finger at the overexploitation and invasion of the habitat of the first by the second, it also seems to be time to get out of our purely epidemiological view of the animal where it is only a vector, reservoir, host. It can also be an inspiration, an auxiliary, or just a support. And the vet wondered: if it was the animals' turn to care about humans in the name of animal biodiversity, would they care so much about the 0.00015% mortality in our species?

Alexis Lecu, Veterinarian, National Museum of Natural History (MNHN)

This article is republished from The Conversation under Creative Commons license. Read theoriginal article.

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