How do infections jump from animals to humans?



Some believe that the deadly coronavirus has been transmitted to humans from pangolins, others argue that the virus has originated in bats. To clear this confusion regarding the origin of the coronavirus and to understand how viruses jump from one species to the other, we asked a few tricky questions to Uma Ramakrishnan, a scientist at the National Center for Biological Sciences, Bangalore.


Asmita Sarkar

Here, Ramakrishnan is collected tiger scat for genetic analyses in Ranthambore Tiger Reserve


1. What is the origin of SARS-CoV-2?


This is something the scientific community is still trying to understand. Solving this problem is actually like solving a mystery. We are trying to understand what happened after the disease has already spread: so we need to look for clues and work backwards. In this case, the coronavirus genomes are the clues which can be put together using evolutionary tools. We sequence the genome of SARS-CoV-2, and compare it to other known coronavirus genomes in humans and other species. When we say ‘compare’, we will build a phylogenetic tree, which is like a family tree that includes a pooled data from the new virus and several other viruses. Using this phylogenetic tree, we will try to answer two questions: what is this virus and what is it closest to? 


The first step is to figure out what type of coronavirus the new one is. This process of categorization or naming is called taxonomy. Scientists have over time detected and sequenced the genomes for several coronaviruses. After the first SARS outbreak, a lot of focus was spent on discovering and characterizing coronaviruses in bats to construct a phylogenetic tree, and it clusters together with other beta-coronaviruses). So, we infer that the new virus is a beta-coronavirus, and it was named based on this and other considerations.


In order to infer the probable origins of this novel virus, we need to look at additional SARS-CoV genomes across animal species. One of the first papers to do this was (, see Figure 1d), where they compared four whole genomes of SARS-CoV2 from patients to various other beta coronavirus genomes. They observed that the current pandemic is very close to a sequence called Bat CoV RATG13, isolated from an insectivorous bat, Rhinolohus affinis from Yunnan, China. 


2. Was it then first transmitted from bats to humans?


The current pandemic is 96.2% similar to the Bat CoV RATG13. This tells us that the closest relatives of this virus is found in an insectivorous bat that is commonly distributed across Southeast Asia and parts of India and China.


It is possible that the original virus was in these insectivorous bats, but how did it spill-over to humans? Is it the same virus that is harboured by bats? 


Probably not, because while there is 96.2% similarity, there are some key differences. First, in the receptor-binding domain site of the spike protein, the region that allows the virus to gain entry into human cells, there are many differences between Bat CoV RATG13 and the human SARS CoV-2. Second, in another region of the spike protein, SARS CoV-2 appears to have acquired a unique sequence pattern not seen in any known coronavirus. Coronaviruses are very good at acquiring parts from other coronaviruses if two distinct viruses infect the same cell. This happens frequently in the spike region. In summary, although the closest known virus to SARS CoV-2 is harboured by bats, there are key differences that establish that the virus did not jump to humans directly from bats.


If not directly, did it come to humans through an intermediary host? 


Knowledge of previous coronavirus outbreaks like MERS or SARS-CoV-1 suggests that an intermediate mammalian host was involved. When we specifically compare the SARS CoV-2 receptor-binding region (from the spike protein) to the same region from other species, the virus harboured by pangolins is more similar than Bat CoV RATG13 . However, we have to remember that there are many unknown viruses whose genome we have not sequenced.


But the fact remains that overall, SARS CoV-2 is most similar to Bat CoV RATG13. There are two possible hypotheses now: recombination and mutation, followed by natural selection. The recombination hypothesis would suggest that some version of the bat virus-infected pangolins, and may have recombined with the pangolin virus, following which it spilled over to humans. The mutation hypothesis suggests that different mutations led to the combination of changes we see in the receptor-binding domain, and these mutations occurred independently in humans and pangolins. In either case, once the mutations in the receptor-binding domain were acquired, this particular version of the virus was more successful at gaining entry into and replicating in human cells, so was naturally selected. 


Remember though, when solving any mystery, your ability to solve it depends on the clues you have. All of our information is based on the data we currently have, and additional clues might change this. Such data may include beta corona virus sequences from other animal species or sequences from early patients that had contact with the wet-market.


3. How does an infection causing species jump from one host to the other?


Just as the virus is transmitted from one human to another, it can be transmitted from one species to another. A susceptible host needs to have a receptive cellular environment for the pathogen of the other species and share space and time with an infected host. This happens when one species is in contact with another. 


4. Does large scale animal farming in Wuhan have a role in spreading the Virus?


We can only speculate about the situation. Given that we think recombination or the mixing of two independent viruses was important for the new virus to be created, clearly, it was important that pangolins, bats and humans interact. This could have happened in the wet-market in Wuhan, but we cannot say for sure.


In the wild, it is very rare to encounter a pangolin. They are nocturnal and shy, and it is unlikely that tourists would encounter them often. On the other hand, recent years have seen extensive hunting of pangolins, they have been traded extensively across Southeast Asia, and this has pushed them to the brink of extinction.


5. How can we tell that COVID-19 has been naturally evolved and not made in laboratories or genetically engineered?


The data does not suggest this. Let us try to address this systematically. If this virus was engineered, it should show very strong similarity to some virus that was being cultured in the laboratory. This is not the case. It differs significantly at two regions: the receptor-binding domain (that is similar to pangolins) and the unique sequence pattern. It also has several differences distributed across the genome. This suggests two things. First, SARS-CoV-2 has a lot of genetic variation and second, it has unique genetic features. Should it have been genetically engineered, both these features are unlikely.


Further, bioinformatics studies have predicted the sequence that would result in the optimal binding to the human receptor, using which the virus gains entry to cells and then replicates. The sequence observed in SARS-CoV-2 is different from the ‘optimal’ one. If one was to engineer a virus, one would do it with the best possible sequence, why would one use something suboptimal?


Overall, most of the evidence suggests the natural evolution of SARS-CoV-2.


6. Can SARS-CoV infect domestic cats and dogs? Do pet owners need to be concerned about the situation? 


In order to understand how animals that we live in close proximity to are susceptible to SARS-CoV-2, some researchers infected cats, dogs, ferrets, pigs and chicken with the virus. These studies revealed that the virus infects and replicates well in cats and ferrets, but not so well in dogs. That said, there are now examples of dogs that have tested positive). However, our current understanding is that the infection is mild in dogs. 


While we know the virus can be transmitted from humans to their pets, there is no evidence yet that pets transmit it back to humans.


7. With reference to the news of the tiger in the Bronx zoo testing positive for Coronavirus, is the infection in the tiger the same as it is in humans?


First, is the virus the same? The zoo authorities at the Bronx zoo in New York think the tiger there was infected by an asymptomatic keeper. This particular tiger was tested and found positive for SARS-CoV-2. So, the virus the tiger has been infected with is the same that we humans are affected by. We now know that several other large cats in the same zoo appear to be infected. 


Second, is the infection the same? To answer this, we would have to understand disease progression in tigers and compare it to humans. Overall, the disease seems similar in terms of the symptoms. 


Does it affect tigers as severely as it does humans? I don't think we are sure about this yet. We will only know when many more tigers have been infected, but I hope that will not happen.
8. Major pandemics such as the Spanish flu, swine flu and the modern Ebola virus disease are all infectious diseases that have jumped from other animals to humans. Why do you think such spill-overs are becoming common these days?


Yes, emerging or re-emerging infectious diseases are becoming more common these days. Approximately 70% of known infectious diseases are caused by zoonoses, or microorganisms from wild or domestic animals. 


A recent meta-analysis combined data from many such disease emergence events and tried to look at the factors that correlate with spillover). This study has found that, while the frequency of emergence did correlate with the biodiversity of mammals, it was also strongly dependent on human-induced land-use change and high human population density. 


I hope you don't take away from this interview that it's all the fault of bats! Not at all, because bats have probably harboured many, many viruses for millions of years. The problems arise because of the human activities that degrade and destroy wild habitats, placing enormous stress on the resident animals and also bring many of these species in close contact with us. Equally important are our current lifestyles that include international mobility and globalization.


9. Is there a way to stop cross-species transmissions? Does vaccination help?


Vaccination will help in the relatively immediate future if it can successfully generate a neutralizing antibody response. There is no doubt we must have a vaccine, and vaccinate as many people as possible. However, vaccines are only reactive measures.


We humans have modified over 70% of the earth and I hope this COVID-19 pandemic at least helps us understand that we cannot continue business as usual! From a very practical perspective, we cannot continue to destroy and exploit the natural world. We must also realize that our health is linked to other wild and domesticated mammals and the environment. This concept is called ‘one health’. 


We cannot stop cross-species transmission, it is part of evolution and nature. But we can dampen the effects of spillover by setting up local one health initiatives, policies and processes to monitor such events and intervene before they become global. But enough ‘gyan’ for now!


Uma Ramakrishnan is an associate professor at NCBS-TIFR, Bangalore. She has spent the last fifteen years studying Indian biodiversity. Her favourite topics of research include tiger conservation genetics and emerging infectious diseases. She is also part of the National Mission for Biodiversity and Human Well-being.


(Interviewed by Asmita Sarkar, a master's student at TIFR, Mumbai)