The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the disease COVID-19, was declared a global pandemic by the World Health Organization on 11 March 2020 . The origins of the outbreak have been traced to ‘wet markets’, selling fresh produce including seafood and live animals, in Wuhan, China; however, the identification of the natural reservoir host of the virus has not yet been confirmed [2, 3]. Pathogens and their natural reservoir host usually co-evolve to strike a balance in which the pathogen can survive and replicate within the host while the host experiences few or no symptoms of disease. Knowledge of where a pathogen naturally, and often benignly, resides is important to be able to understand how and why zoonosis (transmission of a disease from animals to humans) occurs, and allows us to put effective preventive measures in place to limit exposure .
Bats and viruses
There is compelling genetic evidence that SARS-CoV-2 might have originated from bats [2, 5]. If this is the case, SARS-CoV-2 will join the ranks of bat-borne coronaviruses SARS-CoV, the virus responsible for the SARS pandemic from 2002 to 2003, and Middle East respiratory syndrome coronavirus (MERS-CoV), the virus responsible for recurring outbreaks of severe respiratory illness mainly on the Arabian Peninsula [4, 6].
Bats are a highly diverse group of animals comprising more than 1,000 species. They account for around a fifth of all mammal species, and are the only mammals capable of flight . Intriguingly, they seem to harbour a significantly larger proportion of viruses with zoonotic potential (i.e. with a high likelihood of transmission to humans) per species than any other mammal. Notably, many of the viruses for which bats are confirmed or highly suspected hosts cause severe and often fatal disease in humans ; examples include Hendra virus (case fatality rate (CFR) 57%), Nipah virus (average CFR 65%), ebolaviruses (average CFR 50%), Marburg virus (average CFR 50%) and the coronaviruses SARS-CoV and MERS-CoV (CFR: 10% and 35%, respectively) [7, 9–13].
Unique immunological mechanisms in bats
In recent years, the apparent link between bats and highly pathogenic zoonotic diseases has fuelled speculations that there may be something special about the immunological responses of bats that make them particularly well adapted to asymptomatically carry viruses that cause severe disease in humans . Although this is a relatively new field of research, mounting evidence suggests that the mechanisms by which bats limit disease are indeed unique [9, 14, 15].
The innate immune response is the body’s first line of defence against infectious diseases. For intracellular pathogens such as viruses, specialised receptors in the infected cell sense the presence of foreign material (e.g. a viral particle) and initiate signalling cascades that induce a proinflammatory state, which leads to the activation of immune cells to clear the infection.
Interferons (IFNs) are central to the innate antiviral response because they mediate the production of several proteins that inhibit viral replication . In humans, the baseline production of IFN in the absence of an infection is low; however, in bats baseline IFN levels are comparatively high and their cells are seemingly permanently primed for an immediate response to viral infection [9, 15].
Delayed immune responses in humans
Several viruses, including SARS-CoV and MERS-CoV, produce proteins that target and inhibit mediators of the IFN response [4, 9]. Viruses that have co-evolved with their bat hosts may be under strong selective pressure to adapt to and survive in an environment in which they face high IFN activity from the outset of infection.
In the case of a spillover event, in which a virus has been transmitted from bats to humans, the pathogenic potential of the virus may increase because the initial IFN levels it encounters in this new environment are much lower than in the bat. In humans, targeted inhibition of IFN by these viral proteins may results in a failure of the IFN system to launch a timely and effective antiviral response, resulting in high levels of viral replication. In turn, this may result in extensive immunopathogenesis (disease as a consequence of the overactivity of the immune system rather than the direct effect of a pathogen) as the delayed immune response tries to catch up with the high viral load . This hypothesis fits with the knowledge that many severe zoonotic viral diseases are characterised by extensive immunopathogenesis as a driving force behind disease severity and mortality [15, 16]. In fact, severe and fatal cases of COVID-19 have also been associated with excessive immune activation or ‘hyperinflammation’ .
Close contact between animals and humans
Transmission of zoonotic pathogens to humans is an accidental, random and relatively rare event brought about by a range of circumstances that are dependent on a combination of human and host behaviours, along with the ability of a pathogen to make the leap between species . However, factors such as climate change, destruction of natural habitats and the wild animal trade increase the risk of spillover events occurring, as wild animals are forced into closer contact with humans [4, 18]. When looking for methods that limit the impact of emerging zoonosis we should, in addition to reassessing medical strategies and resources, also consider how we as a global population interact with the environment around us.
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