Bats may be uniquely capable of sustaining viral infections in their population clusters, due to a mix of behavioural and biological factors.
Behavioural factors include: the social structure of bat populations, in which distant clusters infrequently mix with each other, lending itself to repeat infection and viral persistence, sonar leading to increased droplet production and gregarious roosting leading to high levels of contact
Biological factors are focused on systems that are designed to prevent the chronic inflammation and cellular damage normally experienced by high-energy mammals. These have the effect of increasing bat lifespan and generating a unique anti-viral immune response that limits viral replication, as opposed to viral clearance. It is thought that viral specialisation to counteract these responses may lead to more severe disease when they jump into humans
As the long summer days in San Antonio, Texas draw to a close and the residents bed in for a sweltering evening, the majority of its inhabitants are just waking up. Just outside the city, at a crescent-shaped opening in the ground, something extraordinary is about to happen. As dusk settles, a vast plume emerges and fills the sky. A writhing, tumultuous mass 30 miles long and 20 miles wide pours out of the opening and spreads into the Texas countryside. This phenomenon happens every evening throughout the summer and is the result of the largest known concentration mammals anywhere on the planet. The boisterous inhabitants are bats, specifically the Mexican free-tailed bat. The crescent-shaped scar in the ground opens out into the Bracken Cave, which is the summer home for over 20 million free-tailed bats. They are a crucial part of infrastructure of the area, hoovering up several tons of insects per night, protecting crops in the process. They also contribute to the pollination and reseeding of plants and forests as they search for food.
U.S. Fish and Wildlife Service Headquarters / Public domain
This population is not alone in its density – indeed, bats are possibly the most abundant, diverse and dispersed vertebrate on the planet. Found on every continent except Antarctica, 20% of all mammalian species that have been identified are bats.
Bats are also old, extremely old. The only mammal to have ever evolved powered flight, these creatures first appeared in fossil records around 50 million years ago. This was a tumultuous period for mammals; not long before bats emerged, mammals had been forced to re-establish themselves after the most cataclysmic extinction event on record.
For the majority of their coexistence, humans and bats had little opportunity cross paths. Bats are nocturnal and their habitats consist of caves, mountain overhangs and other ecological features incompatible with early human life. Even as humans began to swell in number and urbanise, burgeoning cities rarely encroached into these habitats or the dense forests and jungles where bats do most of their hunting and foraging. However, as city limits have been pushed outwards ever further and natural habitats felled in their wake, humans have come into closer and closer contact not only with bats, but with other animals with which we have never previously interacted.
It is through this uneasy proximity to wildlife that humans have become aware of so-called zoonotic diseases, which are those that ‘jump’ from animal hosts to cause disease in humans. Bats have been identified as an animal reservoir for a number of infectious diseases that cause severe disease in humans, including rabies, Ebola, and the coronaviruses responsible for the 2003 outbreak of SARS, the ongoing outbreak of MERS and the COVID-19 pandemic.
Though the viruses responsible for these diseases often made their way into human populations through other animals – primates are thought to be largely responsible for the spread of Ebola into human populations and the palm civet is thought to have introduced SARS to people working in meat markets – bats have been identified as key reservoirs in each.
As the world battles the COVID-19 pandemic and strives to understand the SARS-CoV-2 coronavirus, attention has turned to its roots. With bats once again coming under the spotlight, a great deal of work is being carried out to understand why these unassuming creatures harbour so many of our greatest biological threats. It is hoped that by better understanding the bats that act as reservoirs for infectious disease, we may better understand SARS-CoV-2 and prevent future incursions of zoonotic diseases.
Major reviews into the factors that make bats such good viral hosts were published after the SARS epidemic of 2002-2003. These are receiving new attention in the wake of the emergence of SARS-CoV-2 and have stimulated a number of new studies investigating a range of factors from the dynamics of bat nesting to the unique features of the bat immune system that make them perfect hosts.
Longevity
Bats have a surprisingly long lifespan for a mammal of their size and metabolic rate. Generally, the smaller and more active mammals are, the shorter their lifespan. This is because periods of intense activity generate substances called reactive oxygen species and free radicals that can damage cells and tissues. Over time, this damage accumulates and ultimately limits the lifespan of the animal. Bats, despite being relatively small animals that use up huge amounts of energy through powered flight, have a surprisingly long lifespan. While similarly sized mammals may live for 2 or 3 years, bats can live for up to 35 years.
It has been proposed that if bats can become persistently infected for the duration of their lifespan, and infections are not resolved quickly, infections can be endlessly sustained in populations.
The impact of a long life on viral circulation can be seen on deeper investigation of the R0 – the basic reproduction number, which states how many infections are likely to arise from a single case in a susceptible population. R0 can be summarised as combination of three factors:
From the relationship described above, it is clear to see how a long lifespan and an inability to quickly resolve viral infections could lead to increased contacts and duration of infectiousness and, ultimately, a consistently high R0 value.
Population Structure
Bats tend to roost in enormous populations. Their caves can be tumultuous, with individuals fighting to maintain their perch and flapping their wings to stay balanced and ward off nearby bats trying to steal their spot. This gregarious nature increases the likelihood of community transmission. This behaviour is thought to be directly linked to the only documented discovery of airborne rabies transmission, described in a community of bats.
The integration of distant populations of bats is also thought to be crucial in maintaining viruses for prolonged periods. Bats often exist as metapopulations – distinct groups of the same species living apart from one another. Periodic interaction between infected and susceptible individuals from different metapopulations can sustain viral infections indefinitely. These disease dynamics are summarised in the animation below:
Bat-specific Behaviour
Bats are one of the very few mammal species that can echolocate. This navigation, hunting and foraging technique sees bats generate a high frequency ultrasound wave in the larynx. Bats then use this as a biological sonar, detecting the location of surrounding objects by the echoes of the ultrasound signals.
Work has been carried out that links this echolocation behaviour with increased viral spread. Bats use the muscles in the larynx produce an extremely loud sound, which may have the side-effect of increased production and spread of the kind of droplets and aerosolised particles that contain active viruses.
The Immune System
Though not the initial barrier to infectious pathogens – the skin and mucous membranes are designed to prevent entry of infectious agents in the first place – the immune system is the most important method of fighting pathogens. An intricately integrated system of cellular interactions, the immune system is primed to recognise, destroy and protect against pathogens and other foreign objects. As mammals, the bat immune system is very similar to our own. A number of the cells and proteins that moderate clearance of infectious diseases can be found across mammal species, including the antibodies that are responsible for lasting immunity.
This leads to the question that is at the heart of why bats offer so much intrigue – why, despite having such similar immune systems, can viruses infect and persist in bat communities without causing severe disease, yet be so infectious and deadly in humans?
It was established after the epidemic of SARS that bat populations in southern China were the most likely candidate for an animal reservoir: an astonishingly high proportion of bats tested positive for antibodies to SARS-CoV (up to 84%) but there was no sign of any symptoms in any population.
There is still far more work to be done to understand the dynamics of how viruses interact with bat immune systems. Viruses are known to evade the immune response in many ways, such as the release of small chemicals that switch off immune cells. Might viruses be more able to escape the bat immune system than that of other mammals?
There is some thought that viral persistence in bats may occur because their immune systems have a different goal to ours. It is possible that bat immune responses operate with a focus on limiting the level of viral replication, as opposed to aiming for total viral clearance.
Recent work in response to the pandemic spread of SARS-CoV-2 has added to this theory, that bats respond to viruses completely differently to other mammals. The work centres around a unique feature of bats described previously in this piece – their remarkably long life. At first glance, bats should not live as long as they do. As the only flying mammal, they raise their metabolism to twice the level of a similarly sized animal running. This should be problematic. Sustained high metabolic rates can lead to tissue damage through the release of small molecules and chronic inflammation at sites of minor damage. This partly explains why small mammals with high heart rates have such short life spans; they accumulate too much damage.
Bats, though, are seemingly capable of removing these damaging substances with the ‘hair-triggered’ release of signalling molecules, the most important of which is called interferon-alpha. The rapid release of interferon-alpha, far faster than in other organisms, may have the side effect of limiting the damage that the host immune system causes to the host’s own tissues as viral infections are cleared.
Interestingly, in experiments designed to determine how bats respond to various viruses, viral infections were slowed, but not wiped out completely. This poses the question of whether bats can remain asymptomatically infectious throughout their lifespan, hosting glowing embers of viral replication, ready to ignite in a susceptible host.
It is this unique response against viruses by bats that may explain why those very viruses are so dangerous when they jump into humans. Viruses seem to ramp up their rate of replication in bat hosts to counteract the spring-loaded antiviral response. When those viruses jump into humans, they maintain their high replication rate. This is problematic for the new hosts, as we are less able to immediately suppress viral replication than bats. The aggressively expanding viral populations are then free to wreak havoc.
Recent work that studied bats populations in the region in China from which SARS-CoV-2 is thought to have originated from further clarifies this theory. The Chinese study found that a very small, yet significant, mutation exists in one of the proteins that controls the immune response to viruses. This small change in this protein, called STING, resulted in a slightly reduced production of interferon-beta, a small signalling molecule that controls inflammation and antiviral responses. The reduced level of interferon-beta was not only still enough to control the replication of the virus, but also has the added benefit of preventing the unintended damage to the tissues that causes most symptoms of infection.
It should be said that there are numerous bodies of work that disagree with the research outlined here. It has been claimed that bats are in fact not special at all; it may just be a numbers game. After all, it isn’t surprising, given the sheer number and diversity of bats and their relative similarity to us, that spill-over events occur. If there really is nothing special about bats, then further research should perhaps be directed at regions of overall diversity, not just a specific species.
The emergence of SARS-CoV-2 surprised few in the virology community. It was always a matter of when, not if, a new virus would jump into humans and become a pandemic. Humans are expanding into animal habitats which, along with social and cultural practices, bring us into closer and closer contact with animals that may bear potentially deadly diseases. We must do more to understand the dynamics of how viruses jump into humans and become specialised to infect new hosts. With numerous animal species, and particularly bats, identified as the key reservoirs of emerging viruses, it is clear that the more we understand about the species around us, the more we can understand, and prevent, emerging diseases.
