The COVID-19 pandemic has changed the world in ways like never before. All of a sudden, people are interested in knowing how viruses ‘jump’ from one species to another, parents are calling their kids to discuss how testing is done in two different ways and which one is more reliable (yep, it’s the nasty swab one), chat groups are brimming with continuously updated models, at least a fraction of zoom calls are all about brainstorming possible ways to bring the contagiousness of the virus, measured using R0 – the reproductivity number, below 1. And all this while, grandmas are advising kids to adopt social distancing and governments are talking about ‘flattening the curve’. This new wave of curiosity into the nitty-gritty of niche science subjects comes as a surprise and an opportunity albeit at the cost of tragedy we are currently facing.
Not unlike other pandemics of the past, understanding and learning about the disease and its implications will only help us be better prepared for the near-term and long-term future. I’m sure you have come across bats once or twice in your online travels in the past few weeks. Most scientists believe that the novel coronavirus (SARS-CoV-2) evolved quickly as it transmitted from bats to humans via an intermediate species. In fact, proposals have been made to eradicate the planet completely of bats given the history of previous deadly diseases that can be traced back to bats, including rabies, Ebola, SARS, Nipah, and MERS. No wonder when we think of bats, images of blood-sucking vampires, and Dracula pop up in our minds, and nope, Batman did nothing to make us love bats. But before we condemn them to hell, let’s ask science, are they really evil?
Why so… mysterious?
Picture source here.
Bats bring with them an aura of mystery and darkness, not only because of their deadly nature as infectious disease carriers but also because we hardly understand them at all. They remain the most deceptive and contradictory among all mammals, possessing rare talents such as sustained flight, echolocation, and hanging upside down for most of their life (called roosting, read why here). Their ability to fly often confuses us to think of them as birds. Indeed, bats share more with us than with any bird. The 1401 species of bats make up nearly 20% of all mammals, second only to rodents. Besides, even as bats harbor deadly viruses, they do not like to be around us very much. Bats are largely nocturnal, like to fly for most of their awake time, and the majority are certainly not after our blood. If anything, zoonotic virus transmission from bats to us may be attributed more to human encroachment into their isolated habitats than their intrusion into ours, as discussed here. They even help our species by being excellent pollinators, insecticides, and as natural models for developing sonars.
What has caught my attention and will be the focus of this article, however, is the bat immune system - an invisible but powerful feature that gives them a huge survival advantage over most other mammals by making them immune to high viral loads. This is no miracle, evolution has selected for the traits discussed below because they help bats survive a highly social and energy-intensive lifestyle. To understand how, let’s first take a broad look at how the immune system works in mammals.
Immunity 101
In organization and mechanistic action, the bat immune system is very similar to ours. They make the same types of white blood cells responsible for most immune responses like all other mammals do. To investigate how bat immune system is unique, we need to first understand a few key concepts of immunity, and to keep things simpler, we will refer only to the mammalian immune system when we talk about immunity. There are two distinct kinds of immunities: innate immunity and adaptive immunity. Innate immunity provides us with cells that are pre-programmed to recognize a set of sequences commonly found on germs, also called pathogens. These are variable enough to fight many kinds of pathogens, but not all. Innate immunity is genetically inherited, present at birth, and remains active throughout a lifetime. When a pathogen is identified, innate immunity activates cells that congregate and launch a war against it. Inflammation (like fire in a war) ensues, inducing heat, pain, redness, and swelling as anyone who has ever had an injury knows very well.
On the other hand, the adaptive immune system has to be built from scratch. It gains experience and ‘memory’ as the organism comes in contact with pathogens not recognized by the innate immune system. As such, it is extremely important to first make sure that one’s own cells are not identified as ‘foreign’. Hence, it is also constantly on the job of identifying and remembering the ‘self’ so as not to make ‘killer’ cells that may kill one’s own cells. This is called non-reaction, or immunotolerance. When this system goes awry, our body starts destroying our own internal systems. These conditions are called autoimmune disorders. Meanwhile, if a new pathogen is identified, new strategies are developed to fight it, and these strategies are often remembered, in case the same pathogen strikes back. This is how vaccines work, by injecting a tiny bit of dead or deactivated pathogens to enable the body to remember and fight them. The adaptive immune system takes longer to identify and kill pathogens, is extremely specific, and thus, results in lesser inflammation, if at all. Unlike war, it's like a well-orchestrated attack on a specific bad actor.
A peculiar immune system in bats
Although bats have innate and adaptive immunity as we do, a 2019 study from Duke-NUS Medical School, Singapore found that bats have an extraordinary capability to limit their reaction to pathogens, i.e. inflammation. While inflammation helps in fighting pathogens, it has some cost. Prolonged inflammation can cause permanent damage to tissues, as is also the case with COVID-19 causing severe inflammation in the lungs. The researchers discovered that bats have a uniquely dampened inflammatory response to high viral loads. They attributed it to lower activation of one specific protein (NLRP3), an important inflammation sensor, thus resulting in an underwhelming attack on the virus but also less tissue damage. A previous study had provided evidence of other inflammation-linked mechanisms missing from bats, such as an entire family of PYHIN genes. Hence, although the bat white blood cells identify the foreign object, they pick smaller battles to fight them rather than a huge war. But if there is no war (inflammation), i.e. pervasive killing of the pathogen, how do bats keep the virus in check and remain alive?
I get by with a little help from my friends
A 2020 research study by a collaborative group of scientists from the United States, Germany, Singapore, and the Netherlands showed that when compared to cells derived from our closer cousin, African green monkey, cells derived from bats showed a much higher anti-viral response in a very unique way. Immune cells from two species of bats (of 1401) responded to a viral infection in the lab with an accelerated production of a signaling molecule called interferon-alpha, which is part of the interferon pathway, a very important anti-viral action in all mammals. The interferon pathway activates an anti-viral response in neighboring cells, but the virus can still live and multiply in the host cell and spread to other cells, often with some adaptive changes in its sequence. In war terms, this means that the host cell keeps the virus intact, communicates to its fellow cells not to freak out and shield themselves against the virus. Simple, no mass destruction required (of both host cells and viruses). This, combined with the bats’ ability to curb inflammation, makes for an ideal environment for the virus to spread from cell-to-cell at a high transmission rate within the host, but without causing the host cells to die. Unfortunately, this works both ways. Researchers believe that it is not only the immune system which adapts to the virus, but the virus itself also learns how to trick the immune system to remain undetected or to become more resistant to action - thus turning from a regular virus to a super-virus, that can be potentially deadly if it encounters a different species. Talk about a perfect host!
Wait... but why?
The studies summarized above provide a clue into how bat immunity differs from most other mammals, but not why. Being the only mammal capable of sustained flight, bats have an extraordinarily high metabolism. They spend a lot of energy during flight, and multiple studies have shown that this comes with some selective genetic modifications compared to other mammals. The high metabolic rate results in a higher concentration of DNA-damage causing molecules called ROS (reactive oxygen species). This is usually kept in check by DNA Damage Repair (DDR) machinery. Scientists have shown that bats have evolved to have a greater number of genes that make DDR machinery hyperactive and make it possible to live long with high metabolic rates. Many of the DDR proteins are effective at fighting with DNA-containing viruses and even RNA-containing viruses like the coronaviruses, thus providing bats an extra shield of the immune response against viruses compared to other mammal species. Hence, another way to not cause war is to have smart defense systems that can fight with bad actors when they are still tractable before there is a need for war.
These studies reveal a few pieces of the puzzle of what makes the bat immune system so good at protecting them from diseases but also at hosting a myriad of viruses at any given time. Future research will elucidate how we, humans, can make use of these intelligent systems to help us get better at fighting with viruses. Can we just copy bats? Probably not exactly, but we can, in theory, tweak our immune systems to behave like bats’ in an event of deadly viral infection. As we learn more about proteins and molecules that are key to immunity against viruses, we might just be able to make our own immune cells stronger. Such research efforts take a long time and collaborative efforts are required from all over the world. With newer technologies that enable us to play with genetics, epigenetics, and immune response in a controlled manner, the principles of bat immunity can be effective in fighting pandemics. Until then, let’s not bat an eye and let these awesome creatures live as they do.
References:
4. Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host.
6. Unique loss of the PYHIN gene family in bats amongst mammals: Implications for inflammasome sensing.
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