Humans get a surprising number of very infectious diseases from bats. We get SARS (including the recent COVID-19/SARS-CoV2), Ebola, rabies, and possibly mumps. These are all incredibly infectious, deadly diseases.

This seems weird because human beings aren’t in particularly close contact with bats. They’re nocturnal, don’t have large city populations (for the most part), and humans don’t eat them that often. It should be harder for diseases to pass from them to us. They’re also not very similar to us genetically, so their diseases shouldn’t be able to leap to us so easily.

Part of the answer is that bats are very social creatures. When one bat gets a virus, they pretty quickly pass it onto the other bats in their colony. However, that’s also true of goats and cows, who don’t seem to pass on infectious diseases to us as often.

The more important part of the answer is that bats are “reservoirs” of some particularly virulent viruses. Bats live with long-term infections of SARS or Ebola and are seemingly ok with it. While humans and other mammals either have to clear these viruses from their body or die, bats do not. They will just keep on keeping on, sometimes shedding the virus, sometimes not. It’s more likely that the bat will shed the virus during stressful times (i.e. when it’s in a cage and about to get eaten).

That’s what seems to have happened with COVID-19. A bat shed the SARS-CoV2 virus at some point, probably in a wildlife market. The virus at this point was not in state where it could infect humans. However, viruses can both mutate (change shape) and recombine (swap parts) rapidly. Coronaviruses are especially good at recombining.

The SARS-COV2 virus was shed from a bat (possibly from its saliva or droppings), seems to have recombined with a coronavirus in a pangolin (who was probably in a cage right next to it), and then was in a form where it could be transmitted to a human. Once it by chance was in the right form, that virus could successfully spread itself to humans everywhere.

That’s the short version. There’s an interesting question, though: why don’t these viruses kill bats? Ebola, SARS, and rabies all kill their hosts pretty quickly. How can bats live with these viruses year after year?

Well, that’s complicated. This is going to require a dive into the immune system. Before I start, two brief caveats:

When I discuss bats, I’m discussing 1300+ species across almost every continent. Not all bats are the same, and we haven’t really studied most bats. Generalizations are necessary, but just be aware that they’re happening and might not apply to specific bat species. I’m also generalizing across all bat cells, and what’s true for a cell in the abdomen is not going to necessarily be true for a cell in the testes or brain. When I discuss immunology, I’m discussing an incredibly complicated subject that we still don’t know a ton about. The immune system is the defense force for the entire body, which is a hard enough job in the first place. However, it’s also been in an arms race with bacteria, viruses, and parasites for billions of years, developing defenses, countermeasures, and counter-countermeasures. Discussing the immune system is like discussing season 4,500,000,000 of a TV show that started complicated to begin with.

With those caveats out of the way, let’s start exploring why the bat immune system is so different from humans. Both bats and humans are mammals, which means we have roughly similar immune systems and roughly similar responses to viruses.

When a virus comes into the body, its goal is to invade cells, take over their production capabilities, and use the production capabilities to produce more viruses. Then those viruses produced do the same. It also wants to spread itself outside the body (i.e. by a cough). Viruses want to do this ideally without being noticed by the immune system, and certainly without being disrupted by the immune system.

The body’s goal is, basically, to stop all that. The body wants to stop viruses from coming in. If a virus does come in, the body wants to kill it before it invades any cells. If it does invade a cell, the body wants to know about it immediately. Then it wants to kill that cell and anything inside it. The cell’s role is to let the body know if it’s been invaded, let other cells around it know that it’s been invaded, and to contain the invasion as best as possible.

That is a really, really high level overview. There’s a lot of complexity hidden in there. But, it’s enough that we can dive into the specific difference between bats and humans: the cell’s role in the immune system.

In humans, the individual cell’s role in the immune system is a lot like those “if you see something, say something” posters. Human cells recognize viruses as a sort of lock and key by their pattern recognition receptors. Once they recognize a virus, they start producing interferon.

Interferons interfere with viruses, hence their name. They work as both suppressant and alarm, making it harder to make proteins and RNA (building materials of viruses and human cells), promoting gene p53 (which starts the cells’ self-destruct sequence), alerting the body’s T and NK cells (which kill infected cells), and promoting high temperatures (which make it harder for viruses to replicate).

There are 3 types of interferon: alpha, beta, and gamma. They have a lot of overlap in functionality, but the most important difference is that it seems like alpha acts as the gas in the immune system and beta as the brakes.

That distinction is really important, because that ends up being the key difference between the bat immune system and humans’, as well as the key to why bats can carry these deadly infections.

Bat cells do not work on a “see something, say something” model. Instead, bat cells just continually “say something”. Instead of recognizing viruses and then producing interferon, they continually produce interferon alpha and seem to produce almost no interferon beta: all gas, no brakes.

In other words, bat cells just continually assume they’re under attack and never stop fighting viruses, regardless of whether they’ve detected any. This is surprising. Interferon is a really powerful molecule, and continually producing it should have the same effect on a cell as continually putting a factory on red alert. It should make the cell run much worse, and cause a lot of collateral damage.

After all, when this sort of immune system overreaction happens in humans, humans get serious disorders, like Multiple Sclerosis and Lupus. Bats do not tend to get these. In fact, many bat species live around 20 years on average, which is not only way longer than it should have with its overactive immune system, but is exceptionally long for such a small animal. To give a comparison, rats live a year or two, as do rabbits.

So, how do bats live so long with a hyperactive immune system? Well, the answer seems to be that although their interferon is continually produced, their immune system is never allowed to go to the same extremes as human immune systems.

There’s a couple ways in which they don’t go to extremes. For one, bats seem to lack Natural Killer (NK) cell receptors, which may mean they lack NK cells. NK cells are as heavy duty as their name implies; while their cousins, T cells, kill any cell that displays signs of being infected, NK cells kill any cells that don’t display signs of being not infected. Viruses will frequently prevent cells from indicating that they’re infected, so NK cells just kill any cell that looks like it’s hiding something. Needless to say, this results in a lot of collateral damage.

For another, bat cells also lack a lot of the pathways to go into apoptosis (self-destruct mode). In a human cell, the production of interferon starts readying the cell to self-destruct and stop the virus from using the cell’s machinery. Bat cells lack an associated protein, and seem to have some significant changes at the related p53 gene.

So, bat cells are always ready to fight viruses, but never ready to go the extremes of “kill or be killed” that human and other mammal cells are. This actually works out well for bats. A lot of the damage done in a viral infection is by the overreaction of the immune system in “cytokine storms”, like in the 1918 flu epidemic. Bats avoid all of that.

So, bats just live with the infections instead. They fight them enough that the viruses can’t take over their body, but they don’t clear the infections. This balance can get upset, though, when the bat gets stressed. For instance, when bats get white nose fungus, a really deadly and stressful disease, they also end up with 60-fold higher levels of coronavirus in their intestines.

An added bonus to this is that the lower levels of inflammation in bats might cause their relatively long lifespan by making their biological aging slower. This is an interesting avenue of research for people as well.

Last question, and here’s the most interesting one. Why are bats like this? What made their immune system so weird?

Well, it actually has to do with their flying. Bats are the only mammals that fly. Flying is a really energetic process and can raise bats’ internal body temperature up to 41 degrees Celsius (106 degrees Fahrenheit) for an extended period of time.

That’s really hot. In humans, that would cause serious brain damage. In bats, it’s enough to damage DNA through the production of reactive oxygen species, as well as to release the DNA into the cytoplasm or bloodstream.

This meant obviously that bats had to be really good at regularly repairing their DNA, a tricky process that can lead to cancer. But it also meant that bats couldn’t rely on the classic immune system trick of recognizing foreign pieces of DNA. In other animals, those were likely strands of DNA from a virus or bacteria. In bats, those were likely just pieces of bat DNA that had been damaged and let loose in the wrong place.

Recognition couldn’t work in the same way. So bats’ immune systems decided to be always on, instead. Then, to avoid the problems with that, bats’ immune system also evolved to never reach the same levels of inflammation as other mammals. The end result was that bats were much more able to live with deadly viruses, neither ignoring nor overreacting to them.

Neat, huh?