Why do bats carry deadly viruses?
Apart from the fear that they summon up, what links Ebola and Marburg viruses, rabies, SARS, and even the new pandemic coronavirus we currently have circulating? The answer is that they’re all linked to bats, which seem to tolerate carrying these agents remarkably well. When they get into us though, it’s a different matter. So why are bats such a rich source of zoonotic viruses, and why are their infectious payloads so aggressive? The answer, it turns out, may be because bats are much more resilient, owing to the adaptations they’ve had to make in becoming airborne, and this means their viruses have had to become correspondingly more agile to compensate as well. Speaking with Chris Smith, Cara Brook…
Cara - My lab group published a paper last year where we were able to identify that bats are actually reservoirs for the world's most virulent viruses. But virulence means damage to the host. And in this case we mean virulence to a zoonotic host, so a human. So a zoonotic virus is a virus that spills over from an animal to a human. And in this case we collected case fatality rates of mammalian viruses that have spilled over to humans. And we were able to determine that those that come from bats cause higher case fatality rates than those derived from any other mammal. And so we wanted to understand why.
Chris - We're talking about things like Ebola here, aren't we? Which if it's in a bat, the bat doesn't fair too badly. When that gets into a person, you can have up to an 80% mortality rate.
Cara - Exactly. So with virulence it's important to define the host that you're talking about and what we've observed is that bats host these viruses as natural reservoirs and don't experience ostensible morbidity or mortality themselves. And they're reservoirs for several of the world's most virulent viruses, including rabies and related lists of viruses, Ebola and Marburg filoviruses, hendra and nipah, SARS, MERS, and most recently SARS-CoV-2.
Chris - Couple of questions immediately spring to mind. First question is, why have the bats got these really nasty viruses in the first place? And B, why don't they succumb?
Cara - Bats are the only flying mammal and we think that their resilience to viral infection is related to the physiology of flight. Flight is actually more metabolically expensive than any form of terrestrial locomotion. So a rodent at full speed running will raise its baseline metabolic rate up to seven fold when at full speed, and a human will raise it two or three fold, but a bat will raise its baseline metabolic rate up to 15 fold. So double that of all other mammals. And we would predict based on this high metabolic activity that they would be extremely short lived because normal metabolism results in the accumulation of oxygen free radicals, which then cause oxidative stress. But in spite of these really high metabolic rates, bats are actually the longest lived for their body size of any mammalian taxon. The oldest known bat, the Brandt's bat, it has been documented living up to 40 years in the wild. And so really what we think is that for flight to have ever become physiologically possible to begin with, bats had to first evolve really efficient mechanisms of oxidative damage mitigation. And actually viruses in a cell will incur oxidative damage on that cell and also recruit highly inflammatory immune cells to the site of infection, which causes further oxidative damage. So we think that bats evolved these cellular mechanisms that then enabled flight but had cascading consequences on their longevity and then on their resilience to viral infection.
Chris - So neat hypothesis. What did you actually do to test it though?
Cara - We did viral infection experiments on a series of bat cell lines and then estimated rates of viral spread. So in particular it's been shown that a couple of bat species have constituently expressed interferon alpha. And what that means is that they have a perpetually primed antiviral signalling system. So normally when a virus invades a cell, a mammalian cell will release this protein interferon that signals to neighboring cells that there's the presence of an infection and they need to induce this suite of antiviral responses. But in bats, or some bats anyway, it appears that this defense is perpetually primed. And so basically we grew three different cell lines, bat cells that were either constituently or induced in their interferon response, infected them with a suite of different viruses, and then used a monkey cell line as a control that's deficient in its interferon pathway. And then we modeled the antiviral response of the cell. And then when we estimated the rate of viral spread, we found that the antiviral response was matched by a higher within-host spread rate in the case of the virus. And so we hypothesized that viruses would evolve evolutionary optima in bats, so if a virus coevolves in a bat host, it's going, its baseline within-host spread rate is going to be fine tuned to match that of a bat, but then when it spills over or emerges into a non-bat, we would expect that that organism would experience extensive pathology.
Chris - In other words, the virus has tooled up in order to combat the bat resilience, which means that when it finds itself in a different host, for instance, a human where there isn't that enormous amount of pushback, it's got far more virulence than it needs to have.
Cara - Yeah, it's spreading faster and that then causes virulence. Usually viruses evolve to optimize or balance transmission and virulence. It's often asked why are pathogens pathological? Why do they cause damage to their host? Because it doesn't advantage the virus in any way to kill its host because the virus wants the host to sustain itself as long as possible so that it can continue to infect new hosts. So a virus will always evolve to maximize its rate of between-host transmission. If the virus kills its host too quickly, that's not going to optimize that between-host infection rate.
Chris - And just to finish, how does your current set of findings pertain to what we're seeing with this new coronavirus from China?
Cara - Covid 19 as a pathogen itself is less virulent than many of the previously observed bat viruses, but balancing that trade off it appears to be more transmissible. This virus has adapted and evolved to be transmissible in a human population and typically we would make the prediction that becoming more transmissible means that it's going to be less virulent. Many of these other bat-born pathogens, Ebola as a great example, cause human fatality much too quickly in order to transmit globally in the way that we've seen with this virus that has caused this recent outbreak.