Immune Anomalies: How Our Flying Cousin Became the Boogeyman of Virology




By Alexia Bove


What do Ebola, Coronavirus, and Rabies all have in common? This may sound like the start of a bad joke, but its a real question that many virologists have begun to ask, especially in light of the current Coronavirus pandemic. One of these viruses is responsible for hemorrhagic fever, one for severe respiratory disease, and one for central nervous system damage. They come from three distinct families of virus, and have entirely different structures. What could they possibly have in common?


The answer is more simple than one might think — bats.


In virology, a reservoir refers to an animal in which a virus naturally reproduces, often without showing symptoms of infection. These three viruses, along with over fifty others (that we know of) have all been linked to a bat reservoir. Diseases that can pass from animal reservoirs to cause infections are called zoonotic, and bats are known to carry more zoonotic diseases than any other animal (Sanicas, 2018). So what allows bats to safely harbor so many diseases that are devastating to the human host?


Recently, researchers with DUKE-UNS and the Wuhan Institute of Virology discovered that the answer may lie in the unique immune system of bats — one that is actually less active than that of humans. In 2019, the Ahn group published a paper in Nature Microbiology proposing a mechanism for how bats are able to control their immune response, resulting in the ability to limit the amount of inflammation caused. They do this by reducing activation of a signaling pathway that releases chemicals called cytokines, which act as chemical messengers, inducing an inflammatory response meant to fight off pathogens. We think of signaling pathways as dominoes falling down, with the last domino to fall causing an immune response. Bats are able to stop the first domino from being pushed down, and therefore block the chain reaction that would lead to inflammation. This is possible because the bat’s genome codes for a receptor protein, called NLRP3, that has a slightly different shape that the human version of the protein, which makes it less efficient in transmitting the signal needed to activate the inflammatory response (Ahn et al., 2019). Overall, this paper supports that bats have an enhanced innate immune response rather than an enhanced antiviral defense. This tight regulation of inflammation allows bats to remain asymptomatic while still carrying large amounts of the virus— a perfect storm that allows bats to be the ideal reservoir host.


How can something as counterintuitive as decreasing the immune response be helpful in dealing with such formidable pathogens as Ebola and Coronaviruses? It turns out that while many people associate the pro-inflammatory immune response with killing pathogens, it also does a massive amount of damage to the very organism it's trying to protect. Besides a bat reservoir, the aforementioned viruses have another thing in common — many of the symptoms associated with them are direct results of the immune system’s activity. For example, in COVID-19 patients, overactivation of the inflammatory response has been shown to contribute to intense tissue damage, formation of clots within the blood vessels, and organ failure, all of which contribute to adverse outcomes in those infected (Vaccari et al., 2020). The brilliance of the bat immune response is that through it’s tight regulation, it is able to toe the line between effectiveness and safety, functioning enough to protect the organism from being overrun by the pathogen, but limiting the damage caused.


Understanding the mechanisms by which bats regulate their immune systems could have a profound impact on how we treat infectious disease. These novel findings enable scientists to ask new questions, such as can we create drugs that block pro-inflammatory receptors to decrease their activation frequency? It also gives us a possible glimpse into the future of our species. Humans and bats are both mammals and have many physiological similarities - including many of the same immune pathways. What separates us from our flying cousins in disease response is that what we consider to be an ‘emerging’ pathogen is one bats have co-evolved with for decades, allowing their immune systems to adapt in a way ours haven’t. It’s possible that one day we too will be able to carry these viruses without the intense affects we all know too well. However, this is a slow process, and one we might not have the time to wait for. As humans living in an age where viral pandemics occur with increasing frequency, maybe it’s time we take things into our own hands, and learn some lessons from the bat.



References


Ahn, M., Anderson, D.E., Zhang, Q. et al. Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host. Nat Microbiol 4, 789–799 (2019). https://doi.org/10.1038/s41564-019-0371-3


Sanicas, M. (2018, August 29). What Makes Bats The Perfect Hosts For So Many Viruses? https://healthcareinamerica.us/what-makes-bats-the-perfect-hosts-for-so-many-viruses-3274c019bb4d.


Vaccari, J. C. D. R., Dietrich, W. D., Keane, R. W., & Vaccari, J. P. D. R. (2020). The Inflammasome in Times of COVID-19. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.583373





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