BAT SUPER IMMUNITY
The most recent case count for SARS-CoV-2 infections around the world total over 12.5 million with over 560,000 deaths and counting. The United States alone accounts for 25% of world coronavirus cases despite comprising only 4% of the world’s population, becoming the leader in COVID-19 cases – a statistic the country (and the administration) should be immensely concerned about. Though significant progress in the past several months has been made in understanding the pathology of SARS-CoV-2, the epidemiological characteristics, and clinical features of this virus – many questions still remain that can inform the development of therapies and prevent the spread of another virus with pandemic potential. One area of underexplored study surrounds the impact of viruses in bats. Accumulating evidence suggest Ebola, MERS-CoV, SARS-CoV, and SARS-CoV-2 originated in bats that can induce severe disease in humans, which further highlights the ongoing threat of bat-borne viral emergence. One particular question that has arisen is how bats are so adept at surviving infection from these RNA viruses, yet humans suffer much more intensely? What is it about a bat’s immune system that makes them so enduring?
Before we jump into what makes a bat so averse to disease, we must first understand the differences between bat and human SARS-CoV-2. A study published in February this year showed 96% genetic sequence similarity of human SARS-CoV-2 with virus found in a bat from Yunnan, China. When a pathogen jumps from a non-human animal to a human, a process known as zoonoses, it can exploit the new host’s lack of defenses and cause illness. Although an intermediate host responsible for the zoonotic transmission cannot be ruled out, the evolutionary data suggests “spillover” likely occurred in bats before being passed to humans.
The major difference between the two is the presence of a receptor binding domain found on the spike protein of the human coronavirus, which is critical to their success in entering host cells. What makes SARS-CoV-2 so infectious and fatal is its ability to infect both the lungs and upper respiratory tract. Common cold coronaviruses primarily infect the upper respiratory tract, making transmissibility between individuals very high. While MERS-CoV and SARS-CoV infection in the respiratory tract is more challenging than common cold coronavirus infections, they are much more successful at infecting the lungs, resulting in damage to lung cells that aid in shuttling oxygen into the bloodstream. Combining the transmissibility of the common cold coronavirus with the lethality of MERS-CoV and SARS-CoV results in a dangerous combination that leads to significant infection rates and high mortality (if the infection progresses to the lungs) observed in SARS-CoV-2. In response to lung damage, a robust immune response will work to clear viral infection. In some cases, overreaction of the immune system can cause hyperinflammation and cytokine storm that may lead to permanent lung damage, multiple organ failure, and death.
Previous studies have demonstrated that bats have primed immune systems that are continuously prepared to mount defenses against viruses. Unlike humans, bats keep their immune defenses switched on at all times. They do this by producing a signaling molecule called interferon that triggers cells to go into a defensive state. In humans, a hyper-vigilant immune response would lead to high levels of inflammation that lead to significant damage – but bats have uniquely adapted anti-inflammatory mechanisms that protect them from harmful, self-destructive effects. The classic pathology and disease symptoms to viral infection caused by hyperactivation of the immune system in humans does not occur in bats.
A study published by first author Cara Brook and collaborators from a number of institutions including UC Berkeley, Princeton, and Utrecht University wanted to investigate whether this rapid immune response observed in bats affect a virus’ evolution and ability to kill host cells. To study this, they performed experiments on cultured cells from two cell lines derived from bats with primed immune systems and one control monkey line that does not produce interferon at all. Interestingly, the two bat cell lines were able to hold off infection from three different viruses due to heightened antiviral response and conceivably higher interferon signaling, whereas the monkey line succumbed to infection and was killed by the viruses.
Brook then created a computational model to study the bat immune system in response to infection and found a paradox – while interferon signaling hindered the ability of the virus to kill bat cells, the heightened response ultimately seemed to benefit the virus by allowing it to adapt to the bat’s defensive regime, allowing it to spread more quickly from cell to cell. This suggests that even when bats are infected with viruses that make humans terribly sick, they do not exhibit noticeable disease symptoms. Instead, they carry viruses as long-term persistent infections. Based on their predicted model, the evolution of a faster transmitting virus without causing damage to the bat is driven by interferon signaling and immune defenses. While bats are protected by their heightened immune response and anti-inflammatory traits, the evolutionary adaptation of the virus makes it more virulent to other hosts with immune systems that diverge from them. This includes pigs, pangolins, and humans. Unfortunately, spillover into any one of these hosts will likely be damaging and life-threatening.
Bats represent a largely uncharacterized but critical source of known and unknown human pathogens. Though computational models and cell lines provide important means to study animal viruses, the current tools to functionally characterize them do not meet the scale at which bat viruses are discovered. While methods to develop vaccines and antivirals are rapidly progressing that allow researchers to respond faster to the next outbreak, it is equally important to learn more about the molecular mechanisms underlying zoonotic infection and immunity to help scientists develop better ways to prevent or limit the spread of viruses from bats to humans. It is just as important to understand the trajectory of an infection to predict emergence, spread, transmission, and most importantly, pandemic potential.
Among humans, the majority of disease outbreaks are the result of zoonotic diseases. And for the last few decades, the number of zoonotic diseases has been increasing. There is an inextricable link between the health of humans, animals, and the environment. And with the ongoing COVID-19 pandemic, a considerable increase in knowledge on viral emergence combined with tracing viral transmission from bat to human is needed to prevent the recurrence of this 2020 viral fiasco.
By Anthony Venida
1. https://pubmed.ncbi.nlm.nih.gov/32015507/
2. https://www.biorxiv.org/content/10.1101/2020.03.30.015008v1.full
3. https://elifesciences.org/articles/48401
P.S. Wear a mask.
