Bats & Viruses

Greater horseshoe bat

Image credit: Wikimedia. A Greater Horseshoe Bat.

Summary

The "novel" coronavirus that is currently causing a global pandemic was probably transmitted to humans from bats, either directly or through another host species. Bats can carry numerous viruses, for reasons that are related to their natural history and their molecular biology. The same evolutionary changes that allowed bats to fly also changed their metabolic systems and immune systems in profound ways. These changes have two important outcomes: bats live unusually long for small mammals, and they host a lot of viruses. The underlying genetic mechanisms are connected to some of the core concepts of Bio 6B.

Introduction

bat coverI’ve always liked to start off Bio 6B by showing my students a recently published scientific article that’s related to the course. At the beginning of Winter 2020, I used an article that had recently been featured on the cover of Science Magazine: Comparative Analysis of Bat Genomes Provides Insight into the Evolution of Flight and Immunity. The article is about bats, which are just plain interesting, and it connects several facets of biology that I would normally cover in 6B, so it seemed like a relevant choice for the class. At the time, however, I had no idea just how relevant this piece of molecular biology was about to become. By the end of that quarter, a coronavirus derived from bats swept through the human species, starting a global pandemic that would change everything about how we live. Suddenly, bats went from being a strange and often-ignored branch of the mammalian family tree to playing a key role in human health.

This quarter, I plan to connect some of the core concepts of Bio 6B to coronaviruses and the bats that carry them. Throughout the quarter you'll see references to coronavirus. It's not that the whole course is about the virus; it's that the virus is connected to many different aspects of cell and molecular biology.

How did bats become bats?

Bat phylogeny from Zhang et al.Bat phylogeny and genomic differences, from Zhang et al.

Bats share a common ancestor with all the other mammals, but there are some big differences between bats and all the other mammals. If I asked you to compare bats to other mammals, you might start by pointing out structures that you can see, like wings, or unique behaviors such as echolocation. That would be an organismal biology approach, like you used in Bio 6A. The researchers who wrote the bat genome article used a molecular biology approach to the same question. Rather than asking what differences they could see, they asked which sets of genes were most different in bats compared to other mammals. 

What they found was surprising. The most prominent genetic differences in bats relate to metabolic rates, lifespan, and immunity. As it turns out, those distinctive genetic features tell us a lot about how bats became bats.

Bats have high metabolic rates

Bats are the only mammals capable of powered flight (gliding doesn't count). It takes a lot of energy to fly, so as bats evolved to become flying mammals, their metabolic rates increased. This entailed an increased rate of oxidative phosphorylation (OXPHOS), the part of cellular respiration that generates most of the ATP energy that’s required for muscular work and other cell activities. You'll learn about the mechanisms of oxidative phosphorylation and ATP use in detail later this quarter.

Oxidative phosphorylation efficiently generates ATP, but this oxidative process comes at a price. OXPHOS also generates dangerous oxygen radicals (reactive oxygen species, or ROS). The higher an animal's metabolic rate, the faster it generates ROS. We'll take a close look at why this is so when we investigate cellular respiration later this quarter. These ROS cause cellular damage, including DNA damage. The DNA damage caused by ROS can cause cancer and contribute to aging. 

So bats, by virtue of being high-energy fliers, would seem to be doomed to short lives and high risk of cancer. However, that's not the case.

Bats are long-lived

In general, the maximum lifespan of a mammal can be predicted from its body mass. Larger mammals live longer than small ones. However, bats live much longer than other mammals of the same size. For example, a mouse might have a maximum lifespan of 2 years, while a bat of the same size could live 20 years. For people who would like to live long and healthy lives, the longevity of bats is an intriguing mystery. Aging is controlled (at least in part) by cellular and molecular processes, including:

  • Oxidative damage resulting from OXPHOS.
  • Telomere shortening on the ends of chromosomes.
  • Epigenetic changes, meaning that gene expression changes over time.
  • Cell cycle control mechanisms such as the p53 pathway, which regulate the tradeoffs between aging and cancer risk.

You'll learn more about all these mechanisms in Bio 6B. However, the mystery will remain: how do bats avoid these age-related processes and live such unexpectedly long lives?

Bats carry viruses

All organisms can be infected by viruses, but bats seem to carry more than their share of viruses that are potentially dangerous to humans. Examples include rabies, marburg, ebola, and various coronaviruses. In many cases, the bats don't seem to suffer much harm from the viruses, even when they are deadly to humans.

It's not completely clear why bats carry so many viruses, but several hypotheses have been proposed, including:

  • Bats fly. They often disperse long distances to find food; this increases their exposure to pathogens (disease-causing agents) such as viruses. Animals that don't travel as far might encounter fewer viruses.
  • Bats live a long time, which increases the number of viruses they'll encounter in their lifetimes.
  • Bats roost in large groups. Because they are primarily nocturnal, bats often spend their days in torpor (a low-energy state), and many species of bats gather in large groups in caves or other roosting places. These habits make it easy for bats to spread the viruses they carry.
  • Bats' immune systems might function differently than those of humans, allowing them to tolerate the viral load without disease.

It's clear that bats have some unusual biology that's both potentially useful and potentially harmful to humans. With that in mind, researchers set out to investigate bat genomes and biology.

 Bat genomes

There's a lot that remains unknown about bat physiology and how bats live with so many viruses. In some cases, the ultimate answers to those questions will come from detailed molecular studies of live bats and bat cells in culture. However, there is a quicker way to get some preliminary answers: investigating bat genomes. If bats function differently from other mammals, those differences will be reflected in their genomes. With that in mind, a group of researchers (Zhang et al., listed in the references section below) sequenced the genomes of two kinds of bats in order to ask a basic question: how are the genomes of bats different from the genomes of other mammals?

Genomes and genes

An organism's genome is its complete set of nucleotide sequences. If you look at the raw data from a diploid human genome, you'd find around 6 x 109 nucleotides, represented by the letters G, A, T, and C, and divided into 46 chromosomes. The genome includes all the genes, but it also includes a vast amount of other DNA sequences that don’t code for proteins. Bat genomes tend to be about a third smaller than those of humans, but they still contain billions of nucleotides.

Whether you want to study a human genome or a bat genome, it would be impossible to make any sense of all that data without software. (Later this quarter, you'll use some sequence analysis software to identify specific features of some DNA sequences). In principle, you could use software to simply compare the nucleotide sequences of genomes from two different species, but you'd find numerous differences, and it wouldn't be obvious which genetic differences are biologically significant. Therefore, the bat researchers used a more targeted approach: they focused on protein-coding genes.

The first step was to take the raw nucleotide sequence data and look for genes. In this study, a gene is a section of DNA that encodes a protein. (Later this quarter I'll give you a better, more detailed way of defining genes, and you'll learn to use software to identify genes in a DNA sequence.) Once the researchers identified the individual protein-coding genes in bat genomes, they asked a basic question: which groups of genes evolved most rapidly in bats? In other words, which kinds of bat genes are most different from the genes of other mammals? The researchers found rapid evolution in genes connected to three different processes: OXPHOS, DNA repair, and the immune system.

OXPHOS genes

Genes related to ATP production by oxidative phosphorylation have evolved rapidly in bats, allowing bats to meet the increased energy demands of flight. Some of these genes are found in the nucleus of the cell (the nuclear genome), and some are in the mitochondrion, a cellular organelle that has its own genome and chromosome. Thus, there are two different genomes involved, each of which encodes some of the proteins involved in OXPHOS. In bats, the OXPHOS-related genes of the mitochondrial genome evolved particularly rapidly, faster than genes in the nuclear genome. These mitochondrial genes encode, among other things, some of the proteins involved in the electron transport chain, which we will investigate later in Bio 6B.

DNA Repair

As mentioned earlier, OXPHOS generates essential ATP, which is needed for flight and other work, but it also generates dangerous oxygen radicals (ROS). Bats, with their high metabolic rates, would tend to be subject to a lot of ROS, and therefore a lot of DNA damage. However, there is an evolutionary solution to this problem. 

All oxygen-consuming organisms have mechanisms to reduce or repair the damage; we'll look at some of those later this quarter when we look at cellular respiration. The DNA damage response pathway is an essential part of all eukaryotic cells' adaptations to ROS. In bats, the genes involved in the DNA damage pathway have evolved rapidly, which is likely to be connected to an increased ability to repair the damage caused by increased metabolic rate and ROS. Genes related to the DNA repair pathway include p53, mdm2, and BRCA, all of which you'll encounter later this quarter as part of cell cycle control. The end result of the evolutionary changes in this pathway seems to be that bats are better at dealing with DNA damage, compared to most other mammals. Even though the damage may occur at a high rate, bats can fix it, and they can stop the damaged cells from causing harm to the rest of the body.

Immune system

DNA damage in cells can activate a DNA repair pathway, stop the damaged cell from reproducing itself, and activate immune system pathways such as inflammation. Sometimes this immune system activation can be beneficial, because it helps to trigger repair processes and to eliminate cells that are damaged beyond repair. However, bats probably experience a high rate of DNA damage and other cellular damage because of the high energy demands of flight. If this damage was allowed to continually trigger inflammation, the inflammation response might do more harm than good. In bats, the inflammation response to cellular damage seems to be reduced, so necessary repair processes are initiated, but the immune system doesn't cause further damage through excess inflammation. This is good for bats, but turning down parts of the immune response may also mean that they can carry more viruses.

The immune response to cellular damage overlaps with the response to viral infection. Bats apparently have the ability to turn up a part of the innate immune system that fights virus replication, while turning down the kind of inflammatory immune responses that can cause severe and potentially damaging inflammation. This is particularly important in the context of the COVID-19 pandemic, because much of the damage in severe cases of the disease is caused by the victim's own immune system. Bats don’t seem to have this problem, even when infected by the same virus. Evolutionary changes in bats' immune systems, connected with adaptations for flying, may help explain how bats are able to carry viruses without being harmed by infection.

In addition, this modulation of the immune system may help to explain the mysteriously long lives of bats. In humans, possible explanations for aging include accumulated DNA damage and unchecked inflammation, while bats seem to be better at handling both these things. Clearly, we have a lot to learn from bats.

Bats are good

Bats can harbor viruses that could potentially become human pathogens, but I hope you won't jump to the conclusion that we'd be better off without bats. Earth's 1000+ species of bats play many critical ecosystem roles, including pollinating flowers and consuming insects that might otherwise spread human diseases. We're better off with bats around, but it's also probably best if we don't mess with them. In many cases, zoonoses (diseases transmitted from animals to humans) originate when humans disrupt wildlife habitats or kill wild animals for food. If we avoid doing these things, we'll experience fewer zoonotic diseases. Meanwhile, lessons from bat biology may teach us to live longer and healthier lives.

Check out 13 Awesome Facts About Bats!

How this will relate to the rest of Bio 6B

I'm going to refer to the bats and viruses story in several sections of the course:

  • Protein structure: You'll need a clear picture of how the structure of proteins and other macromolecules is controlled in cells, and why it's important.
  • Cell  & membrane structures: The coronavirus life cycle interacts with several important parts of its host cells. By examining the virus life cycle, you'll get a picture of cell structure in general.
  • Cellular respiration: The mechanisms of cellular respiration are at the heart of bats' unique biochemistry; you'll see that cellular respiration does more than just make ATP. Oxidative phosphorylation (OXPHOS) is at the heart of cellular respiration.
  • Genome evolution: The kinds of evolutionary changes that occurred in bats have shaped the genomes of all eukaryotes.
  • Cell cycle biology and cancer: We'll return (briefly) to bats in the section on cell cycle control, and see what key cancer-fighting genetic features are shared by both bats and elephants. 

This is a lot of biology to cover; I don't expect you to understand it all on day one. We'll revisit these ideas throughout the quarter. Bats and  especially coronavirus will be recurring themes throughout the course. The most important unifying concept here is the core idea of molecular biology: by studying genes and proteins, we can learn about how organisms work

Review 

Terms & concepts

  • DNA repair pathway
  • Gene
  • Genome
  • Inflammation
  • Mitochondrial genome
  • Nuclear genome
  • Oxidative phosphorylation (OXPHOS)
  • Pathogen
  • Reactive oxygen species (ROS)
  • Zoonosis (plural: zoonoses)

Review questions

Use these questions to guide and self-test your understanding of the concepts on this page. I will give you a quiz on Canvas covering these topics.

  1. What categories of genes evolved particularly rapidly in bats? Why did researchers want to ask this question?
  2. Why do bats experience high rates of ROS production compared to most other mammals? What problems are caused by the ROS?
  3. Why is the DNA damage response pathway so important for bats?
  4. Why do bats carry so many viruses?

Open questions

The evolution of bats and coronavirus raises numerous biological questions, many of which are directly connected to the core concepts of Bio 6B. At the beginning of the quarter, I will leave these questions open, but I hope you'll be able to answer them by the end of the quarter.

  1. How do genes code for proteins? Why is defining a gene as "a sequence of nucleotides that codes for a protein" inadequate?
  2. How can you analyze DNA sequence data?
  3. How does cellular respiration, including oxidative phosphorylation, work?
  4. How does increased metabolic rate cause DNA damage?
  5. What are reactive oxygen species (ROS), and how are they generated in cells? How is ROS-related damage controlled?
  6. Why do mitochondria have genes? In other words, why is there a mitochondrial genome in addition to the nuclear genome?
  7. Why have mitochondrial genes evolved rapidly in bats?
  8. What is the DNA damage checkpoint? How is it connected to lifespan and the probability of cancer?
  9. If bats live so long, does that mean that they are likely to get cancer?
  10. What is the difference between the innate immune system (which includes the inflammation response) and the adaptive immune system?

References

These references aren't required reading for Bio 6B, but if you're interested in diving deeper into these topics, these articles will be good places to start.

Video

Why gats don't get sick. Bannerjee, TEDEd.

Easy reading

How Do Bats Live With So Many Viruses? New York Times Jan. 28, 2020. Excellent article and easy to read. Includes links to scientific research papers. One of the points made in this article is that scientists have known for years that there was a high risk of a coronavirus pandemic caused by a virus jumping from bats to humans. If politicians had been willing to listen, we might have been much better prepared.

Where Did This Coronavirus Originate? Virus Hunters Find Genetic Clues In Bats. NPR News, April 15, 2020. Good overview, with links to scientific sources.

Bats control viral replication and dampen inflammation. LabXchange.

Bat Flight and Inflammation. LabXchange. Shows a pathway connecting DNA damage to inflammation.

Why do bats have such bizarrely long lifespans? Ars Technica, 2019.

The Virus, the Bats and Us. David Quammen, New York Times, 2020. A longish and interesting article that gives a broader perspective on the interactions between bats and humans.

Scientific literature

"Scientific literature" in this case means publications by scientists for a scientific audience. These articles are dense with information, and they assume you have a foundation in biology. As a biology student, you will probably find these challenging, but taking the time to learn to read primary literature will help you in any career related to biological sciences.

Comparative Analysis of Bat Genomes Provides Insight into the Evolution of Flight and Immunity. Zhang et al., Science, 2013 (abstract only; you can probably access the whole article through the library). This is a challenging technical article. This article was highlighted in several news articles, including Bats’ Immunity Against Deadly Viruses Linked To Their Ability To Fly (AsianScientist.com). Quote: "We hypothesize that genetic changes during the evolution of flight in bats likely included adaptations to limit collateral damage caused by by-products of elevated metabolic rate.... We further hypothesize that the long-term coexistence of bats and viruses must have imposed strong selective pressures on the bat genome, and the genes most likely to reflect this are those directly related to the first line of antiviral defense—the innate immune system."

Going to Bat(s) for Studies of Disease Tolerance. Mandl et al., 2018, Frontiers in Immunology. This excellent review explains why bats are reservoirs for human viruses. As a bio student, you can read and understand this article, though it should raise numerous questions. Quote: "Bats have an array of unique life history characteristics that not only allow them to be particularly good reservoirs for viruses that are highly pathogenic in other species, but also appear to have shaped their immune systems."

Immunological Control of Viral Infections in Bats and the Emergence of Viruses Highly Pathogenic to Humans. Schountz et al., 2017. Frontiers in Immunology. This article proposes the hypothesis that bats' innate and adaptive immune systems are regulated somewhat differently than humans, possibly explaining why bats can be relatively unaffected by viruses that are deadly to humans.

Novel Insights Into Immune Systems of Bats. Banerjee et al., 2020. Frontiers in Immunology. Read it if you dare! This article presents the current state of knowledge clearly and concisely. but it's far beyond Bio 6B. Quote: "The evolution of flight in bats seem to have selected for a unique set of antiviral immune responses that control virus propagation, while limiting self-damaging inflammatory responses." The article explains how.

Adaptive evolution of energy metabolism genes and the origin of flight in bats. Shen et al., 2010. PNAS. Quote: "Both mitochondrial and nuclear-encoded OXPHOS genes display evidence of adaptive evolution along the common ancestral branch of bats, supporting our hypothesis that genes involved in energy metabolism were targets of natural selection and allowed adaptation to the huge change in energy demand that were required during the origin of flight."

Bat Coronaviruses in China. Yi Fan et al., 2019, MDPI. Written just before the the COVID-19 pandemic got going. Quote: "It is generally believed that bat-borne CoVs will re-emerge to cause the next disease outbreak. In this regard, China is a likely hotspot. The challenge is to predict when and where, so that we can try our best to prevent such outbreaks."

Accelerated viral dynamics in bat cell lines, with implications for zoonotic emergence. Brook et al., 2020. eLife. The scientific details of this article will be hard going for 6B students, but there are some important points. From the digest: "Bats have a suite of antiviral defenses that keep the amount of virus in check. For example, some bats have an antiviral immune response called the interferon pathway perpetually switched on. In most other mammals, having such a hyper-vigilant immune response would cause harmful inflammation. Bats, however, have adapted anti-inflammatory traits that protect them from such harm, include the loss of certain genes that normally promote inflammation." In this article, the researchers show that while the bats' innate immune system, mediated by interferons, slows the reproduction of viruses in bats,  the viruses respond by evolving in ways that make them more dangerous to humans. For more (and easier) information, see the research website of first author Cara Brook at UCB, along with this related news article: Coronavirus outbreak raises question: Why are bat viruses so deadly?

Six reference-quality genomes reveal evolution of bat adaptations. Jebb et al., 2020. Nature. A recent and detailed look at bat genomes. "Our genome-wide screens revealed positive selection on hearing-related genes in the ancestral branch of bats, which is indicative of laryngeal echolocation being an ancestral trait in this clade. We found selection and loss of immunity-related genes (including pro-inflammatory NF-κB regulators) and expansions of anti-viral APOBEC3 genes, which highlights molecular mechanisms that may contribute to the exceptional immunity of bats. Genomic integrations of diverse viruses provide a genomic record of historical tolerance to viral infection in bats. Finally, we found and experimentally validated bat-specific variation in microRNAs, which may regulate bat-specific gene-expression programs."

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