randombio.com | science
Friday, May 08, 2020

Watty: why are bats immune to coronavirus?

Bat viruses will find their way to humans sooner or later. We need to understand why they kill humans but not bats

B ats are a wonderful, or maybe not so wonderful, source of deadly viruses: SARS, ebola, Marburg, MERS, many paramyxoviruses—viruses of the mumps family—not to mention rabies and other lyssaviruses that cause lethal encephalitis, and now SARS-CoV-2. Bats are even more likely to be infected with zoonotic diseases than rats.[1]

It's true that bats don't practice social distancing. But you never see one dropping dead from ebola or even COVID-19. Bats seem to be immune from SARS and MERS.[2] Why?

Flying raises the metabolism of a bat by 15–16-fold. A flying bat can reach temperatures up to 42°C (107.6°F), equivalent to a high fever in humans. So O'Shea et al.[3] speculated that the searing temperatures encountered in bat flight impair viral replication and enhance production of immune cells (monocytes, killer T cells, and antibody-producing B cells; see here for a description) and protective molecules (oxygen radicals, interferons, heat-shock proteins, and complement proteins). They suggested that somebody else who has some bats ought to do some research on this.

Bats are long-lived—some live up to 41 years, and much of that spent in hibernation, where their metabolism is slowed down. This raises doubt about the hyperthermia theory, and other researchers have suggested that the high oxygen usage during flight damages their DNA, so perhaps bats are selected for more efficient DNA damage checkpoint molecules. Since checkpoint molecules are similar to molecules in the immune system, this could have improved bat immunity[6].

How RNA viruses generate an immune response

Many cells have special proteins on their outer surface or in cellular compartments called endosomes called pattern recognition receptors. They are an important part of the innate immune system, which reacts rapidly to invading organisms.

One class of these receptors is called Toll-like receptors or TLRs. RNA viruses are detected by TLR-7 and TLR-8, which bind to single-stranded RNA. When an RNA molecule binds to TLR-7 or 8, the receptor signals the cell that it must make interferons and inflammatory cytokines such as TNF-α, interleukin-1β, and interleukin-8. These are small proteins that leave the cell and cause neighboring cells to activate the expression of interferon-stimulated genes.

Bats are known to have TLR-1, 3, 8, and 10, but bat TLR-9 receptors seem to be non-functional.[5]

But the immune system seems to be the real key. Like humans, bats have two different immune systems called innate and adaptive immune systems. When a pathogen like a virus shows up, the innate immune system, which identifies pathogens by their shared chemical proper­ties, is the one that first attacks it.

Its speed comes at a cost: in humans, a major cause of death in some diseases (including COVID-19 and toxic shock syndrome) is cytokine storm, also known as cytokine release syndrome or CRS, where the innate immune system overreacts, causing widespread organ damage. It turns out that bats are missing a critical component of the innate immune system: PYHIN proteins[4], which are DNA sensors in the inflammasome that recognize DNA viruses and host DNA that has been damaged, are not found in bats. Toll-like receptor TLR-9, which is a pattern recognition receptor for DNA, is non-functional in all the bats studied so far (see box).

But some of the worst viruses, like SARS, MERS, Marburg, and Ebola, are RNA viruses, which don't contain DNA. So other researchers point to the fact that bats produce smaller amounts of inflammatory cytokines like TNFα and more anti-inflammatory cytokines like interleukin-10 than humans. Bats also have a dampened inflammasome response (which is another way of producing cytokines), so they produce a lot less of the inflammatory protein interleukin-1β.[2] All this would protect them from cytokine release syndrome.

Bats also have a mutation in a protein called STING, or stimulator of interferon genes, that makes them less effective in activating the synthesis of interferons.[7] Bats may also shed viruses at a higher rate,[8] meaning viruses leave their body faster, which is good for the bat but not so good for everyone else.

There are many other wonderful and exciting viruses in bats just waiting to infect humans. For example, the Hendra virus in Australia and Nipah virus in Malaysia, which use horses and pigs, respectively as intermediate hosts,[11] are both transmitted by bats. MERS was transmitted from bats to camels before infecting humans, and bats carry novel forms of hepatitis C and pegiviruses (which are related to GB virus C, the so-called “good boy” virus).

Bats are practically immune to Hendra and Nipah. Why? One theory is that bats can harbor the viruses in their intestines, lungs, or spleen while remaining uninfected. Or maybe the virus might become latent, which means it's incorporated into the bats' own DNA where it lies dormant until an environmental stress[9] causes it to reactivate. This is known to happen with γ-herpesvirus, where antibodies drive the virus into latency during hibernation.[10]

At the moment there are more questions than answers. That's something that will change only slowly because most animal care centers aren't set up to work with bats. Even fewer have the hideously expensive BSL-4 level facilities that are needed to handle pathogenic viruses. And no one wants to be blamed for accidentally releasing a virus, as has happened with Marburg and SARS.

Some people claim that human expansion into wildlife areas will bring these and other as-yet undiscovered viruses into our population, but that is a myth: those viruses are out there already. Regardless of what we do, sooner or later they will find their way to humans. COVID-19 has convinced us that vaccines often come too late to do any good. What we really need is to understand why our immune system turns against us. For that we need to go batty . . . so to speak.

1. Luis AD, Hayman DT, O'Shea TJ, Cryan PM, Gilbert AT, Pulliam JR, Mills JN, Timonin ME, Willis CK, Cunningham AA, Fooks AR, Rupprecht CE, Wood JL, Webb CT (2013). A comparison of bats and rodents as reservoirs of zoonotic viruses: are bats special? Proc Biol Sci. 2013 Feb 1;280(1756):20122753. doi: 10.1098/rspb.2012.2753. PMID: 23378666

2. Banerjee A, Baker ML, Kulcsar K, Misra V, Plowright R, Mossman K (2020). Novel Insights Into Immune Systems of Bats. Front Immunol. 11, 26. doi: 10.3389/fimmu.2020.00026. pmid: 32117225 PMCID: PMC7025585

3. O'Shea TJ, Cryan PM, Cunningham AA, Fooks AR, Hayman DT, Luis AD, Peel AJ, Plowright RK, Wood JL. (2014). Bat flight and zoonotic viruses. Emerg Infect Dis. 20(5), 741–745. doi: 10.3201/eid2005.130539. https://www.ncbi.nlm.nih.gov/pubmed/24750692 PMID: 24750692

4. Ahn M, Cui J, Irving AT, Wang LF (2016). Unique loss of the PYHIN gene family in bats amongst mammals: implications for inflammasome sensing. Sci Rep. 6, 21722. doi: 10.1038/srep21722

5. Escalera-Zamudio M, Zepeda-Mendoza ML, Loza-Rubio E, Rojas-Anaya E, Méndez-Ojeda ML, Arias CF, Greenwood AD (2015). The evolution of bat nucleic acid-sensing Toll-like receptors. Mol Ecol. 24, 5899–5909. doi: 10.1111/mec.13431 PMID: 26503258

6. Zhang G, Cowled C, Shi Z, Huang Z, Bishop-Lilly KA, Fang X, Wynne JW, Xiong Z, Baker ML, Zhao W, Tachedjian M, Zhu Y, Zhou P, Jiang X, Ng J, Yang L, Wu L, Xiao J, Feng Y, Chen Y, Sun X, Zhang Y, Marsh GA, Crameri G, Broder CC, Frey KG, Wang LF, Wang J. (2013). Comparative analysis of bat genomes provides insight into the evolution of flight and immunity. Science 339, 456–460. doi: 10.1126/science.1230835 PMID: 23258410

7. Xie J, Li Y, Shen X, Goh G, Zhu Y, Cui J, Wang LF, Shi ZL, Zhou P. (2018). Dampened STING-Dependent Interferon Activation in Bats. Cell Host Microbe 23, 297–301. doi: 10.1016/j.chom.2018.01.006. PMID: 29478775

8. Subudhi S, Rapin N, Misra V (2019). Immune System Modulation and Viral Persistence in Bats: Understanding Viral Spillover. Viruses 11, E192. doi:10.3390/v11020192 PMID 30813403

9. Plowright RK, Peel AJ, Streicker DG, Gilbert AT, McCallum H, Wood J, Baker ML, Restif O (2016). Transmission or Within-Host Dynamics Driving Pulses of Zoonotic Viruses in Reservoir-Host Populations. PLoS Negl. Trop. Dis. 10, e0004796. PMID 27489944

10. Gerow CM, Rapin N, Voordouw MJ, Elliot M, Misra V, Subudhi S (2018). Arousal from hibernation and reactivation of Eptesicus fuscus gammaherpesvirus (Ef HV) in big brown bats. Transbound. Emerg. Dis.

11. Mandl JN, Schneider C, Schneider DS, Baker ML (2018). Going to Bat(s) for Studies of Disease Tolerance. Front Immunol. 9, 2112. doi: 10.3389/fimmu.2018.02112. PMID: 30294323 https://www.ncbi.nlm.nih.gov/pubmed/30294323

may 08 2020, 6:43 am

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