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Did bats lose their Cytokine storm immune response when they became able to fly? Questions about bat immune responses only became high-profile after some recent human disease outbreaks pointed to bats as their main reservoirs. However, virtually nothing is known about bat immunology, indeed very little is known about bat cytokines, and certainly there’s no peer-reviewed published data on bat capacity or lack thereof to make cytokine storm-type immune responses. Let’s start with the last bit first.

Though abundantly available for studying mouse immune responses and less so for studying human immune responses, there are currently hardly any specific research reagents and tools to assess bat immune responses. Cytokines are key chemical messengers involved in immune responses and yet current state-of-the-art to study bat cytokines is so limited that as recently as 2013, a study used a kit designed for mouse cytokines to measure circulating bat cytokines (1). Unsurprisingly, the effort was rather futile as the authors themselves attest, ‘ Circulating Cytokines. Of the nine cytokines that we attempted to detect using the multiplex cytokine array with mouse specific reagents, IL-4 was the only analyte that was detected with any consistency’ (1).

Bats are supposedly the main reservoir for deadly viruses such as Ebola (2) even as they remain resistant to them. How could that be? In the absence of knowledge and certainly absence of hard data, a plausible hypothesis suggests bats are ‘exceptional in their ability to harbor and transmit viruses‘ (3, 4, 5). This hypothesis literally acquired wings following a high-profile peer-reviewed 2013 paper (6) that compared genome sequences of two bat species, the Australian black flying fox (Pteropus vampyrus) and David’s Myotis (Myotis davidii). Key take-homes from this study:

  • Both bat species apparently lost all members of the PYHIN gene family, which is important in DNA sensing and Inflammasome formation.
  • Reduction in natural killer cell receptors.

In other words, some striking differences in bat immune elements at the genomic level.

Thus, in recent years, and in absence of actual hard data, a narrative about bat immunity suggests they’re tolerant to infectious disease agents that are deadly to humans and other animals. Yet, are bats carriers of deadly diseases while remaining immune/resistant to them? Especially, do bats lack capacity for cytokine storm-type immune responses? Since actual bat cytokine data are largely lacking, we need to infer them from the outcome of bat infection studies, such as they are.

Let’s explore some answers by sifting through three sets of available data.
I. Are bats a major source of human infectious diseases?
II. Epidemiological data on bat infections and mortalities.
III. Experimental bat infections and mortalities.

I. Are bats a major source of human infectious diseases?
A resounding no from not one or two but three meta-analyses (3, 7, 8). Bats are a minor, not major, source of infectious diseases relevant to humans. Figure below is from reference 7.

Figure below is from reference 3 analyzing data from reference 8.


These meta-analyses of epidemiological surveys do not support the idea that bats have been a major source of human infectious diseases.

II. Epidemiological data on bat infections and mortalities.
Bat fungal diseases
White-nose syndrome (WNS), a decimating bat disease (9, 10) suggests they may not be immune to cytokine storms.

  • First observed in 2006 in the Northeastern United States in the insect-eating little brown bat, Myotis lucifugus.
  • It’s a skin infection caused by a ‘cold-loving’ fungus, Pseudogymnoascus (formerly Geomyces) destructans.
    • First, the nose, ears and wing membranes are covered with a white, powdery filamentous growth.
    • Second, the WNS infection prematurely arouses bats from hibernation in mid-winter.
    • Third, bats awaken at a time when their food source, insects, are scarce. Result? Emaciation (11).
    • Fourth, bat wing membranes become ulcerated, necrotic and scarred. Infected bats have elevated circulating leucocytes (1). Emerging prematurely from hibernation, acute neutrophil infiltration into fungus-infected wing tissues followed by acute wing necrosis and edema causes what seems to be an immune reconstitution inflammatory syndrome (IRIS; 12).
  • A mechanistic physiological model (13; see figure below) suggests their premature awakening from hibernation at a time when their natural nutrition sources, insects, are scarce, causes WNS bats to die from unsustainable metabolic energy usage.
  • Though exuberant immune responses (IRIS/cytokine storm?) likely contribute to WNS, their mechanistic role is as yet completely unexplored.
  • Estimated bat mortality? ~ 95%, i.e. ~ 4 to 6 million bat deaths in the US from WNS since 2006 til date.


Bat bacterial diseases
A recent meta-analysis examined bacterial infections reported in wild bat colonies since the 1960s, and concluded, ‘bats are vulnerable to several infectious agents common in bacterial diseases of humans and domestic animals like enteric (e.g.Salmonella, Shigella, Yersinia and Campylobacter spp.) and arthropod-borne bacterial pathogens (Bartonella, Borrelia spp. and members of the family Rickettsiales) and pathogenic Leptospiraspecies. Some of these bacterial agents are also associated with pathological lesions and systemic disease in bats themselves‘ (14).

Bat viral diseases
Wilbur Downs was the Director of the Trinidad Regional Virus Laboratory when he found a near-dead great fruit-eating bat (Artibeus literatus) on his front porch (15). When he ground up the bat’s tissues and injected them into mice, they developed disease. It wasn’t rabies. A new virus was identified, the Tacaribe arenavirus. Many bats died from this disease during this epidemic in the 1950s (16).

III. Experimental bat infections and mortalities.
Certainly, bats have several unique traits

  • The only mammals that fly.
  • Second most diverse mammal (after rodents).
  • Of ~5000 mammalian species, ~1230 are bat species.
  • Live in extremely dense social communities (For example, colonies of the Brazilian free-tailed bat, Tadarida brasiliensis, can number in the thousands).
  • Relatively long life for their body size.
  • Found on every continent except Antarctica.
  • Essential ecosystem functions: plant pollination, seed dispersal, insect predation.
  • Yet basic research on bats is sparse, only heating up since the mid-2000s. What changed? Potential importance of bats as vectors (carriers) for Emerging Infectious Diseases (EID) such as Ebola, MERS-CoV (Middle East respiratory syndrome coronavirus) and SARS (Severe Acute Respiratory Syndrome).

Yet bats are also difficult to study

  • Bat flight ensures their home ranges cover a very large area.
  • Bats are nocturnal.
  • Currently no bat breeding stocks are available for experimental use.
  • Bat colonies require we capture, quarantine, transport and breed wild bats. Expensive and tricky, to say the least.
  • Some zoos maintain captive bat colonies but don’t have the tradition of engaging with and working alongside biomedical researchers.
  • Wild bats have an unknown infection history, and absence of circulating anti-infection antibodies (seronegativity) does not guarantee absence of prior infection.
  • Breeding bats? Not so easy. For one, their litter sizes are small even in the wild. For another, technical staff trained and experienced in handling bats? Practically non-existent (outside select zoos).
  • Strict laws also restrict access to bats for experimental use. For example, European bats are protected as endangered species.


Experimental bat infections are thus few and far between. What do such studies tell us about bat immune (and maybe cytokine) responses?

A. A 2012 experimental Tacaribe virus infection of Jamaican fruit bats induced high mortality (17; see figure below).


B. Big brown adult bats are quite susceptible to experimental rabies virus infection (18; see figure below).


C. Just as we’ve learned from decades of mouse model studies, turns out route of infection also plays an extremely important role in bat susceptibility to experimental infections. When infected with Lyssaviruses (Rabies is an e.g.) using different infection routes (19; see figure below),

  • Intracranial (IC) induces ~100% mortality.
  • Intramuscular (IM) and subdermal (SD) induce variable mortality, which vary according to the virus.
  • Intranasal induces no mortality.


D. And not all experimental bat studies are equal. For example, some studies (20, figure below) used different infection routes for bats and for known susceptible animal species. Are bats infected in this manner really resistant or were they infected through an injection route that did not cause productive infection? Open question.


A confluence of specific factors created our current notion that bats are resistant reservoirs of infectious diseases

  • On the one hand, monitoring bat populations for circulating anti-infection antibodies (seroprevalence) is and has been routine for decades. Such seroprevalence studies were state-of-the-art immune response assessments through the mid-20th century but are now recognized as limited and poorly sensitive. In the intervening decades, our ability to probe and dissect mouse and human immune responses has exponentially expanded while remaining stagnant for bat immune responses.
  • OTOH, molecular biology tools exquisitely sensitive for picking low titers of viruses can be directly applied to bats and doing so has led to identification of numerous viruses including many new ones. Are such results biologically relevant or artifacts of exquisitely sensitive technical assays? Open question.


Thus, while state-of-the-art bat immunology remains circa1970 with no reagents available to even identify bat T and B cells, bat molecular biology has directly fast-forwarded to the 21st century. Hypotheses regarding bat immune responses that arise from the latter approach remain unproven flights of fancy as long as the current wide chasm separates the study of bat immunology and molecular biology.

Bibliography

  1. Moore, Marianne S., et al. “Hibernating little brown myotis (Myotis lucifugus) show variable immunological responses to white-nose syndrome.” PloS one 8.3 (2013): e58976. Page on plosone.org
  2. Leroy, Eric M., et al. “Fruit bats as reservoirs of Ebola virus.” Nature 438.7068 (2005): 575-576.
  3. Olival, Kevin J., et al. “Are bats exceptional viral reservoirs.” New directions in conservation medicine: Applied cases of ecological health (2012): 195-212.
  4. Baker, M. L., Tony Schountz, and L‐F. Wang. “Antiviral immune responses of bats: a review.” Zoonoses and public health 60.1 (2013): 104-116.
  5. Bean, Andrew GD, et al. “Studying immunity to zoonotic diseases in the natural host [mdash] keeping it real.” Nature Reviews Immunology 13.12 (2013): 851-861.
  6. Zhang, Guojie, et al. “Comparative analysis of bat genomes provides insight into the evolution of flight and immunity.” Science 339.6118 (2013): 456-460. Page on www.chinacdc.cn
  7. Woolhouse, Mark EJ, and Sonya Gowtage-Sequeria. “Host range and emerging and reemerging pathogens.” Ending the War Metaphor:: The Changing Agenda for Unraveling the Host-Microbe Relationship-Workshop Summary. Vol. 192. National Academies Press, 2006. Page on cdc.gov
  8. Jones, Kate E., et al. “Global trends in emerging infectious diseases.” Nature 451.7181 (2008): 990-993.
  9. Blehert, David S., et al. “Bat white-nose syndrome: an emerging fungal pathogen?.” Science 323.5911 (2009): 227-227. Page on whitenosesyndrome.org
  10. Reichard, Jonathan D., and Thomas H. Kunz. “White-nose syndrome inflicts lasting injuries to the wings of little brown myotis (Myotis lucifugus).” Acta Chiropterologica 11.2 (2009): 457-464. Page on caves.org
  11. Veilleux, J. P. “Current status of white-nose syndrome in the northeastern United States.” Bat Research News 49.1 (2008): 15-17.
  12. Meteyer, Carol U., Daniel Barber, and Judith N. Mandl. “Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome.” Virulence 3.7 (2012): 583-588. Page on nih.gov
  13. Verant, Michelle L., et al. “White-nose syndrome initiates a cascade of physiologic disturbances in the hibernating bat host.” BMC physiology 14.1 (2014): 10. Page on biomedcentral.com)
  14. Mühldorfer, K. “Bats and bacterial pathogens: a review.” Zoonoses and public health 60.1 (2013): 93-103.
  15. Schountz, Tony. “Immunology of Bats and Their Viruses: Challenges and Opportunities.” Viruses 6.12 (2014): 4880-4901. Immunology of Bats and Their Viruses:  Challenges and Opportunities
  16. Downs, Wilbur G., et al. “Tacaribe virus, a new agent isolated from Artibeus bats and mosquitoes in Trinidad, West Indies.” Am J Trop Med Hyg 12.4 (1963): 640-6.
  17. Cogswell-Hawkinson, Ann, et al. “Tacaribe virus causes fatal infection of an ostensible reservoir host, the Jamaican fruit bat.” Journal of virology 86.10 (2012): 5791-5799.
    asm.org

    Tacaribe Virus Causes Fatal Infection of An Ostensible Reservoir Host, the Jamaican Fruit Bat

  18. Turmelle, A. S., et al. “Host immunity to repeated rabies virus infection in big brown bats.” Journal of General Virology 91.9 (2010): 2360-2366. Host immunity to repeated rabies virus infection in big brown bats
  19. Banyard, Ashley C., et al. “Bats and lyssaviruses.” Advances in Imaging and Electron Physics 79 (2011): 239-289. Banyard et al Advances in Virus research 2011 _2011/links/09e4150f6d4936958f000000.pdf
  20. Middleton, D. J., et al. “Experimental Nipah virus infection in pteropid bats (Pteropus poliocephalus).” Journal of comparative pathology 136.4 (2007): 266-272.

https://www.quora.com/Why-did-bats-lose-their-cytokine-storm-immune-response-at-the-time-they-became-able-to-fly/answer/Tirumalai-Kamala

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