Episode 325: Bats and viruses
Based on a short review in Nature (Ep325-0) I have been digging in the literature to get an overview on why bats are so often encountered as a reservoir for zoonotic viruses. Apparently, bats are viral vessels: various bat sub-species have co-evolved over millions of years with many different viral families(Ep 325-1). There is a number of ecological and behavioral aspects that influence the viral reservoir status of bats (Ep 325-2).
Remarkably, bats do not seem to get sick from these viruses, while humans do. We are just starting to unravel the reason for this difference, because there are few reagents to characterize immune cells in bats.
- The first reason is a beneficial balance between the potent antiviral response (e.g. type 1 IFN) and the low inflammatory “side effects”. In fact, an exaggerated inflammatory reaction is the main reason why SARS-CoV-2 infection can become so severe in human, while the related bat virus are innocent in their “natural host” (Ep 325-2 and -3)
- With whole genome sequencing the molecular determinants of this equilibrium are being unraveled: e.g. a mutation in ISG-15 (interferon stimulated gene 15): Ep 325-6.
- With other techniques, contribution of cellular immunity are gradually becoming clear: increased activity of antiviral Natural Killer and CD8 T cells in conjunction with dampening of inflammation via enhanced immune suppressive IDO production by neutrophils and immune suppressive cytokines (IL-10 and transforming growth factor beta) by regulatory CD4 T cells (Ep 325-4 and -5)
Enjoy the scientific discovery of the wonderful and still a bit mysterious world of bats and their viruses in the paragraphs below.
Ep 325-1: Jin Tian Cell Reports June 2022 Very comprehensive review of association between bat species and viruses
We know that bats are a reservoir of many viruses and that some of those have been transmitted to humans: these include various Coronaviruses; Filoviruses (EBOLA, Marburg), Henipaviruses (Hendra and Nipa) as well as Rheoviruses (ROTA) and others (e.g. Noro).
An enormous variety of bats (according to geographic region) and of associated viruses: 12,000 bat-associated viral sequences belonging to at least 30 (out of 168) viral families have been detected:
But there are “headlines” to reduce complexity
- With regard to viruses
- DNA viruses = minority: Herpes (large double stranded DNA) Parvo and Circoviruses (small ss DNA)
- RNA viruses are more frequent:
- Most frequent Corona (+ ss RNA=positive single strand); Rabdo (- ss RNA e.g. Rabies); Paramyxo (also - ss e.g. Henipa) and Astro (+ ssRNA, causing diarrhrea).
- Also present: Filoviruses (- ssRNA e.g. EBOLA, Marburg); Flavi and Calci (+ssRNA); Picobirna and Rheoviruses ( doble stranded RNA e.g. ROTA)
- With regard to bats: 80 % of RNA viruses in 3 bat families
- Rhinolophus (horseshoe bats) with SARS-like viruses
- Pteropodidae (flying foxes) may harbor Paramyxo (Henipa); Filo (Marburg, EBOLA?) and Rheovirus (ROTA)
- Verspertilonidae (evening bats): e.g. MERS
Clinical epidemiology in bats:
- Viral infections asymptomatic: they are “tolerant” to viruses
- Spread virus via blood, feces, nasal secretions and saliva (aerosols)
- Wildfires (climate change) also contribute by chasing the bats from their “wild” into “domestic environment.
- Often via intermediary host (e.g. horses, camels, pigs, palm civets, raccoons, where virus can “adapt” before jumoing to humans): these animals are in contact with bats, because of agriculture in arboreal areas, where bats fly over, rest (roost) or feed on the domestic animal food
Human cellular receptors:
ACE-2 for SARS-CoV and SARS-CoV-2 = angiotensin converting enzyme-2 in the renin-angiotensin-aldosterone system
DPP4 for MERS = di-peptidyl peptidase 4: adenosine deaminase complexing protein 2 or CD26: surface enzyme that regulates immune and signaling functions
Niemann-Pick C1 (NPC1) receptor for EBOLA and Marburg = regulates cholesterol trafficking
Ephrin-B2 and Ephrin-B3 for Hendra and Nipah = , members of a large family of membrane-bound tyrosine kinases
Histo-blood group antigens (HBGAs) Heat shock cognate protein 70 and integrins for Rotavirus.
Ep 325-2: Victoria Gonzalez iScience Aug 2022 Ecological and behavioral aspects that influence the viral reservoir status of bats
- Flight and elevated body temperature
Bats are the only mammals capable of true flight. During flight, the core body temperature of bats,
rises to over 40_C.
Some in bats, such as filoviruses, are capable of replicating at elevated body temperatures
In addition, ebolavirus and bat paramyxoviruses have been detected in fecal matter and/or urine of experimentally and naturally infected bats suggesting that some viruses may be transmitted during defecation.
Bats are also capable of discarding food remnants, such as fruits, which may be contaminated with virus-infected biological matter, allowing foraging animals to potentially become infected upon consumption.
- The ability of bats to fly long distances may allow for the transmission of novel viruses and variants amongst bat populations and potentially into humans and other animals.
- Bats might produce aerosols while echolocating, which would potentially allow for the dissemination of viruses that replicate within the respiratory tract, such as Rabies.
- Temperate bats are known to hibernate during winter, allowing viruses, such as rabies virus, to be maintained for extended periods of time. Also nightly
- Bats have an exceptional long life-span, which increases their reservoir capacity, since they tolerate viral infections very well.
- Bats roost in multi-species colonies. Living in dense clusters may facilitate the spread of viruses and other pathogens between different bat species and within immune and naive individuals of the same species.
- Bats may have co-evolved with some viral families over 64 million years to develop fine-tuned antiviral responses that limit host damage and promote viral tolerance
A very extensive list of viruses and corresponding bat species is provided. Flaviiruses as an example
Furthermore, tolerance to viral infection could be explained by the equilibrium between a very efficient innate immune system and a mitigated inflammation.
Recognition receptors for ssRNA and dsRNA:
A,B: Toll-like receptors (TLRs) 3, 7, and 8 within the endosome ,
(C) Cytoplasmic receptors, such as retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) may also detect dsRNA in the cytosol
(D)Leading to the activation of downstream adaptors, such as mitochondrial antiviral signaling protein (MAVS)
Recognition of viral DNA
(E) Viral DNA (vDNA) present within endosomes or cytosol can be detected by TLR9 and (F) cytosolic DNA sensors with the latter signaling through the stimulator of interferon genes (STING) (G).
(H) Bats have also lost certain DNA sensors, such as the PYHIN gene family, ultimately leading to a dampened NLR-family PYRIN domain containing 3 (NLRP3)- mediated inflammasome response .
In addition, a recent study demonstrated that bats have reduced STING activation because of a point mutation at amino acid position 358.
(I) Upon recognition of viral nucleic acid by TLRs, RIG-I, MDA5 and cytosolic DNA sensors, cellular kinases within the infected cell are activated
(J) which activate transcription factors, like interferon (IFN) regulatory factor 1 (IRF1), IRF3 and IRF7.
This will ultimately lead to the induction of type I IFNs (K), such as IFNa and IFNb, which will be secreted (L) by the infected cell to induce an antiviral state in an autocrine and paracrine manner.
(M) Signaling through TLRs may also lead to the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) (M),which in turn induces the expression (N) and secretion of proinflammatory
cytokines, such as tumor necrosis factor alpha (TNFa), interleukin 8 (IL-8), and IL-1 (O).
Altered NF-kB signaling, which may contribute to bats having a higher tolerance toward viruses.
In this schematic, dampened responses are indicated by the red arrows (Y).
Finally an overview of bat-borne viruses with zoonotic potential and likelihood of interhuman transmission
Ep 325-3: Aaron Irving Nature Jan 2021 Lessons from the host defences of bats, a unique viral reservoir
The potential zoonotic transmission cycle for coronaviruses.
Coronaviruses may transmit naturally (black arrows) among humans, bats and other wildlife (such as racoon dogs, hedgehogs, pangolins, palm civets, camels (as is known for MERS-CoV) and mink.
Human interventions may amplify the spread (red arrow).
Transmission cycles may be amplified in urban areas that are normally at a minimal risk of exposure, increasing transmission to humans and accelerating an outbreak scenario.
(1) Natural zoonotic infection cycles from domestic animals or wildlife (including bats) to humans and vice versa;
human populations at risk include bat guano farmers, or individuals living and working in areas that overlap with bat habitats.
(2) Natural enzootic cycle between different species of wildlife (including bats), and domestic animals and wildlife.
(3) Amplification and spread between overlapping bat populations—as, for example, seen among species in the Rhinolophidae and Hipposideridae for SARS-related coronaviruses.
(4) Amplified zoonotic infections and spread to urban areas via human interventions, including wildlife trade and increased urbanization.
(5) Anthropozoonotic infections from humans back to domestic animals or wildlife (for example, as in mink farming.
(6) Human migration patterns facilitate spread to urban areas (for example, during holiday seasons160). (7) Amplified viral spread among humans or animals and humans in dense urban settings.
The unique balance between host defence and immune tolerance in bats. Bats show an excellent balance between enhanced host defence responses and immune tolerance through several mechanisms.
Examples of enhanced host defences include constitutive expression of IFNs and interferon-stimulated genes (ISGs), increased expression of heat-shock proteins (HSPs), a higher base level expression of the efflux pump ABCB1 and
On the other hand, dampened STING and suppressed inflammasome pathways—such as dampened NLRP3 inflammasome, loss of PYHIN and downstream IL-1β—contribute to immune tolerance in bats.
Schematic of the multilevel mechanisms of dampened inflammasome activation in bats.
a, In human or mouse, pattern recognition receptor (PRR) priming and subsequent activation by RNA viruses, danger
signals or intracellular double-stranded DNA activate the NLRP3 or AIM2 inflammasome with intact ASC speck formation, pyroptosis and IL-1β secretion.
b, By contrast, bats have dampened transcriptional priming (1) and reduced protein function (2) for NLRP3, loss of PYHIN including AIM2 (3), and reduced caspase-1 activity (4) and/or IL-1β cleavage (5), which leads to an overall
reduction in inflammation.
EMERGING EVIDENCE of T and NK INVOLVEMENT
Ep 325-4: A Gamage Immunity 2022: Single-cell transcriptome analysis of the in vivo response to viral infection
in the cave nectar bat Eonycteris spelaea.
Infection with bat Orthorheovirus PRV3M: transcriptome analysis of lung tissue:
- Alveolar macrophages and classical monocytes drove antiviral interferon signaling.
- Neutrophils express high IDO-1 (indoleamine 2,3 deoxygenase) = immune suppressor mechanism which can reduce inflammation.
- NK cells and T cells were the most abundant immune cells in lung tissue.
- Three distinct CD8+ effector T cell populations could be delineated by differential expression of KLRB1, GFRA2, and DPP4.
- Select NK and T clusters increased expression of genes involved in T cell activation and effector function
- Also induction of rapid tissue repair mechanisms.
→ Efficient innate and adaptive antiviral response with minimal inflammation and rapid tissue repair.
Ep 325-5: Burke bioRxiv 20 Feb 2023: Tolerance to SARS-CoV-2 in a model bat infection
Model = Jamaican fruit bats are poorly susceptibility to SARS-CoV-2 but that expression of human ACE2 in their lungs leads to robust infection, but no overt sign of disease or weight loss .
Adaptive immune response with
- low-titer antibodies
- a regulatory T cell-like response (with enhanced immune suppressive IL-10 and TGF-beta in CD4+ CXCR4+ T cells)
that may explain the lack of prominent inflammation in the lungs.
Ep 325-6: Michael Hiller SSRN preprint Feb 2023 Reference-quality bat genomes illuminate
adaptations to viral tolerance and disease resistance
There is a positive selection in bats for immune genes involved in viral entry, virus detection, and antiviral
responses by the innate, adaptive, and complement systems.
Several selected genes regulate inflammatory responses by inhibiting the production of pro-inflammatory
cytokines and participating in negative feedback control of interferon signaling, indicating that these genes may contribute to preventing uncontrolled inflammation during viral infection in bats
Genes under selection are involved in immune responses during viral infections.
- Overview of biological processes involved in a synchronized immune response triggered by viral infections.
(B-F) Schematic showing how ISG15 and genes under selection in bats (highlighted in blue) are involved in viral entry into cells and detecting viral patterns (B), regulating antiviral and inflammatory responses (C-D), B cell signaling (E), and activation of the complement system (F).
Colored backgrounds correspond to the processes in (A).
Interferon stimulated gene 15 (ISG15) has a Cysteine deletion in position 78 in bats (as compared to human). This could be one of the factors that contribute to the ability of Rhinolophid and Hipposiderid bats to launch effective antiviral responses without triggering excessive inflammation.
- This deletion prevents the activity of the SARS-CoV-2 PLprotease, which inactivated the antiviral activity of ISG-15 in humans. Hence iSG15 antiviral activity is better preserved in bats.
- Cys78 deletion may reduce ISG15’s extracellular pro-inflammatory function
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