Abstract
The COVID-19 pandemic that started in December 2019 in Wuhan city, China has created chaos all over the world with over 185 million infection cases and 4 million deaths world-wide. The pathogen behind COVID-19 has been identified as severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) that is more close to the previous SARS-CoV responsible for SARS epidemic 2002–2003. Although, SARS-CoV-2 also differs from SARS-CoV in many aspects as indicated by genetic studies. For example, SARS-CoV does not have a furin binding domain or site, whereas its presence in SARS-CoV-2 spike (S) protein increases its potential for infectivity. The horseshoe bats (Rhinolphus species) from China are considered as primary animal reservoirs for SARS-CoV and SARS-CoV-2. However, along with CoVs, bats also harbor many other viral pathogens (Ebola, Nipah, and Hendra viruses) without having serious infections. The bat physiology plays a crucial role in harboring these viruses along with adaptations to longevity and slow aging process. The immune system plays a crucial role in the clearance or establishment of the infection. Present chapter discusses different immunological aspects (innate immune response comprising the virus recognizing pattern recognition receptors (PRRs), type 1 interferon production, pro- and anti-inflammatory immune response, and adaptive immune response) that help bats to control viral infection without getting a severe infection as compared to other mammals, including humans.
Keywords
- Bats
- innate immunity
- autophagy
- infection
- IFNs
- adaptive immunity
1. Introduction
Bats and flying foxes, including large flying foxes (
Bats are crucial primary reservoirs for emerging viral infections that can be transferred to humans or cross the species barrier to infect other wild or domesticated animals through spill over [6]. Studies have indicated that they harbor higher numbers of zoonotic viruses per species than rodents [7]. Even they have higher (3.9 times stronger) sympatry than bats and sympatry within a taxonomic order serves as a most crucial host trait for zoonotic virus enrichment [7]. Of note, despite harboring more zoonotic viruses per species than rodents, the total number of zoonotic viruses found in bats (61) are lower than rodents (68) due to double the number of rodent species than bat species. However, bats are the primary host for more virulent viruses than other mammals, including rodents [8]. Before, the emergence of recent virus infections, including severe acute respiratory syndrome (SARS), middle-eastern respiratory syndrome (MERS), Ebola virus infection, and most recent Coronavirus disease 19 (COVID-19) pandemic caused by SARS-CoV-2, MERS-CoV, Ebola virus or
Fruit bats, including
Also, Panamanian Seba’s short-tailed bats (
2. Innate immune adaptation of bats as preventing to develop severe infections
The innate immune system is primary or first line of the defense against invading pathogens. The pattern recognition receptors (PRRs), including toll-like receptors (TLRs), Nod-like receptors (NLRs), absent in melanoma-2 (AIM2)-like receptors (ALRs), retinoic acid-inducible gene-1 (RIG-1)-like receptors (RLRs, RIG-1 and melanoma differentiation-associated protein 5 or MDA5), C-type lectin receptors (CLRs), and cyclic GMP (guanosine monophosphate)–AMP (adenosine monophosphate) synthase (cGAS) and stimulator of interferon genes (STING) signaling pathways play a crucial role in the host defense and the generation of pro-inflammatory immune response (cytokine, chemokines, reactive oxygen and nitrogen species (ROS and RNS), and type 1 interferon (IFN) production) [29, 30, 31, 32, 33, 34]. TLR4 is a crucial PRR to recognize Gram-negative bacterial lipopolysaccharide (LPS) as a potent microbial or pathogen-associated molecular pattern (MAMP or PAMP) to induce a potent pro-inflammatory immune response to clear the infection. However, its overactivation may cause severe inflammation. Pallas’s mastiff bats (
The immune challenge among bats does not alter their oxidative stress irrespective of their pre-migration and migration seasons [38]. However, bats have higher baseline leukocytes but lower neutrophil numbers during their migratory seasons as compared to their pre-migratory season. Their plasma haptoglobin (a humoral innate immune component) levels also remain same during both seasons [38]. However, plasma haptoglobin level of migratory bats increases upon an immune (LPS) challenge that remains unchanged in non-migratory or pre-migratory bats under the same immunogenic stimulation. Of note, bats do not upregulate genes associated with chronic inflammation with the advancement of age that is seen in other mammals, including humans [39]. Hence, this protects them from age related inflammatory diseases and predisposes them towards healthy aging and longevity along with tolerance to infections, including Ebola, Nipah, and many more. Also, the bat microbiota (Firmicutes and Proteobacteria are dominant bacteria) differs from other terrestrial mammals (strict anaerobic phylum Bacteroidetes in mice and humans), and remains intact throughout their life that further protects them from age-associated inflammation and inflammatory diseases [40, 41]. On the other hand in mice and humans gut microbiota changes with time and aging that predispose them to age-associated inflammatory diseases associated with gut bacteria dysbiosis [42, 43, 44].
A study has shown the TLR3, TLR7, and TLR9 expression at mRNA levels in different organs of Leschenault’s Rousette bats (
Flying fox bats (
The activation of MAVS involves the RIG-1 and MDA5 dimer formation [57]. Also, the IFIT1 generated exerts an anti-inflammatory action via suppressing TLR-dependent NF-κB-mediated pro-inflammatory cytokines (TNF-α, IL-1β) and chemokines (CCL3) through activating Sin3A-histone deacetylase 2 (HDAC2) transcriptional regulatory complex containing SAP25 that has an inhibitory action (Figure 1) [56]. Hence, these PRRs protect bats from developing severe viral infections through increased type 1 IFN production but low tissue damaging pro-inflammatory immune response. It should be interesting to observe that viruses harboring bats as their primary reservoirs may have evolved strategies to escape this innate immune mechanism to recognize cytosolic dsRNA viruses or bats have developed other mechanisms to escape from exaggerated pro-inflammatory innate immune response upon recognizing cytosolic dsRNA viruses. The MERS-CoV replicates efficiently in Jamaican fruit bats (
The bat cells repeatedly select for the mutant MERS-CoV called delta open reading frame (ΔORF5) MERS-CoV and are resistant to superinfection by wild type (WT) MERS-CoV due to deficiency of MERS-CoV binding receptor dipeptidyl peptidase 4 (DPP4) and increased type 1 IFN levels [61]. Additionally, the Australian black flying foxes in response the cytosolic TLRs and RLRs recognizing viral PAMPs (dsRNA) also activate IRF7, which also induces type 1 IFNs mediated antiviral immune response (Figure 1) [62]. The deficiency or the defective activation of IRF7 in bats enhances viral replication and the development of the productive infection. Of note, virus (bat paramyxovirus, Tioman virus) infection to bats also induces protective type III IFN production that further provides protection from the development of productive infection (Figure 1) [63]. Egyptian rousette bats (
Bat immune cells exert protective type 1 (IFN-α, β, and ω) type II (IFN-γ) IFNs against Filoviruses (Marburg and Ebola viruses) but human immune cells fail to do so (Figure 1) [66]. Myxovirus resistance 1 (Mx1, a GTPase) is another antiviral protein induced in response to the IFNs is evolutionary conserved in vertebrates and can restrict a wide range of viruses in host cells (Figure 1) [67]. In bats these Mx1 proteins protect against Ebola and Influenza viruses through reducing the polymerase activity of these viruses along with other circulating viruses [68]. However, bat Mx1 does not inhibit Thogoto virus (enveloped negative sense ssRNA virus of
The cGAS-STING signaling-mediated type 1 IFN production against DNA viruses is lost in bats due to the loss of serine AA at 358 (S358) position of the STING (Figure 1) [71, 72]. The S358 AA of the STING from other non-bat mammals is conserved and its phosphorylation is crucial for STING-dependent IRF3 activation and type 1 IFN release. For example, in human STING the S3666 and S358 phosphorylation is crucial for IRF3 binding and activation, but not for TBK1 [73]. Also, the TLR9-dependent cytosolic DNA recognition in bats is not as functional as in other mammals, including humans as result to adapt its high metabolic rate that increases the body temperature over 41°C during migratory flight that can induce DNA damage and its migration to the cytosol (Figure 1) [49]. Along with, defective cGAS-STING and TLR9 signaling for cytosolic DNA recognition, absent in melanoma 2 (AIM2) and gamma-interferon-inducible protein Ifi-16 (IFI16 or p204 in mouse) or interferon-inducible myeloid differentiation transcriptional activator are the PYRIN and HIN domain containing (PYHIN) proteins also recognizing cytosolic DNA are absent the genome of most bats, including
The pteropodidae or cave nectar bat (
Lower NLRP3 inflammasome activation in the cytosol prevents exaggerated inflammatory immune response in immune cells bats due to lower ROS production (crucial for NLRP3 activation) and apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and secretion of interleukin-1β (Figure 1) [88]. Also, bats produce less TNF-α due to the interaction of c-Rel (a member NF-κB family) with the promoter sequence of TNF-α [89]. The antiviral innate immune response in bat macrophages in response to the virus-derived PAMPs is also accompanied by sustained production of an increased amount of anti-inflammatory cytokine (IL-10) (Figure 1) [90]. These unique anti-inflammatory mechanisms in bats, including greater mouse-eared bats,
Autophagy is an essential cellular process through which cells maintain homeostasis, including immune homeostasis [94, 95, 96]. Autophagy involves the breakdown of cellular components and the sequestration of the portion of cytoplasm into the double or multi-membraned vesicle called autophagosomes, which then fuse with cellular suicide or waste bags or lysosomes (contain hydrolases in their lumen and their membranes have permeases) to form autophagolysosomes or autolysosomes [96, 97, 98]. Autolysosomes are the junk crashers of the cell, in which luminal materials, including internal membrane, are degraded and exported out of the cell through permeases to recycle in the cytosol [96]. Hence, autophagy is the renewal process for cytosolic components through which cytoplasmic macromolecules mobilize to generate energy-rich compounds to meet cellular energy requirements during conditions with decreased internal and external energy resources. The impaired autophagy predisposes the host towards premature aging and inflammatory and degenerative diseases. Hence, autophagy helps the host to escape from premature aging and different diseases (cancer, neurodegeneration, and other chronic inflammatory conditions) through cellular self-digestion [99].
Autophagy also plays a crucial role in immune response to infections and inflammation that works downstream to different PRRs (TLRs, NLRs, RLRs, and cGAS-STING signaling) discussed earlier (Figure 1) [100, 101, 102]. The increased autophagy in Australian black fly foxes also dampens the severity of the lyssavirus infection through suppressing the virus replication and increases the tolerance to the prolonged infection with lesser cell death than humans (Figure 1) [103]. Autophagy increases with the increases in the viral load in bats. The pharmacological activation of the autophagy decreases the virus replication that shows its antiviral action. Another virus called Nelson Bay Orthoreovirus (NBV that in humans causes severe respiratory tract infection) isolated from the Australian fruit bat increases autophagy in host cells depending on the viral replication without causing severe infection [104]. Hence, increased autophagy along with increasing longevity and suppressing aging mechanisms among bats also increases their antiviral immune response to protect them from severe productive infection.
3. Adaptive immune response in bats to make them resistant severe viral infections
We do not have greater immunological data for adaptive immunity in bats as compared to humans due to lack of experimental reagents specific for bats and corresponding appropriate animal models. The genes [MHC-I and II, TCR (TCR-α and –β) and co-receptors, including CD3, CD4, CD8, and CD28 along with B cell-specific markers (CD22, CD19, CD20, CD27, and Igs)] involved in adaptive immunity in other species are conserved in bats [21, 22, 23]. The transcripts of both pro- and anti-inflammatory cytokines (IL-2, IL-4, IL-5, IL-6, IL-12a, IL-12b, IL-17a, IL-23, IL-10, TGF
The maternal Abs transferred to Egyptian Rousette bats against the Marburg virus last for their first five months after birth and Abs last for approximately 1 year in these bats infected naturally [111]. However, the reinfection of bats with the same virus induces anamnestic immune or Ab response within 5 days of the post viral infection clearing the virus systemically as well as from major organs (salivary glands, intestine, urinary bladder, and the reproductive tract). Hence, reinfection with the virus to bats in the natural environment is not sufficient to induce the productive infection. Another study indicates that the maternally-derived Abs (MDAs) in seasonally breeding bats (African fruit bats) do not last long for other viruses, including Lagos bat lyssavirus (LBV, a member of genus lyssavirus and gamily
The Abs-mediated virus neutralization is not a universal mechanism for protection against Ebola, Marburg, and Sosuga (a recently discovered pathogenic Paramyxovirus in Uganda) viruses in the Egyptian Rousette bats [113, 114]. Similarly, maternal Abs to the Henipavirus become undetectable between 4 and 12 months after birth [115]. The seasonal horizontal transmission of the virus makes seronegative bats seropositive for Abs and seasons of late pregnancy/lactation in bats may increase the risk of zoonotic diseases. Further studies have shown that in the straw colored fruit bats (
Abs specific to the glycoprotein GP2 to another
4. Future perspectives and conclusion
Bats always remain the source of attraction and fascinate humans. Even in Hollywood movies the character of the Dracula has been inspired from bats living on blood and coming out for the prey in night time. However, they became important to the medical community upon the first recognition of transfer of rabies virus to the animals serving as their prey for blood in 1959 in Trinidad. Since, then different have been suggested as the career for many viral pathogens that are responsible for different endemics, epidemics, and pandemics, including Nipah virus infection, Hendra virus infection, Ebola virus infection, SARS, MERS, and the current COVID-19 or SARS-CoV-2 infection. However, the direct causal virus for COVID-19, called SARS-CoV-2 has not been directly isolated from them, but genetically related or more close viruses have been identified in them [9, 10]. Hence, understanding the factors responsible for no severe pathogenic outcomes in the bats as compared to other mammals, including humans becomes crucial by keeping in mind the damages (both, life and economical) associated with current COVID-19 pandemic. The bat immune system has evolved in such a way to guard itself through the damages associated with high speed flight for long migration. For example, low ROS production to protect from DNA damage and inflammation. However, to keep a check on invading pathogens, especially viruses it has evolved the potent IFN-dependent antiviral immune response without inducing severe pro-inflammatory immune response as seen in other mammals, including humans during Ebola virus and severe COVID-19 infection. A recent study has shown that the Ebola virus in humans and fruit bats (
5. Conclusion
Bats are unique mammals with a potential to have true flight, harboring different viral pathogens that have caused or may cause severe infections to humans and other mammals. Understanding their immune system associated uniqueness may open avenues to deal effectively with zoonotic diseases coming from them.
Author contribution
The author developed the idea, wrote and compiled the manuscript, and developed the figure.
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