INTRODUCTION:

Seasonal and regional disease outbreaks are known to happen when a disease begins to infect relatively high number of people in a community and may spread to several countries. These outbreaks can last from months to years. In contrast to this an epidemic occurs when an infectious disease begins to infect huge number of population in a short time¹. For an infectious disease to become an epidemic its basic reproduction number (R₀) must be greater than 1. Mathematically explaining R₀ is number of secondary infection an infected person can cause in a population in which all the individuals are susceptible. If the R₀ becomes >1 the infection caused by the pathogen will increase and cause an epidemic². The ongoing global COVID-19 pandemic has highlighted a recurring trends in the emergence of high virulent pathogens of zoonotic origins^3,4,5. The association between human zoonotic diseases and the bats has been known for over a century now, from the identification of first rabies (Lyssavirus) in the vampire bats which were otherwise asymptomatic in 1911⁶.

Having been identified as the source of COVID-19 the bats have again gained the limelight. Bats are unique creatures being the only mammal capable of flying, they enjoy a pretty long life compared to their size and also in terms of various viruses that they harbor⁷. Many viruses harbored by bats have shown to be zoonotic that is they are transmissible to humans from bats. Some viruses that have been found to be zoonotic are filovirus, lyssaviruses, henipavirus, and coronavirus⁸. It is interesting to note that despite harboring such an array of viruses the bats show almost no sign of illness from these viruses (except lyssaviruses) but, these same viruses cause diseases in humans with high virulence^{9, 10}. Though a lot of debate is going on these viral transmissions by the bats, they are not the only group of vertebrates that are capable of transmitting the viruses or disease to the humans. A study shows that more than sixty percent of infectious diseases are caused by pathogens shared by domestic and wild animals^{9, 11}and the bats harbor a significantly high proportions of viruses causing zoonosis than all other mammalian orders¹².There are about half the bat species as of rodents, still somehow data suggests that the bats are capable of spreading more zoonotic disease than them¹³. In this review keeping the zoonosis and bats in center we will use the pre-existing literature to answer some questions such as:

A. What determines virulence of a viral strain

B. Why are bats special as viral hosts

C. Despite being the reservoir how does bats escape virulence

D. What are the consequences and perspective

Determination of virulence:

The way COVID-19 has impacted the world¹⁴ it has arisen some serious questions on study of virulence. According to Paul Ewald’s theory of evolution of virulence^{15, 16} the ‘transmission mode’ is a key variable in the determination of the virulence of any viral strain. The theory states that parasites use the host to reproduce and get distributed to the other potential hosts. According to the theory the parasite will tend to keep the host healthy and alive if the transmission of parasite is dependent on the movement of the host. On the contrary if the transmission of the parasite is not affected by death or poor health of the host and the parasite is able to ‘sit and wait’ for the new host to come around so that it can infect it, it will use all the available vital resource in the host body to maximally reproduce as happens in the case of anthrax. In above two cases the natural selection will favor the less virulent strain. In the first scenario the distribution of the offspring is dependent on the motility of the host and thus less virulent strain will thrive. On the other hand in second scenario the more virulent strain will be preferred over the less virulent as it will be able to reproduce more and hence spread more. Ewald in 1991 argued that the 1918’s Spanish flu developed from a less virulent strain from the favorable conditions of the moist trenches, soldier camps and tents and the overcrowded hospitals. This claim of Ewald’s can be also correlated with the hypothesis of the other scientists who believe that the Russian influenza (1889-1892) was caused by the H3Nx strain which circulated until 1918 and then with favorable conditions and reassortment events caused 1918 Spanish flu outbreak¹⁷. The another reason identified for the increased pathogenicity of the influenza virus during the 1918 pandemic was the absence of pre-existing cross-reactive antibodies for the influenza virus in the young population^{17, 18}. Thus we can say that the virulence of the strain may depend on the transmission mode as argued by Ewald but is not limited to that alone. The virulence may also be dependent on the presence of the pre-existing antibodies, viral reassortment events, antigenic mutations and absence of suitable therapy for the viral infection^{17, 19, 20}. The virulence factor as in case of bacteria can have other aspects too^21-25 but, we will here adhere to viruses only.

Bats as special viral hosts:

The bats may remain persistently infected and yet show no sign of the illness¹⁷. Studies done on the bat aggregates all over the world shows that more than 15 virus families causing zoonotic diseases have been found in about 12 bat families comprising of at least 200 species^{9, 12, 26, 27}. So, why are the bats special as viral reservoir? Well there are many evolutionary and physiological explanations to this question. The bats are gregarious and they prefer living in the dense aggregation. The aggregations can be so dense that density per square meter can reach 3000 bats and the whole roost can be of million member¹³. Ewald’s theory of evolution of virulence here implicates that bat living in this dense aggregation will most likely favor the evolution of more virulent strain of virus as they will continue to spread the disease to other bats even if they becomes immobilized by the disease. It is interesting to know, that it’s not only the dense roosting sites of the bats that favors the virulent strains to develop but also multispecies roosting¹³ that is responsible for zoonosis as it helps the virus in adapting itself to the species jumping. The rodents on the other hand don’t typically form the roosting sites and hence the bats become the preferred one. Also, the bats being blessed as the only mammal with flight have a longer action radius as compared to any other terrestrial mammal and hence they are able to disperse more viruses to the animals and humans⁷. The elevated core temperature of bats >40°C during flight also helps the virus to adapt to a range of temperature higher than fever temperature of normal mammals²⁸. Apart from the roosting habit and elevated core temperature of bats there are evolutionary factors too that make the bats as the favorable reservoir for the viruses. Several studies and meta-analysis have shown a long co-evolution between the bats and viruses^{13, 27, 29-31}. In fact recent studies have proved bats as the most ancestral host for many viruses such as coronaviruses³², whole paramyxovirus family⁹, hepaciviruses³³ and hepadnaviruses³⁴. The oldest known fossil of bats dates back to 52.5 million years ago³⁵. Assuming this is correct, the bats and the viruses have been in an ‘arm fight’ for a long time during which the viruses may have grown to be more virulent and on the other hand bats must have gone under natural selection process favoring only those bats which were able to live and reproduce despite having viral infection⁸. Now the question arises whether or not this mechanism of co-evolution and physiology is specific for certain diseases only or for all the pathogens altogether. The obvious answer to this question is no, Tacaribe virus and rabies notably have been known to cause widespread mortality in bats in 1950s and in other experimental conditions³⁶. Not only the viruses but also many enteric batcteria³⁷ extracellular pathogens such as Borellia spp.³⁸ and Pasteurella multocida³⁹ which acts as both intracellular and extracellular pathogen have been known to cause pathogenicity in the bats. Table 1 shows a wide range of infections to the bats and their immune response towards them⁵. The pathogenicity in the bats is very complex and many theories have been put forward to solve it.

Mechanisms of bat escaping virulence:

Just like all the mammals the bats also have innate and adaptive elements of the immune system¹⁰. Until recently most of the knowledge about bats immunity was derived from studying the adaptive humoral immune response, this was due to the fact that well developed tools for detection of antibodies are present³⁰. Bats as all other mammals are also found to mount the antibody response against various infections, but sometimes these responses are distinct³¹. In particular, the recruitment of antibodies is sometimes delayed in the bats cells compared to other vertebrates post-infection⁵¹. Apart from the adaptive humoral response the bats also are equipped with cell-mediated immunity and in response to infection produce cytokines, mainly signaling molecules known as interferon (IFN) that are known to regulate apoptosis in tumor and intracellular virus infected cells^52,
53. Many viruses have been shown to antagonize type I IFN signaling pathways in the infected hosts. However antagonism of complementary type III and type I IFN have been demonstrated and is found to be common in both bat and human cells lines for the infection by Henipavirus⁵⁴. Providing an-evidence that bats may have been using other mechanism other than IFN mediated response to control Henipavirus replication. The Bats in addition to have IFN-I and complementary IFN-III also possess a type II IFN which normally functions for the coordination of innate and adaptive immune response pathways against an infection⁵³. The bats are a bit more evolved to control their immune system also in due course of evolution they have modified their immune systems for example the genome analysis done for M. davidii and P.alecto shows absence of whole locus of gene family PHYIN which otherwise plays a critical role in innate immunity regulation. Not only this the receptors for the NK cells have also been found to be absent or completely reduced⁵⁶. So why would the bats suppress their own immune system to favor viruses? In most of the cases the mortality is associated with the immunopathological response of the host and not the pathogen itself (except rabies)^{48, 56}. In their review, O’Shea et al. proposed that in order to evade this immunopathology induced mortality and morbidity bats have favored incomplete clearance of the viruses³⁰. The bats suppress their immune responses to escape from immunopathology in case of those viruses only, with whom they share a deep co-evolutionary history. The recent discoveries of some viral elements (endogenous) in genome of animals suggest that, the bats are able to evade the immune response by recognizing the viral elements as ‘self’⁵⁷.

Another speculative hypothesis ‘flight-as-fever’ has been discussed over time and again. The speculations have been made that the evolution of flight in the bat is related to viral control mechanism in the bats^{30, 53, 58}. Usually the fever in mammals is concurrent with the high metabolic rates and elevated immune response^{59, 60}. The metabolic rate of the bats during the flights increases and is estimated to be elevated about 15-16 folds²⁸ when compared to their resting condition, while that of rodents running to exhaustion is 7 fold and of bird is 2 fold only^{61, 62}. The core body temperature of a mammal during fever may vary between the species but is generally between 38^oC-41^oC⁵⁹. The metabolically expensive flight of bats results in the high core temperature of the body that typically is in the range of fever⁶³. The flight and other metabolically expensive activities produce reactive oxygen species (ROS) as byproducts which tend to damage cell structure and also the mtDNA⁶¹. Despite of increasing the metabolic rate to 16 folds and producing the ROS in the propositional amount, some bats have been known to live about 40 years in wild⁶¹. For longevity and other negative effects of the mitochondrial ROS, these needs to be dealt with at the site of production⁶⁴. Paradoxically, the ROS also has some positive effects such as upregulating the cellular pathways namely apoptosis and autophagy, helping in the repair of the cell or destructing it if damaged beyond repair⁶⁵. The research has found that the rapid evolution of the mitochondrial DNA damage and repair pathways in bats are concordant with the emergence of metabolically active flight⁶⁶. The intracellular pathogens have been known to cause oxidative damage to the cell either directly or by recruiting cytokines⁶⁷. Thus, if evolved damage and repair pathways of bats treat the oxidative stress caused due to the pathogen similar to that of metabolically caused oxidative stress, the bats can very easily regulate the infections by either apoptosis or autophagy⁶⁸.

Consequences and perspective:

The ongoing effect of the COVID-19 pandemic is a constant reminder for us that we are living in the world full of zoonotic disease and are terribly susceptible to them. The far less appreciated fact is that we are totally unable to predict any new zoonotic disease and the approaches used till date are insufficient. We need more self-sufficient and bold approaches⁶⁹. If we look at the history, the Russian influenza (1889-1892) caused more than 1 million deaths, Spanish flu in 1918-1919 caused around 50 million deaths, Asian influenza (1957-1958) caused about 2 million deaths and Hong Kong influenza of 1968 killed around 1 million people^70-75. The UN has predicted that by year 2050 the human population on earth will reach 9 billion and with half of the population already living in the urban area the challenges will be faced in disease control⁷⁶. Study of zoonotic disease and animal-human interface remains a complex challenge. The combined knowledge of human and animal medicine, ecology, microbial diversity, sociology and the underlying mechanism of the increased transmission is required^{77, 78}. One such novel project has already been started with the name PREDICT by the One health institute, University of California. Covering around 30 countries and involving around 2500 researchers from various educational backgrounds, it’s boosted to be the largest track down effort for the emerging disease. The sole purpose of the project is to identify the microorganism which could be possible cause for and outbreak and make an educated guess of the place outbreak could happen⁷⁹. Some local initiatives have been also taken in identification of disease outbreaks⁸⁰.

Concluding remarks:

The field of zoonosis and disease outbreak remains still to be explored in the depths. The recurring zoonotic diseases especially the viral diseases have taken human lives again and again rising the death toll to the millions each time. Since these diseases get transmitted to humans by the animals and have the potential to become pandemic even before we could figure out the mechanism of their infection, the best bet we have is to stop them before they infect us. This can be done only through mutli-organisation approach and the world coming together under one roof to fight against them. More project such as the PREDICT projects need to be started which can study the zoonosis and its ecology. We also need to side ourselves from such practices which bring us in direct contact with the pathogens and making as vulnerable, the practices such as eating raw meat, wildlife trade etc.

ACKNOWLEDGEMENT:

We would like to extend our sincere thanks to all the authors who have been cited in this review. We would also like to thank Prof. Deepali Rajwade, Department of Biotechnology, Nagarjuna Post Graduate College of science, Raipur for reviewing first draft of this manuscript and her valuable suggestions.

CONFLICT OF INTEREST:

We declare no conflict of interest.

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Received on 19.12.2020 Modified on 17.04.2021

Research J. Pharm.and Tech 2022; 15(4):1877-1882.

DOI: 10.52711/0974-360X.2022.00314

Sr. no.	Pathogen	Class	Documented pathology	Reference
1	Lecithodendrium spp.	Helminth	Minimal	40
2	Trypanosoma spp.	Protozoa	No	41, 42
3	Plasmodium spp.	Protozoa	No	43
4	Pseudogymnoascus destructans	Fungi	Yes	44
5	Histoplasma capsulatum	Fungi	No	45
6	Henipavirus spp.	Virus	No	46
7	Lyssavirus spp.	Virus	Yes	47, 48
8	Bartonella spp.	Bacteria	No	49
9	Borellia spp.	Bacteria	Yes	50