**3. Etiology and associated diseases**

Globally, a small proportion of the approximately 55,000 annual human deaths caused by rabies virus are the result of infection by variants or virus associated with bats [19]. Human rabies caused by bat *lyssavirus* (genotype 1: rabies virus; genotype 2: Lagos bat virus; genotype 4: Duvenhage virus; genotype 5: European bat lyssavirus type 1, EBLV-1; genotype 6: European bat lyssavirus type 2, EBLV-2; genotype 7: Australian bat lyssavirus) was regularly reported in South and North America, Africa, Europe and Australia [20–22].

a limited spread to other countries in the Middle East (except in individuals traveling back from Middle East). So far, 2081 people were infected with MERS-CoV among which 722 died from the disease (case fatality rate 34.7%). It is worth noting that during the 2012–2014 outbreak of MERS-CoV, "superefficient" person-to-person transmission apparently did not occur. However, the MERS-CoV outbreak that affected the Republic of Korea in 2015 was caused by a single person (68 years old "index patient") who developed fever 2 weeks after returning from 2 weeks travel in the Middle East. Once back to Seoul, this person visited the Samsung Medical Centre on 17 May and was isolated the day after on suspicion of MESR before being finally diagnosed with MERS on 20 May. A total of 186 people were infected out of which 36 died; some 44.1% of the cases were patients exposed in hospitals, 32.8% were caregivers, and 13.4% were healthcare personnel. Interestingly, a total of 83.2% of the transmission events were epidemiologically linked to five "superspreaders," all of whom had pneumonia characterized at the first medical consultation. In August 2015, 1413 laboratoryconfirmed cases of MERS have been reported worldwide of which 502 died [35]. The cause for superspreading events is still unclear and could be consequence of virus mutation, high viremia linked to higher level of virus shedding, environmental factors such as co-infection, or host-altered immune status. A recent study of a virus closely related to Middle East respiratory syndrome coronavirus (MERS-CoV) found in a *Pipistrellus* bat supports the bat-borne

Bats, Bat-Borne Viruses, and Environmental Changes http://dx.doi.org/10.5772/intechopen.74377 117

Ebola hemorrhagic fever is also caused by a zoonotic virus discovered during an epidemic outbreak that affected people in villages of Democratic Republic of Congo (DRC; more than 300 infected people) and Sudan (almost 300 people infected), in 1976 [37]. Ebola virus is responsible for a severe and frequently fatal illness characterized by a nonspecific viral syndrome followed by a fulminant septic shock, multi-organ failure, and coagulopathy resulting in severe bleeding complications). Though silent during a few years, Ebola virus continued to circulate in these regions and re-emerged in Sudan in 1979 (34 infected people) and Gabon and DRC in 1994–1995 (more than 350 infected people). Between 1996 and 2014, several outbreaks were reported in different African countries, each episode affecting from a few people

Although the recent emergence of viruses known to be carried by bats have not led to very large epidemic outbreaks (a few hundred to a few thousand infected people), the fact that some of these viruses can adapt to spread from person-to-person, and the high mortality associated with these infections (case fatality frequently above 30% of infected persons) has contributed to consider them a major public health risk by international medical authorities. This partly explains why after a period of relative disorganization in the face of the threat (e.g. SARS, MERS and Ebola outbreaks), each emergence was subject of a rapid response by the health authorities. In some cases, treatment of the disease is largely limited to supportive therapy and requires appropriate control measures. This proved true for the 2014′ Ebola outbreak in West Africa, which was the largest in history. Ebola hemorrhagic fever was diagnosed in Guinea in December 2013 and outbreaks next appeared in Liberia, Nigeria, Senegal, and Mali. By 18 September 2014, WHO reported of 5335 cases with 2622 deaths (case fatality around 50%). Early 2015, additional cases were reported in Mali and

origin of MERS-Cov [36].

to thousands for the 2014 epidemic, case fatality 52% [38].

In 1994, an outbreak of an acute respiratory illness occurred in a human and 14 horses in Hendra, a suburb of Brisbane, Australia. These EIDs finally affected 2 humans and 22 horses [23]. Four additional outbreaks were observed during years 1994, 1999, and 2004, infecting two humans and five horses and killing all but one human. A virus of the *Paramyxoviridae* family, genus *Henipavirus*, carried by *Pteropus* bats, and named Hendra virus was shown to be the etiologic agent of this disease. Nipah virus (NiV), another member of the *Paramyxoviridae* family found in *Pteropus* bats, associated with encephalitis in humans, was discovered in an outbreak in Malaysia in 1998 that affected 283 persons and caused 109 deaths (case fatality rate 39%) [24]. Direct contact with infected pigs was identified as the predominant mode of human infection. Subsequently, outbreaks of NiV have been observed almost every year in Bangladesh [25] and occasionally in India [26]. Bangladesh outbreaks were shown to be linked to consumption of fresh data palm sap contaminated by NiV-containing *Pteropus* bats' secretions and excretions [27]. In 1997, another member of the bat-borne *Paramyxoviridae* family, described as Menangle virus, was isolated from stillborn piglets in Australia; two of 250 humans living in contact with the infected animal showed febrile illness with measles-like rash and had high titer of anti-Menangle virus antibodies [28]. These people never get in contact with flying foxes, suggesting that this bat-borne virus was transmitted to the humans after infection of pigs/piglets [29]. Before 2002, although coronaviruses (CoV) were known to be agents of respiratory infections in humans (e.g.; common winter cold), they lent little attention. Human CoV (HCoV) strongly gained in notoriety after being identified as responsible for the severe acute respiratory syndrome (SRAS) outbreak in humans [30]. SRAS emerged in 2002 in China and spread across 29 other countries, causing more than 8000 infected patients and almost 800 deaths worldwide (case fatality rate about 10%). Serological analysis of healthy human samples collected in Hong Kong in 2001 revealed a prevalence of 1.8%, suggesting that the circulation of SARS-related viruses had occurred prior to the 2003 epidemic. Indeed, SARS-like CoV circulating in Chinese horseshoe bats had spread and adapted to wild Himalayan palm-civet often sold as food in Chinese markets [31]. After mutation, this CoV adapted to humans and became able to spread from person-to-person. During SARS outbreaks in Toronto and Taiwan, certain persons were very efficient at transmitting SARS-CoV and were named "Superspreaders" [32]. A few years later, the emergent Middle East Bats Respiratory Syndrome (MERS)-CoV was reported in Saudi Arabia in 2012) [33]. Once again, the human MERS-CoV likely originated from a bat-CoV-related virus and was likely transmitted through camel-human contacts [34]. The MESR epidemics displayed a limited spread to other countries in the Middle East (except in individuals traveling back from Middle East). So far, 2081 people were infected with MERS-CoV among which 722 died from the disease (case fatality rate 34.7%). It is worth noting that during the 2012–2014 outbreak of MERS-CoV, "superefficient" person-to-person transmission apparently did not occur. However, the MERS-CoV outbreak that affected the Republic of Korea in 2015 was caused by a single person (68 years old "index patient") who developed fever 2 weeks after returning from 2 weeks travel in the Middle East. Once back to Seoul, this person visited the Samsung Medical Centre on 17 May and was isolated the day after on suspicion of MESR before being finally diagnosed with MERS on 20 May. A total of 186 people were infected out of which 36 died; some 44.1% of the cases were patients exposed in hospitals, 32.8% were caregivers, and 13.4% were healthcare personnel. Interestingly, a total of 83.2% of the transmission events were epidemiologically linked to five "superspreaders," all of whom had pneumonia characterized at the first medical consultation. In August 2015, 1413 laboratoryconfirmed cases of MERS have been reported worldwide of which 502 died [35]. The cause for superspreading events is still unclear and could be consequence of virus mutation, high viremia linked to higher level of virus shedding, environmental factors such as co-infection, or host-altered immune status. A recent study of a virus closely related to Middle East respiratory syndrome coronavirus (MERS-CoV) found in a *Pipistrellus* bat supports the bat-borne origin of MERS-Cov [36].

**3. Etiology and associated diseases**

[20–22].

116 Bats

Globally, a small proportion of the approximately 55,000 annual human deaths caused by rabies virus are the result of infection by variants or virus associated with bats [19]. Human rabies caused by bat *lyssavirus* (genotype 1: rabies virus; genotype 2: Lagos bat virus; genotype 4: Duvenhage virus; genotype 5: European bat lyssavirus type 1, EBLV-1; genotype 6: European bat lyssavirus type 2, EBLV-2; genotype 7: Australian bat lyssavirus) was regularly reported in South and North America, Africa, Europe and Australia

In 1994, an outbreak of an acute respiratory illness occurred in a human and 14 horses in Hendra, a suburb of Brisbane, Australia. These EIDs finally affected 2 humans and 22 horses [23]. Four additional outbreaks were observed during years 1994, 1999, and 2004, infecting two humans and five horses and killing all but one human. A virus of the *Paramyxoviridae* family, genus *Henipavirus*, carried by *Pteropus* bats, and named Hendra virus was shown to be the etiologic agent of this disease. Nipah virus (NiV), another member of the *Paramyxoviridae* family found in *Pteropus* bats, associated with encephalitis in humans, was discovered in an outbreak in Malaysia in 1998 that affected 283 persons and caused 109 deaths (case fatality rate 39%) [24]. Direct contact with infected pigs was identified as the predominant mode of human infection. Subsequently, outbreaks of NiV have been observed almost every year in Bangladesh [25] and occasionally in India [26]. Bangladesh outbreaks were shown to be linked to consumption of fresh data palm sap contaminated by NiV-containing *Pteropus* bats' secretions and excretions [27]. In 1997, another member of the bat-borne *Paramyxoviridae* family, described as Menangle virus, was isolated from stillborn piglets in Australia; two of 250 humans living in contact with the infected animal showed febrile illness with measles-like rash and had high titer of anti-Menangle virus antibodies [28]. These people never get in contact with flying foxes, suggesting that this bat-borne virus was transmitted to the humans after infection of pigs/piglets [29]. Before 2002, although coronaviruses (CoV) were known to be agents of respiratory infections in humans (e.g.; common winter cold), they lent little attention. Human CoV (HCoV) strongly gained in notoriety after being identified as responsible for the severe acute respiratory syndrome (SRAS) outbreak in humans [30]. SRAS emerged in 2002 in China and spread across 29 other countries, causing more than 8000 infected patients and almost 800 deaths worldwide (case fatality rate about 10%). Serological analysis of healthy human samples collected in Hong Kong in 2001 revealed a prevalence of 1.8%, suggesting that the circulation of SARS-related viruses had occurred prior to the 2003 epidemic. Indeed, SARS-like CoV circulating in Chinese horseshoe bats had spread and adapted to wild Himalayan palm-civet often sold as food in Chinese markets [31]. After mutation, this CoV adapted to humans and became able to spread from person-to-person. During SARS outbreaks in Toronto and Taiwan, certain persons were very efficient at transmitting SARS-CoV and were named "Superspreaders" [32]. A few years later, the emergent Middle East Bats Respiratory Syndrome (MERS)-CoV was reported in Saudi Arabia in 2012) [33]. Once again, the human MERS-CoV likely originated from a bat-CoV-related virus and was likely transmitted through camel-human contacts [34]. The MESR epidemics displayed

Ebola hemorrhagic fever is also caused by a zoonotic virus discovered during an epidemic outbreak that affected people in villages of Democratic Republic of Congo (DRC; more than 300 infected people) and Sudan (almost 300 people infected), in 1976 [37]. Ebola virus is responsible for a severe and frequently fatal illness characterized by a nonspecific viral syndrome followed by a fulminant septic shock, multi-organ failure, and coagulopathy resulting in severe bleeding complications). Though silent during a few years, Ebola virus continued to circulate in these regions and re-emerged in Sudan in 1979 (34 infected people) and Gabon and DRC in 1994–1995 (more than 350 infected people). Between 1996 and 2014, several outbreaks were reported in different African countries, each episode affecting from a few people to thousands for the 2014 epidemic, case fatality 52% [38].

Although the recent emergence of viruses known to be carried by bats have not led to very large epidemic outbreaks (a few hundred to a few thousand infected people), the fact that some of these viruses can adapt to spread from person-to-person, and the high mortality associated with these infections (case fatality frequently above 30% of infected persons) has contributed to consider them a major public health risk by international medical authorities. This partly explains why after a period of relative disorganization in the face of the threat (e.g. SARS, MERS and Ebola outbreaks), each emergence was subject of a rapid response by the health authorities. In some cases, treatment of the disease is largely limited to supportive therapy and requires appropriate control measures. This proved true for the 2014′ Ebola outbreak in West Africa, which was the largest in history. Ebola hemorrhagic fever was diagnosed in Guinea in December 2013 and outbreaks next appeared in Liberia, Nigeria, Senegal, and Mali. By 18 September 2014, WHO reported of 5335 cases with 2622 deaths (case fatality around 50%). Early 2015, additional cases were reported in Mali and Sierra Leone. On April 2015, the Ebolavirus outbreaks had already resulted in more than 10,880 deaths among 26,277 cases [38]. On March 2016, WHO reported a total 11,323 deaths among 28,646 cases, indicating a decrease in the spreading of the virus in human. There is no direct evidence that bat is the reservoir for ebolavirus-inducing disease in humans. Yet, Ebola-related virus were found in tissues of several bats (the hammer-headed fruit bat: *Hypsignathus monstrosus*; the Franquet's epauletted bat: *Epomops franqueti*; and the little collared fruit bat: *Myonycteris torquata*) [9], and experimental infections of the Angola free-tail bat (*Mops condylurus*), little free-tail bat (*Chaerephon pumilus*), and Wahlberg's epauletted fruit bat (*Epomophorus wahlbergi*) with a Zaire strain of Ebola virus led to viral replication in these bats [39]. Widespread infection of cave-dwelling bats by Crimean Congo hemorrhagic fever virus (CCHFV) has also been reported, suggesting a role of bats in the life cycle and geographic dispersal of this virus [40].

It is generally admitted that bats are a source of high viral diversity that may directly or indirectly (following genomic recombination, gene mutations, gene duplication loss/gain) cause a new outbreak. Since the past 20 years, a massive international effort was devoted to the identification of viruses in different families of bats. As shown in **Figure 2**, the total number of bat-associated sequences in GenBank has grown exponentially in the last 20 years. A review of articles referring to bat-borne viruses (**Figure 3**) indicates that rabbies (55,000 persons infected each year, case fatality nearly 100%) is the most prominent topic with 2792 articles (33%). Surprisingly, as shown in **Figure 3A**, the virus family that rank second is *Coronaviridae* with 2622 articles (31%), while the total number of cases accumulated the different episodes remains relatively low (cumulative cases about 8000 individuals; mean case fatality around 10%). Moreover, the number of scientific report about virus family indicates that Coronavirus rank first in terms of publications when MeSH terms concern viruses and

> *Rhinolophidae* bats (**Figure 3B**) and second when MeSH terms concern viruses and frugivorous bats (**Figure 3C**). It suggests that the number of articles published concerning bat-borne virus does not correlate with the number of infected persons and the case fatality, but rather reflect the perception of a risk felt by the public authorities, health authorities, and funding agencies according to societal demand and presentation of the threat by the media. Even if the accumulation of knowledge through research works is probably influenced by these problems of perception of the risks, the example of coronavirus remains very interesting to tackle emergence phenomena. The increasing risk of pathogen transmission between bats, animals and humans in South East Asia is a consequence of the growing human population and of anthropization of environment (deforestation, agriculture) which have largely altered

> **Figure 3.** Distribution by virus family. (A) Overall data distribution by virus family. Adapted from the database of bat-associated viruses (http://www.mgc.ac.cn/cgi-bin/DBatVir/main.cgi, updated February, 18, 2018). Rhabdoviridae come first with 2792 articles (32.7%), followed by Coronaviridae with 2622 articles (30.7%), Paramyxoviridae with 839 articles (9.8%), Astroviridae with 494 articles (5.8%), Reoviridae with 244 articles (2.9%), Adenoviridae with 232 articles (2.7%), Circoviridae with 218 articles (2.6%), and Herpesviridae with 189 articles (2.2%). Others represent different virus families such as Flaviviridae (2.3%), Parvoviridae (1.5%), Picornaviridae (1.3%), Filoviridae (1.2%), Polyomaviridae (0.8%), Papillomaviridae (0.6%), and other virus families ranking 2.9%. (B) Ranking of virus family distribution (top 1–6) in Rhinolophidae. (C) Ranking of virus

Bats, Bat-Borne Viruses, and Environmental Changes http://dx.doi.org/10.5772/intechopen.74377 119

The biological interaction of viruses and their hosts is usually antagonistic, with a delicate balance of actions and counteractions between host immune system and virus escape mechanisms. Parasite-induced reduction in host fitness enhances selection for host resistance

landscapes [41].

**4. Coevolution between bats and viruses**

family distribution (top 1–6) in Frugivorous bats.

**Figure 2.** Data increase of bat-associated viruses during the past 20 years. This figure illustrates the total number of sequences of bat-associated viruses available in GenBank according to the database of bat-associated viruses (http:// www.mgc.ac.cn/cgi-bin/DBatVir/main.cgi). During the same period (1997–2017), the total number of publications about bat-associated viruses in PubMed increased from 2 to 367 publications/year.

**Figure 3.** Distribution by virus family. (A) Overall data distribution by virus family. Adapted from the database of bat-associated viruses (http://www.mgc.ac.cn/cgi-bin/DBatVir/main.cgi, updated February, 18, 2018). Rhabdoviridae come first with 2792 articles (32.7%), followed by Coronaviridae with 2622 articles (30.7%), Paramyxoviridae with 839 articles (9.8%), Astroviridae with 494 articles (5.8%), Reoviridae with 244 articles (2.9%), Adenoviridae with 232 articles (2.7%), Circoviridae with 218 articles (2.6%), and Herpesviridae with 189 articles (2.2%). Others represent different virus families such as Flaviviridae (2.3%), Parvoviridae (1.5%), Picornaviridae (1.3%), Filoviridae (1.2%), Polyomaviridae (0.8%), Papillomaviridae (0.6%), and other virus families ranking 2.9%. (B) Ranking of virus family distribution (top 1–6) in Rhinolophidae. (C) Ranking of virus family distribution (top 1–6) in Frugivorous bats.

*Rhinolophidae* bats (**Figure 3B**) and second when MeSH terms concern viruses and frugivorous bats (**Figure 3C**). It suggests that the number of articles published concerning bat-borne virus does not correlate with the number of infected persons and the case fatality, but rather reflect the perception of a risk felt by the public authorities, health authorities, and funding agencies according to societal demand and presentation of the threat by the media. Even if the accumulation of knowledge through research works is probably influenced by these problems of perception of the risks, the example of coronavirus remains very interesting to tackle emergence phenomena. The increasing risk of pathogen transmission between bats, animals and humans in South East Asia is a consequence of the growing human population and of anthropization of environment (deforestation, agriculture) which have largely altered landscapes [41].
