Tracking arboviruses

Bats and other small mammals that chronically harbour viruses act as disease reservoirs, though the exact pathways through which these are transmitted to humans are not always clear. It is an area that needs research if epidemics are to be prevented.

Published : Jul 19, 2017 12:30 IST

An Indian flying fox (Pteropus giganteus). In a 2013 study of this bat’s virome, scientists discovered 55 viruses, 50 of them previously unknown.

An Indian flying fox (Pteropus giganteus). In a 2013 study of this bat’s virome, scientists discovered 55 viruses, 50 of them previously unknown.

Many high-profile epidemics caused by viruses have been traced to bats and several species of small mammals. These animals seem especially adept at harbouring and spreading diseases. Scientists are also discovering new bat-borne viruses all the time. There is also sufficient evidence about their role in the natural cycle of Kyasanur forest disease (KFD), dengue and Ebola. Bats are suspected to be involved in Zika too. Bats can, therefore, be called zoonotic reservoirs. According to K.F. Meyer, the father of zoonoses research, “ parasitic diseases of man and animals are a part of a broad evolutionary development ”.

The study of the role of bats is so important that we just cannot ignore it anymore. Bats (and other species such as small mammals) which chronically harbour viruses are known as disease reservoirs (zoonotic reservoirs). Most of the time, these reservoirs stay intact, with infected animals rarely showing symptoms of disease. But sometimes they leak, letting a virus infect new and much more vulnerable species. This is almost certainly what happened with the Ebola outbreak in West Africa, which began with a trickle in December 2014 and infected at least 8,900 people and killed more than 4,400 . Scientists suspect bats are to blame for this epidemic , which overwhelmed Guinea, Sierra Leone and Liberia.

It should be remembered that bats (chiropterans) had evolved in the Eocene period (which began 56 million years ago and ended 33.9 million years ago), much earlier than man. Bats seem to carry a disproportionately high number of scary viruses but have not been given enough importance.

Opinion is divided over whether bat-related epidemics are simply a numbers game: there are so many species and so many individuals that the emergence of bat-borne illnesses is not surprising. There is also a strong lobby which feels that bats are indeed special, and that there is something special about their physiology or their lifestyle that makes them exceptionally good viral repositories. What that something is yet to be determined.

Tracing the routes of viruses from their reservoirs to humans is tricky. Even now, scientists do not know all the pathways. One known mode of transmission is the consumption of an infected animal. Bats, primates, and other wildlife are often consumed in parts of West Africa. In several parts of India, some people eat the meat of flying foxes (bats of the genus Pteropus). Other pathways are less clear. Saliva, urine or faeces from infected fruit bats could contaminate fruit that might then be eaten by a human or an intermediate host.

In Bangladesh, the Nipah virus appears to pass directly from bats to humans via date palm sap. In South-East Asia, Nipah first infects pigs, which then infect humans. In Australia, the Hendra virus appears to use horses as an intermediate species. And Ebola has infected primates that people eat. The vampire bat is known to transmit the rabies virus to man through bite (saliva). Other mechanisms of transfer of infection between bats and man are not clearly known, unless there is an arthropod vector involved.

Is there a genetic factor peculiar to bats? Even though bat genomes contain many of the same ingredients as other mammals, bats use them differently. The results, reported in Science in December 2012, correspond with the previous observation that DNA damage repair genes are frequent targets for invading viruses, which could be what is applying the evolutionary pressure.

The findings by Wang and others in Australia suggest that unlike in humans or mice where defences such as anti-tumour and anti-viral genes are activated only in response to a threat, in bats these genes seem to be perpetually turned on. That keeps the levels of any harboured viruses simmering below the point at which they could cause harm. Wang suggests a link with flight, which boosts a bat’s metabolic rate to a level many times higher than when it is resting. An article in Emerging Infectious Diseases suggests that bat flight might generate enough heat to mimic a fever . As part of the normal immune response in many animals, fevers help combat infection by raising body temperature to levels that will kill or disable invading pathogens. Though no experiments have been done to test the idea, some scientists say it is plausible that one reason bat-borne viruses are so lethal when they spill over into humans or other animals is that they have evolved to withstand the bat’s especially active immune system. “We don’t have that sort of immune system,” says Angela Luis, a disease ecologist at the University of Montana, and an author of the fever-flight study. Once free from the bat’s hyper-vigilant, perpetually turned-on defences, those viruses might have no problem overwhelming more feeble immune systems.

With more than 1,200 known species, bats comprise more than 20 per cent of the mammal species on the earth. And among mammals, they are outnumbered only by rodents. But in many areas, bats are more numerous than rodents, with millions living in a single colony. In a 2013 study, Olival and colleagues in Australia examined the virome of a giant bat called the Indian flying fox, Pteropus giganteus. In that one species, they detected 55 viruses, 50 of them previously unknown . That is roughly the total number of bat viruses identified in a 2006 study that reviewed all of the relevant research done at the time.

From Australia, there is also a report of finding antibodies to the dengue virus. If one looks at the broad spectrum of what we know about mammal virus diversity, all have diverse groups of viruses. The groups that do not have viruses are the ones we have not looked at enough.

I think we in India have not investigated the role of bats adequately as reservoir hosts for many viruses. Kalyan Banerjee in Pune did study viruses in flying foxes a decade or so ago, but no firm conclusion could be drawn about their role. Another important thing is their ecology, and thinking about where these animals live and how humans come into contact with them. Or, is there any connecting link like an arthropod transmitting viruses from bat to man? What is really important is the way humans interact with bats, or, rather, the ways in which humans interact with and encroach upon bat habitat. The natural cycles of the majority of the arboviruses are unknown. Even with the yellow fever virus—which belongs to Casals’s Group B—where extensive investigations have shown the natural cycle to involve forest-dwelling primates and mosquitoes, many scientists think that there still remains at least one other as yet undiscovered cycle of virus maintenance.

In order to control these diseases, steps must be taken to identify the reservoirs of viruses in the animal population, and attempts to control these natural reservoirs should be made. Many arboviruses are mosquito borne, but it is not clear how these viruses can survive the cold winter months in temperate zones as the mosquito vectors are not active in these periods. Several possible theories exist: latent infection and recurrent viraemia in a vertebrate host (Sulkin 1962).

It has been estimated that an insectivorous bat may consume 50 to 100 per cent of its body mass in insects in a 24-hour period. Contact with arboviruses is therefore inevitable. Antibodies against more than 30 arboviruses have been found in naturally infected bats, and some viruses, including West Nile, chikungunya, Sindbis and Rift Valley fever viruses, have also been isolated from bats. It is also known that bats can be infected with certain arboviruses via the oral route. For example, bats can be infected with the yellow fever virus following ingestion of as few as a single infected mosquito.

Evidence suggesting the involvement of chiropterans in the natural history of several human diseases, including those caused by arboviruses such as Q-fever and tick-borne encephalitis, exists. However, although bats have been associated with the rabies virus, arboviruses and several fungal agents, only rabies and histoplasmosis are recorded as having been transmitted by bats directly to man. Aedes aegypti (the yellow fever mosquito) readily feeds on several species of bats. It was observed on numerous occasions that when bats were placed in cages containing unfed mosquitoes, the mosquitoes took blood from them. Experiments in bats with the yellow fever virus and with Japanese, Venezuelan and St. Louis Encephalitis viruses demonstrated the presence of the virus in several organs following experimental infection, while none of the bats showed any sign of encephalitis or developed neutralising antibodies. Mosquitoes were also seen to feed on bats at cave temperatures (10 °C) and to transmit infection under these conditions. In addition, bats inoculated subcutaneously with the Japanese encephalitis virus maintained the virus during hibernation and had a detectable viraemia two to five days after they were moved to room temperature conditions. In one case, a bat developed viraemia nine days after the ingestion of three infected mosquitoes.

A natural cycle

It, therefore, seems possible that in the case of arboviruses, a natural cycle between bats and mosquitoes does exist in nature and that only after heavy rainfall, causing an increase in the mosquito population, does an overflow to other animals occur. The reservoir host for the Rift Valley fever virus (RVFV) in inter-epizootic periods remains unknown although the Tamaqua rock rat, Aethomys namaquensis , has been implicated. The viraemia in these animals is of very short duration, making efficient transmission to arthropod vectors unlikely. In a preliminary study by Boiro et al. (1987) to investigate bats as possible reservoir hosts for RVFV in South Africa, it was shown that some species can be infected with RVFV without showing any clinical signs.

In caves or large temple corridors (like the ones in south India), one often comes across colonies of small bats flying around, particularly where there is darkness during the day, or at dusk and night-time. The common insectivorous bat, Pipistrellus pipistrellus , is a small bat whose very large range extends across most of Europe, North Africa, south-western Asia, and possibly into Korea. It is one of the most common bat species in the British Isles. It is also seen in old abandoned buildings and its presence can be recognised by the stench it produces.

Bats of this species usually roost in groups in abandoned buildings, dry caves, or in the cavities of huge trees, and carry their young ones for two months after birth. I do not know what tick or mite ectoparasites they have, but I have collected many years ago a muscid fly ( Nycteribidae ), called bat fly. Bat flies are wingless and there are published reports of them transmitting bat malaria. These are commonly found on bats. It is more than likely, considering their lifestyle, that they have acarine ectoparasites, which needs to be investigated to find out their role as zoonotic reservoirs of arboviruses.

Bats and KFD

While studying the natural cycle of the KFD virus, this writer encountered a colony of insectivorous bats, Rhinolophus rouxi, in an abandoned well in a remote village in Shivamogga district of Karnataka. They feed exclusively on insects. They are nocturnal and can be seen flying about and hunting for insects. They must also be feeding on the ticks infesting them in their habitat. These bats were found infested with a soft tick, Ornithodoros, and a new species was collected from them, O.rhinolophi . The KFD virus was isolated from several bats collected from the wall of the wells, and from the Ornithodoros ticks on the bats and from the wall of the wells. There seems to be a closed bat-tick-bat zoonotic cycle silently occurring in nature.

How the virus got out of this cycle and entered the small mammal-hard tick-monkey-man cycle must be another fascinating story. And this aspect has not been investigated. In recent years, many States in the western part of India, such as Kerala, Karnataka, Goa and Maharashtra (Tamil Nadu had a small pocket in Nilgiris district), have reported sporadic human cases of KFD as well as monkey deaths in isolated pockets. From where did the virus spring up in these areas? Did the virus get out of the bat cycle? The finding of the virus in bats and their soft tick parasites did not evoke sufficient attention among researchers/public health authorities. But the awareness is there, and many people want to know what can be done about it.

KFD is a zoonotic disease. The virus exists in an enzootic cycle with the involvement of several species of small mammals and passerine birds that inhabit the forests adjoining human habitations. The virus has been isolated from several species of ticks parasitising these small mammals. These mammalian hosts were also found to circulate high titres of the KFD virus for various durations, infecting their Ixodids ectoparasites and playing an important role in distributing infected ticks within the range of their movement within the forest. New susceptible hosts replace the immune ones in quick time. Among the ticks are several species of Haemaphysalis , the chief vector to man, and two species of Ixodes, I.petauristae and I.ceylonensis . The most important small mammal is the common shrew, Suncus murinus , an insectivore (often mistakenly classified as a rodent) which is heavily parasitised simultaneously by both Haemaphysalis (the vector to man and monkeys) and Ixodes . The virus has been isolated from Ixodes and Haemaphysalis ticks collected from the forest floor and as ectoparasites from rodents and shrews.

After several years of continuous studies in the forests, it was found reasonable to conclude that small mammals, particularly shrews, play a significant role in the transfer of infection to Ixodes spp. This is very important in the epidemiology of the KFD virus, since the parasite population of Ixodes predominates that of Haemaphysalis during the prolonged monsoon season, when both human cases and monkey deaths are rare.

One of the hypotheses which need to be investigated is whether ticks of Ixodes genus are the medium of survival of the KFD virus during the monsoon season since they survive for longer duration during the heavy rains. The nymphs of Haemaphysalis turturis has also been found to help in the trans-monsoonal survival of the virus. Then there is the question of the soft tick, Ornithodoros , from which the KFD virus has been isolated. It is well known that O.savignyi , the vector of African sleeping sickness, is known, as a fed adult, to live for more than two years. From the closed bat-tick cycle, how does the virus enter the forest ecosystem of the small mammals- tick-monkey-man cycle?

For purely academic reasons, if not epidemiological, the mechanism of survival of the virus in the ecosystem should be investigated, particularly when there is no epidemic of KFD in man, or an epizootic in monkeys. This also applies to dengue. How can one explain the sudden and sporadic appearance of KFD human cases and monkey deaths sporadically in different parts of India in recent years? And the recurrent seasonal appearance of dengue? It needs special ingenuity and adequate funding to pursue long-term investigations, similar to what the Rockefeller Foundation carried out at the Virus Research Centre, Pune(1950-70), if you want to find out what is happening.

An American Scientist, Dr Holly Lutz, is now (2016) working on bats and their roles in disease maintenance, in the Zika forest of Uganda. This is where the headline-grabbing Zika virus was first discovered by the Uganda Virus Research Institute. She is trying to identify the natural reservoir of the Zika virus. “We want to continue sampling; we still have a lot of basic biodiversity exploration to do in Africa and other areas of the world,” she says. I wish someone in India says so.

P.K. Rajagopalan is a former Director of the Vector Control Research Centre in Puducherry, an institute of the Indian Council of Medical Research.

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