Possible importance of carcasses for ebolavirus persistence in the ecosystem

Possible importance of carcasses for ebolavirus persistence in the ecosystem

Journal Pre-proofs Possible Importance of Carcasses for Ebolavirus Persistence in the Ecosystem Takahiro Namiki, Satoshi Hayakawa PII: DOI: Reference:...

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Journal Pre-proofs Possible Importance of Carcasses for Ebolavirus Persistence in the Ecosystem Takahiro Namiki, Satoshi Hayakawa PII: DOI: Reference:

S0306-9877(19)31340-4 https://doi.org/10.1016/j.mehy.2020.109595 YMEHY 109595

To appear in:

Medical Hypotheses

Received Date: Revised Date: Accepted Date:

11 December 2019 12 January 2020 22 January 2020

Please cite this article as: T. Namiki, S. Hayakawa, Possible Importance of Carcasses for Ebolavirus Persistence in the Ecosystem, Medical Hypotheses (2020), doi: https://doi.org/10.1016/j.mehy.2020.109595

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© 2020 Published by Elsevier Ltd.

Title Possible Importance of Carcasses for Ebolavirus Persistence in the Ecosystem

Authors Takahiro Namiki Nihon University School of Medicine Satoshi Hayakawa Nihon University School of Medicine, Division of Microbiology, Department of Pathology and Microbiology

ABSTRACT Some outbreaks caused by ebolaviruses have been associated with wildlife mortalities in the past. Here, we discuss the possible roles played by animal carcasses during an ebolavirus outbreak. Corpses of wild animals that died due to ebolavirus

infection or

other reasons

might be

eaten by

vertebrates and

invertebrates, spreading live ebolaviruses to other animals, including humans. To prevent and contain an ebolavirus outbreak, not only potential reservoirs but also all organisms with a high likelihood of virus exposure need to be investigated.

INTRODUCTION Ebola virus disease (EVD), formerly known as Ebola hemorrhagic fever, is a rare but often fatal infection in humans. Recently, the EVD pandemic in African countries has become an important health concern, with the possibility of the spread of infection to countries in Europe and the Americas. EVD is caused by ebolaviruses, which belong to the family Filoviridae, order Mononegavirales [1]. The known ebolaviruses are the Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV),

Bundibugyo ebolavirus (BDBV), Tai Forest ebolavirus (TAFV), and Reston ebolavirus

(RESTV); the Bombali virus (BOMV) is also likely an ebolavirus [2][3]. Ebolaviruses and other filoviruses were once considered to be the causes of endemic viral diseases in isolated areas of rain forests in Africa and the Philippines. However, a recent EBOV outbreak in West Africa from 2013 to 2016 made it clear that there is an inherent risk of widespread viral transmission in urbanized regions. After the West African outbreak, three other outbreaks occurred in the Democratic Republic of Congo (DRC), and the second largest outbreak is still ongoing along the eastern border of the DRC [4]. Moreover, many serological studies have shown that filoviruses may be more widely distributed in Africa and Asia than previously thought, and the recent discoveries of Lloviu cuevavirus (LLOV) in Europe and Měnglà virus (MLAV) in China showed that filoviruses are not confined to equatorial areas [5][6][7]. Bats are thought to be important hosts for filoviruses. Marburgviruses, LLOV and MLAV have been isolated as live viruses from bats. In contrast, definitive proof that bats are reservoirs for ebolaviruses is still lacking [8]. In addition, field studies to find viruses in organisms have focused mostly on identifying reservoirs, and the roles played by other organisms in the spread and maintenance of the virus have never been fully investigated.

HYPOTHESIS Animal carcasses play important roles in the maintenance and/or spread of ebolaviruses in the ecosystem through contacts with multiple organisms.

THE IMPORTANCE OF ANIMAL CARCASSES FOR EBOLAVIRUS SPREAD AND CIRCULATION In previous ebolavirus outbreaks, there were sometimes wildlife die-offs before the appearance of the first human cases, the index cases. In some outbreaks, the index cases apparently contracted the viruses by consuming animals found dead in the forest [9]. The death of wild mammals during an ebolavirus outbreak may have an impact on the dissemination of the virus in the ecosystem due to the significant prevalence of viruses in carcasses. While anti-ebolavirus antibodies or ebolavirus RNA are usually found in less than 10% of bats [10][11][12], more than 30% of animal carcasses have been discovered to contain anti-EBOV antibodies in an outbreak area [13]. A study in Gabon showed that the prevalence of anti-EBOV antibodies among live dogs increased linearly as the distance from an epidemic area decreased, and more than 30% of dogs had detectable levels of anti-EBOV antibodies in some villages. Dogs in these areas are not fed by people but apparently survive by scavenging and are likely to be exposed to EBOV through the

consumption of infected animal flesh [14].

Mammals at risk of exposure An animal carcass can be consumed by various vertebrates. For example, bush pigs are omnivorous and known to consume carrion [15]. Recent studies with the experimental infection of pigs with ebolavirus showed that pigs were able to spread viruses to other pigs and nonhuman primates [16]. Bush pigs inhabit areas that are close to where domestic pigs are kept [17], and they are often consumed by people as bush meat [18], making them important targets for virus monitoring. Duikers are common in the rainforest of Africa and may consume carrion [19]. Among the fruit bats, Hypsignathus monstrosus is not strictly frugivorous, and it has been observed attacking chickens and scavenging on scrap meat [20]. Although the food habits of

H. monstrosus are not fully understood, it could acquire the ebolavirus by consuming animals that died due to the virus, which could partly explain the relatively high prevalence of antibodies against EBOV among H. monstrosus. Surprisingly, this fact has rarely been mentioned in the literature concerning ebolaviruses. Careful interpretation is needed with regard to past field study results, as the changes in the prevalence of anti-EBOV antibodies among bats during

an outbreak [12] could be either the cause or the result of the outbreak. While H.

monstrosus has repeatedly been suggested as a possible reservoir for the ebolavirus, the study results do not necessarily support this view. H. monstrosus travels very widely from the central African rainforest to the western African regions, as indicated by the phylogenetic pattern [21]. Recent genomic analyses of EBOV, however, showed that there may be more than three major variants of EBOV, and these variants could be geographically separated [22]. Given the apparent existence of geographically separate strains, reservoirs are unlikely to travel broadly across the continent. There are many other possible mammals that consume carcasses such as African palm civets or mouse deer [23][24]; however, the ecology and food habits of these animals are poorly understood.

Other vertebrates at risk of exposure Besides mammals, other vertebrates including birds or reptiles are at the risk of direct exposure to ebolavirus from carcasses. Birds of prey, corvids or storks are known to scavenge on carcasses [25]. Although, scavenging activities of birds in the African rainforest is still little understood, they may serve at least as temporal vectors of ebolaviruses when carcasses are abundant. Some birds such as

storks which often visit swamps or rivers may contaminate these environments by excretion and aquatic organisms face some risk of exposure to viruses. Reptiles may also consume carrion directly. There are some evidences that snakes also consume carcasses [26][27] but the frequency of carrion utilization among reptiles in the African rainforest is largely unstudied.

Invertebrates at risk of exposure There are vast numbers of invertebrates, especially insects, that consume carrion. Diptera and Hymenoptera are commonly found in carrion [28]. Dung beetles (Scarabaeidae) consume the dung of animals and are important in the dispersal of plant seeds, but they also may consume fruit or carrion [29]. Carrion beetles (Silphidae) preferentially consume carcasses [30]. These organisms may have contact with infected carcasses and have the potential to spread viruses in the environment through the food chain. Viruses may not necessarily replicate in invertebrates, but invertebrates still comprise an important aspect of an ebolavirus outbreak because they may contribute to the spillover to humans and the persistence or dissemination of viruses among the reservoir species (Figure 1). It should also be figure 1 noted that many animals consuming carrion are omnivorous and may contract viruses

by consuming contaminated fruit or plants as well. In the case of insects, they could contaminate fruit or leaves with excretions or saliva. Furthermore, they could be accidentally swallowed while feeding on fruits or intentionally consumed by animals. Among fruit bat species, Rousettus aegyptiacus is known to occasionally consume insects [31]. R. aegyptiacus has sometimes tested positive for anti-EBOV antibodies, and it is also thought to be an important host of marburgviruses [32]. Invertebrates could also connect ebolavirus to amphibians, reptiles or even aquatic organisms like fishes or crustaceans. However, the amphibians and reptiles in the African rainforest are little explored and the ecological importance of the carcasses in the land/water interfaces in general is also not well characterized [33][34]. Recently, RNA sequences of new filovirus species have been discovered in fishes but live viruses have not been recovered and direct comparison with ebolaviruses is not yet possible [35]. Mayflies (Ephemeroptera) are considered as possible reservoirs of ebolaviruses [36] and insectivorous fishes and their carcasses could therefore be potential sources of infection. Although, some viruses cause outbreaks in amphibians, reptiles or fishes [37], there is still no report of mortalities of aquatic organisms during an ebolavirus outbreak even though past outbreak areas were often close to rivers or swamps.

Indirect effects Even when the cause of the death of the animal is not the ebolavirus infection, animals gathering on a carcass may have an increased risk of infection due to secondary contamination of the carcass with saliva or excretions from infected bats or other infected organisms. There could also be more indirect effects of carrion. The bodily fluid from the carrion may seep into the ground or a nearby swamp, contaminating the water. Water fleas (Daphnia) can accumulate avian influenza viruses in the body and may inactivate viruses to speed the clearance from the water [38]. It is not clear if similar accumulation and inactivation of ebolaviruses in crustaceans occur. EBOV in the blood can be infectious for up to 7 days after the death of an infected nonhuman primate [39]. In the tropics of Central Africa, animal carrion undergoes the fresh stage (0-2 days postmortem), bloated stage (3-4 days postmortem), putrid stage (5-9 days postmortem), dried stage (10-73 days postmortem), and skeletonized stage (74-77 days postmortem)[28]. Organisms that contact a carrion before the dried stage, therefore, have the highest possibility of EBOV transmission and should be the main target when

searching for the virus.

Genetic diversity during the Gabonese outbreaks in the 2000s The genomic diversity of the EBOV in the Gabonese outbreaks in the 2000s has figure 2 not been fully explained; during those outbreaks, distinct strains of EBOV were discovered even during the same year, appearing as a single outbreak. Although only minor genetic mutations were observed, there were apparently multiple introductions

of the

EBOV into

humans. The

Gabonese outbreaks

were also

characterized by large-scale wildlife die-offs involving thousands of gorillas [40][41]. It can be speculated that a rapid increase in the number of carcasses might have caused a sudden concentrating of the reservoirs due to reproduction or migration from neighboring areas to a relatively confined region (Figure 2). Chimpanzee mortality was also observed during the outbreak caused by TAFV, but the probable number of the affected animals was fewer than twenty, which was far smaller than the number of affected animals in the Gabonese outbreaks, and only one nonfatal infection occurred in a human [42]. The number of obtained genome sequence samples was too small to explore the possibility of multiple introductions of TAFV. Regarding the two largest outbreaks, the West African outbreak from 2013

to 2016 and the ongoing outbreak along the eastern border of the DRC, there has been no report of large-scale animal die-offs. The presence or the absence of a wildlife die-off may not have much impact on the magnitude of an outbreak in humans, as person-to-person transmission is the chief driver of viral spread among humans. However, unwitnessed or unreported deaths of wildlife need to be identified as they may point to the source of the spreading virus. Focused monitoring in highrisk areas is vital for the prevention of another human outbreak. A limitation of our hypothesis is the lack of knowledge of the duration of ebolavirus infectivity in natural environments. Ebolavirus, which is an enveloped RNA virus, is thought to be less stable than unenveloped viruses. In addition, the presence of the viral genome does not necessarily indicate infectivity. However, the WHO recommends that health care maintain high levels of protection because there have been many reports of people being infected while treating patients with suspected or confirmed EVD. This tragedy occurs as a result of close contact with patients while failing to strictly adhere to infection control precautions, such as donning proper personal protective equipment and avoiding touching a corpse during a burial [43][44]. Therefore, it is necessary to examine the maintenance of infectivity in a corpse and the animals that have fed on it.

CONCLUSION The reservoirs of Ebola virus have been investigated for more than four decades, and bats have emerged as the most plausible candidates. However, there have been some conflicting results in previous studies. Field searches for ebolaviruses in organisms have focused on finding reservoirs and lacked a systematic approach to detect and control all organisms involved in an outbreak. Organisms that scavenge on carcasses are at a high risk of exposure to the virus, and they can potentially spread the virus to humans or to other organisms. Wildlife die-offs may not have a significant impact on the magnitude of an outbreak in humans, but they might be important for the persistence of the virus in the ecosystem. To fully understand the nature of ebolaviruses and to better control an outbreak in the future, both potential reservoirs and organisms with a high likelihood of exposure to the virus should be investigated.

CONFLICTS OF INTEREST We declare that we have no conflicts of interest.

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Figure legends Figure 1 A schematic representation of the potential spread of ebolavirus from a carcass to other organisms in the ecosystem Ebolavirus can be transmitted from carcasses among diverse organisms through the food chain (lines). The recognized routes of exposure of ebolavirus to humans are through other mammals or carcasses themselves (arrows).

Figure 2 Hypothetical mechanism of ebolavirus spread in outbreaks in Gabon Reservoirs (ellipses) harbor the Zaire ebolavirus (EBOV) with minor strain differences (A, B and C). An EBOV strain (A) infected the first animals, and the subsequent virus transmission (D) resulted in the spillover to humans. The large number of animal carcasses caused migration of reservoirs (black arrows) and another strain (B) is brought to the same region to cause viral transmissions to animals and to humans (E). In another scenario, the increase of carcasses caused a local expansion of reservoirs (double arrows) and resulted in the rise of likelihood of exposure to different EBOV strain (C) to cause another outbreak (F).

Figure 1

Figure 2