Search goes on for future animal disease threats

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Hirofumi Sawa and his colleagues enter a cave in Zambia to collect bat feces. The inset shows a fruit bat (Eidolon helvum).
Hirofumi Sawa and his colleagues enter a cave in Zambia to collect bat feces. The inset shows a fruit bat (Eidolon helvum).

Many people are surprised at the myriad diseases and infections that can be passed from animals to humans, and this includes horse to human transmission.

These are zoonotics, and they can be deadly. Recent public attention has focused on emerging zoonoses, such as severe acute respiratory syndrome (SARS), influenza, bovine spongiform encephalopathy (BSE), equine besnoitiosis, and monkey pox. Fortunately, there is no evidence that horses can contract Covid-19, or that they would be able to spread the disease to other animals or humans; there is also no evidence that equine enteric coronavirus poses a threat to humans or other species of animals.

Another is Rhodococcus equi, a bacterium that can cause pneumonia in foals. The first human case of this was in 1967 in a stockyard worker, and a 2016 study reported that it was far more common among pigs than horses.

But as well as the new, deadly agents, there are also old diseases to consider. One of these, glanders (Burkholderia mallei), has a fatality rate of more than 50%, and there is great interest in it as a biological weapon. Another to re-emerge is rabies, with an increase in human cases in the 1990s attributed to bat exposure. Yet another is the horse-killing Shuni virus in Africa, which is thought to be transmitted by blood-feeding insects. Antibodies against the virus were identified in 3.9% of veterinarians involved in equine, wildlife and livestock services in South Africa.

Other diseases that can be transmitted from horses to humans include brucellosis, anthrax, salmonella, leptospirosis, and Lyme disease, as well as methicillin-resistant Staphylococcus aureus (MRSA), which can also be transmitted from humans to horses.

There’s also the bat-borne Hendra virus in Australia, which has killed both horses and people. Animals such as mosquitoes, flies, fleas, and ticks transmit vector-borne infections.

According to one researcher, mosquitoes are the most dangerous: They can carry Eastern equine encephalitis, Western equine encephalitis, Venezuelan equine encephalomyelitis (VEE), and West Nile virus from birds to horses and people.

Among those working at the coal face to help protect both humans and animals from zoonotics is Japanese researcher Hirofumi Sawa MD, PhD.

Professor Hirofumi Sawa
Hirofumi Sawa, MD, PhD, Professor and Deputy Director of the Research Center for Zoonosis Control (CZC).

Sawa started his career three decades ago working as a clinical cardiologist conducting basic research at Hokkaido University’s Graduate School of Medicine. Developing an interest in viruses, he started research on JC polyomavirus, which causes fatal demyelinating disease of the central nervous system, under Dr Kazuo Nagashima. He joined the newly established Research Center for Zoonosis Control (CZC) at Hokkaido University, as professor and deputy director in 2005.

The CZC conducts comprehensive research to prevent outbreaks of zoonotic and other infectious diseases. In collaboration with the World Health Organisation and other organizations, it has been actively engaged in identifying pathogens, host animals and transmission routes, as well as developing diagnostic methods and antiviral drugs.

Sawa leaves his lab three to four times a year to conduct research in the field in Zambia, catching mosquitos and collecting wildlife and arthropods in caves. Indeed, his work style fluctuates from being a researcher at state-of-the-art medical institutions at Hokkaido University and Washington University in St Louis to working in the wild where there is no electricity or other modern comforts.

“I have always navigated my career path to a direction that has interested me,” Sawa said. “I aspired to be a medical doctor because I wanted to cure patients. Now I am devising preemptive measures against zoonoses. Broadly speaking, this has the same goal. My strategy is just a bit different from many of my colleagues.”

Discovering new zoonosis viruses

Pathogens that pose a huge threat to public health, such as the human immunodeficiency virus (HIV), Ebola virus and Zika virus, are believed to have originated in Africa, where yellow fever and malaria are also endemic. This makes Africa a key continent for conducting research on infectious diseases.

Sawa's team investigating viruses carried by rodents.
Sawa’s team investigating viruses carried by rodents.

“If we want to control zoonoses, it is important to conduct research in developing countries where outbreaks of known and unknown infectious diseases are reported,” Sawa said. “It is difficult to eradicate infectious diseases, but we can prevent zoonoses from spreading across the globe if we implement evidence-based preventive measures.”

To that end, Sawa said, “In addition to unravelling the diversity of viruses carried by animals, we also need to search for new viruses, and determine their host range, pathogenicity and possible transmission routes. This task deserves proper attention considering that over 70 percent of emerging infectious diseases originated from wildlife.”

Sawa’s research team has been credited with detecting and isolating more than 20 new viruses carried by wild animals and arthropods.

Sawa’s colleague Dr Michihito Sasaki, a lecturer at Hokkaido University, detected a virus belonging to the paramyxoviridae family from feces of wild baboons in Zambia. Other members of this family include two well-known viruses — measles virus and mumps virus, which are mainly associated with human respiratory disorders. Detection of paramyxoviruses in wild baboons was made possible by employing a method called reverse transcriptase-polymerase chain reaction (RT-PCR) with the use of degenerate primers, which is simply a mixture of primers that are similar, but not identical. Using this method, his research team identified one of the viruses as human parainfluenza type 3 (HPIV3), which is most closely related to HPIV3 strain Riyadh 149/2009, isolated from a hospitalized child in Saudi Arabia in 2009.

“We believe that the virus is transmitted from baboons to humans and from humans to other animals,” Sawa said. “Baboons tend to come close to humans in search of food. Because of this close contact, the virus can be transmitted from baboons to humans and vice versa.”

6590 known virus species

According to Sawa, next-generation sequencing (NGS), which enables sequencing of DNA and RNA much more quickly and comprehensively than previous techniques, has revolutionized genomic and molecular biology. RT-PCR (used for analyzing RNA viruses) and PCR (used for analyzing DNA viruses) are instrumental when the targeted virus is known, but NGS becomes a powerful tool when researchers do not know exactly what kind of virus they are dealing with. NGS allows for a comprehensive and cost-effective sequencing of known and unknown pathogens, such as DNA and RNA viruses.

Thanks to these new technologies, the number of virus species acknowledged by the International Committee on Taxonomy of Viruses increased from 1898 in 2005 to 6590 as of May 2020.

Specifically, Sasaki employs shotgun metagenomics, an approach that involves shearing DNA or RNA extracted from samples and subsequent sequencing of the small fragments using NGS. The generated information is analyzed using bioinformatics tools. Now, the team has a convenient, portable sequencing device capable of detecting viruses in the field.

Using the latest technologies, the team detected Group A rotavirus in insect-eating bat species from Zambian caves. Rotaviruses have a double-stranded RNA genome consisting of 11 segments. Rotaviruses detected by Sasaki had six genome segments highly similar (96 percent to 99 percent) to the human rotaviruses, while the remaining five segments were similar to those of rotaviruses found in livestock and wild animals. “The result suggests that rotaviruses carried by bats have a similar genetic profile to those found in humans. This is also evidence of cross-species transmission and probable genetic reassortment being behind the high genetic diversity seen in rotaviruses,” Sawa said.

Furthermore, Sasaki detected several new viruses in insect-eating white-toothed shrews, which inhabit some rural residential areas in Zambia. A new picornavirus found in shrews was similar to human picornaviruses, which cause gastroenteritis. Additionally, his team detected a new cyclovirus that was markedly different from other known cycloviruses found in animal feces. This new cyclovirus was very similar to viruses detected in the cerebrospinal fluid of encephalomyelitis patients.

“These findings suggest that white-toothed shrews, which are found widely around the globe, carry viruses unique to them, and can, therefore, be a potential host to zoonotic viruses,” Sawa warned.

“Collecting samples from wildlife and isolating viruses from them are time-consuming tasks, but they are integral parts in the fight against zoonoses,” Sawa said. To shorten the process, Sawa and his collaborators are developing a system to effectively isolate viruses by making optimal cells needed for replication of viruses and then rotary-culturing cells and viruses together to boost viral replication.

Mosquitos the “most dangerous insect”

Dr Yasuko Orba, who works with Sawa, focuses on virus surveillance in mosquitos, which are widely considered to be the world’s most dangerous insect because they are a vector for many diseases. From 2012 to 2019, Orba collected more than 17,800 female mosquitos from different places in Zambia in search of known and unknown viruses.

A total of 17,826 female mosquitos were gathered between 2012 and 2019 in Zambia. Traps that produce odor attractant and a common mosquito Culex quinquefasciatus (inset) that was found to be a vector of West Nile virus.
A total of 17,826 female mosquitos were gathered between 2012 and 2019 in Zambia. The traps attracted the likes of the common mosquito Culex quinquefasciatus (inset) that was found to be a vector of West Nile virus.

This effort culminated in the first isolation of West Nile virus in Zambia. Orba also surveyed birds, horses and humans based on the West Nile virus transmission route: From mosquitos to birds; birds to mosquitos; and finally to horses and humans.

“Preemptive measures can be taken based on research on the diversity of viruses wild animals and arthropods carry, as well as studies on the natural hosts and pathogenicity of viruses,” Sawa said. For instance, Sawa is helping one of his colleagues, Dr Akihiko Sato from Shionogi & Co., Ltd., to develop an antiviral drug to treat arthropod-borne viruses (arboviruses) and coronaviruses.

“As a doctor conducting basic research on human cardiovascular diseases, I never imagined that I would visit Zambia to research infectious diseases,” Sawa said. “It’s not easy, but I’ve been able to keep up because I like Zambian people for their kindness and humility.”

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