21 Mar 2022
Issue 97: Japanese Encephalitis part 1: arboviruses, togaviruses, flaviviruses and bunyaviruses
Written by Nobel Laureate Professor Peter Doherty
With cultural sensitivities in mind, we no longer give viruses names that refer to their place of discovery. Classified as a member of the arbovirus (arthropod-borne) family, Japanese encephalitis virus (JEV) has been circulating in the Pacific countries to our north for a very long time. All the arboviruses that we know to be causing human disease in Australia are mosquito-borne, though sandflies and ticks, particularly on colder landmasses, are also ‘vectors’. The tick-born encephalitis viruses include Russian spring/summer Encephalitis (RSSE) and louping-ill virus (LIV) which, a cause of disease and death in economically important sheep and grouse populations in Scotland, was the subject of my PhD from the University of Edinburgh.
The Moredun Research Institute – where I did this work in the late 1960s – made the first LIV vaccine back in the 1930s by taking brains from infected sheep, grinding them up, centrifuging a little to get rid of the ‘gunk’, then inactivating any infectivity with formalin. Substitute mice for sheep and you have, sold commercially from 1954, the first JEV vaccine. Back when I was working with LIV, JEV was known as ‘Jap B’ – which is even less culturally aware – and the arboviruses were classified as A, B, C and D. Since then, the ‘As’ have become the togaviruses, the ‘Bs’ are flaviviruses and C and D are now subsets of the bunyaviruses. Back at the Australian National University (ANU) in the 1970s, I worked for a time with the Semliki Forest virus (SFV) togavirus, which is extremely lethal for mice but a very mild infection in people.
The main arbovirus of concern in Australia back then was Murray Valley Encephalitis virus (MVE) which was causing sporadic cases of encephalitis (infection and inflammation of the brain) in wet summer seasons. When cases of MVE first became of concern around 1951, some thought it was poliomyelitis, but that was soon clarified when Eric French at the WEHI and John Miles, in South Australia, isolated the causative virus. Eric later moved to the CSIRO and, with veterinarians Ian Parsonson and Bill Snowden, founded the veterinary virology program that led to the construction of the ultrahigh security laboratory at Geelong, now called the Australian Centre for Disease Preparedness. Born and trained in England and serving as a pathologist in the army during World War 2, John Miles moved on to found the still outstanding microbiology program at the University of Otago in Dunedin.
The profile with MVE is that it is endemic in northern Australia, with regular incursions into northern Victoria in years of high rainfall. The likely maintaining and ‘transferring’ species are water birds, especially the Nankeen night heron, darters and pelicans. Monitoring for that has included the maintenance of flocks of sentinel chickens, which were bled regularly to test if, infected by a virus-carrying mosquito, they’ve developed serum antibodies specific for MVE. I wrote about this in Sentinel Chickens: what birds tell us about our health and our world (MUP 2012). Now, using more modern technology like PCR, the arbovirologists may just check local mosquito populations for the presence of viruses of interest.
The other arbovirus that has been of major clinical concern in Australia is Ross River Virus (RRV), a togavirus that causes epidemic polyarthritis with rash, a debilitating but generally non-fatal disease that can take a long time to resolve clinically. Also an ‘Australian native’, Barmah Forest virus (BFV) causes similar symptoms, as does Chikungunya virus (Chik) that’s not onshore, but circulates in the Indo/Pacific region. Back in the 1950s, the US Rockefeller Foundation was funding groups across the planet to discover new mosquito borne viruses. Some based in colder climates had teams going out into tropical countries. An example is YARU, the Yale Arbovirus Research Unit headed by Jordi Casals, the brother of renowned cellist Pablo Casals, then by Bob Shope, the son of virologist Richard Shope, the first to isolate an influenza virus (from pigs in 1931) and two cancer-causing viruses of rabbits, Shope fibroma virus and Shope papilloma virus. One sub-tropical/tropical arbovirus group was led by my eldest cousin, medical doctor Ralph Doherty, who was then Director of Brisbane’s Queensland Institute of Medical Research. The QIMR/Berghofer, as it’s now called, is in a magnificent building on the Royal Brisbane Hospital site. Back then, it was in old army huts on the nearby golf course.
The isolation of RRV was fortuitous, and happened because a retiring entomologist had to find some use for his mosquito collection before it was thrown out. The Ralph Doherty lab ground the mossies up in fluid and, after settling that by centrifugation, injected the supernate into the brains of two day old suckling mice, the standard protocol for detecting arboviruses back then. When the mice became ill, they isolated a new virus, then ran it against stored sera from clinical cases of PUO (pyrexia of unknown origin) from north Queensland. All those with antibodies were from cases of polyarthritis with rash. Such is the process of discovery! To be continued…