Kunjin Virus

Introduction

Australia hosts at least 75 species of arboviruses, several of which are associated with mild to life-threatening human disease. Among these are encephalitic flaviviruses, such as the Kunjin strain of WNV (KUNV), Japanese encephalitis virus (JEV), and Murray Valley encephalitis virus (MVEV). Australia is also home to Ross River and Barmah Forest alphaviruses, which cause severe, and sometimes chronic, polyarthritis. The numbers of locally acquired dengue virus (DENV) infections have been increasing as well, resulting in fever, intense bone pain, and hemorrhagic manifestations. Alfuy virus, a close relative of MVEV, has been isolated from mosquitoes in northern Australia and may also cause mild disease in humans. Kokobera and Stratford viruses are other flaviviruses that infect humans in Australia and are discussed in Chapter 8 . Other flaviviruses that have recently emerged in Oceania and Southeast Asia include Edge Hill and New Mapoon viruses in Australia, Sitiawan virus in Malaysia, and ThCAr virus in Thailand. Though infection with these viruses may currently be asymptomatic in humans or cause mild disease, there is always the threat that they may undergo minor mutations that lead to large changes in virulence, as it was the case in the 2011 KUNV outbreak in horses (discussed in the following section). These viruses may also expand their geographical range by genetic adaptation to climatic conditions, human modification of the environment, or carriage by migratory birds. The latter is believed to have been the case for KUNV spread to new regions of Australia east of the Great Dividing Range.

Although WNV and KUNV were originally categorized as separate but related viruses, on the basis of genetic and antigenic studies, KUNV is now considered to be an Australian cluster of lineage 1 WNV. Members of the KUNV cluster share 94% identity in the E protein gene and 90% in NS5/3′UTR nucleosides. Since WNV is the subject of a separate chapter in this book, this chapter will focus primarily on KUNV, and how it differs from other lineage 1 WNVs. KUNV is present primarily in the northwestern portions of Australia and, rarely, in the temperate regions of central and southern Australia during periods of heavy rainfall.

Instances of KUNV-associated disease typically appear as isolated, sporadic cases or as occasional small outbreaks in humans. However, KUNV is present in a large proportion of people in some regions of the continent. In a study of indigenous populations in rural endemic regions in the top end of the Northern Territory in 1988 and 1989, KUNV seroprevalance increased with age and was 30% overall in adults ( n = 834). Serological data suggest that KUNV may also be present from New Guinea to parts of the eastern Indonesian archipelago, Borneo, and Cambodia. It is not known whether this seropositivity is associated with KUNV infection or merely reflects exposure to a similar antigen on another flavivirus. A virus that is genetically very closely related to KUNV has been isolated in Iran and another close relative is found in Malaysia, although the latter has been placed into a separate WNV lineage.

History

Infection with WNV primarily led to occasional cases of mild febrile illness at the time of its discovery in 1937 in the West Nile district of Uganda. For several decades, infections were generally mild and infrequent. In 1957, however, an outbreak produced severe neurological symptoms in residents of Israeli nursing homes. Such serious disease manifestations remained uncommon until the mid-1990s, when large outbreaks of severe disease became increasingly common and widespread in Africa, Europe, and the Middle East. Cases of mild to severe infection were first seen in the Americas in New York City in 1999 and spread across the continent to the Pacific Coast during the next several years. WNV is now endemic throughout much of North, South, and Central America.

In 1960, KUNV was detected in Culex annulirostris mosquitoes from northern Queensland, Australia. It became enzootic across the northern parts of the Northern Territory and the Kimberly region of Western Australia and has since extended its range southward. While a 2019 report by the Australian National Arbovirus and Malaria Advisory Committee found no reports of KUNV infection in Australia in 2014–15, the epidemiology of KUNV has recently changed. The virus has now spread into new areas of Australia in a manner that is not linked to floods. Using high-throughput sequencing together with bioinformatics to study archival KUNV genomic material, Huang et al. traced the evolution of KUNV over 50 years and found the presence of only a single long-term lineage in affected regions of the continent. At most six fixed substitutions are present in individual proteins. Most of the changes are in variable regions, indicative of stochastic drift. The substitutions in functional domains are conservative and lead to minor changes at most.

In 2011, a major change in KUNV virulence occurred as a strain with far greater pathogenicity sickened almost 1000 horses. A study of KUNV isolates from a variety of locations in Australia from 1960 to 2012 found additional isolates in 1984, 2000, and 2012 that were of similar virulence in mice as the highly pathogenic 2011 outbreak strain, despite the fact that no disease in animals was reported in 2000 or 2012. Potentially virulent strains of KUNV have, therefore, been present in Australia for at least 30 years and neuroinvasive strains may be circulating in the absence of associated disease outbreaks, thus having the potential to severely infect horses or cause zoonotic infection in humans without warning.

The Disease

The Virus