Mosquito-Borne Viruses and Non-Human Vertebrates in Australia: A Review

Mosquito-borne viruses are well recognized as a global public health burden amongst humans, but the effects on non-human vertebrates is rarely reported. Australia, houses a number of endemic mosquito-borne viruses, such as Ross River virus, Barmah Forest virus, and Murray Valley encephalitis virus. In this review, we synthesize the current state of mosquito-borne viruses impacting non-human vertebrates in Australia, including diseases that could be introduced due to local mosquito distribution. Given the unique island biogeography of Australia and the endemism of vertebrate species (including macropods and monotremes), Australia is highly susceptible to foreign mosquito species becoming established, and mosquito-borne viruses becoming endemic alongside novel reservoirs. For each virus, we summarize the known geographic distribution, mosquito vectors, vertebrate hosts, clinical signs and treatments, and highlight the importance of including non-human vertebrates in the assessment of future disease outbreaks. The mosquito-borne viruses discussed can impact wildlife, livestock, and companion animals, causing significant changes to Australian ecology and economy. The complex nature of mosquito-borne disease, and challenges in assessing the impacts to non-human vertebrate species, makes this an important topic to periodically review.     

Geographic distribution of arbovirus antibodies in indigenous human populations in the Indo-Australian archipelago.

Sera from lifetime residents in 16 localities of the Indo-Australian archipelago and adjacent areas were tested for hemagglutination-inhibition antibody against four alpha-viruses (Sindbis, Getah, chikungunya, and Ross River) and for neutralizing antibody against six flaviviruses (dengue 2 and 3, Japanese encephalitis, Murray Valley encephalitis, Kunjin, and Edge Hill). Mosquito collections were carried out in some of the localities to study vector relationships to distribution of the arbovirus antibodies. Antibodies specific to Sindbis and Getah viruses were rare except in north Australia. Chikungunya virus-specific antibody was highly prevalent in localities of the Oriental zoogeographic region and Wallacea, rare in west New Guinea, and absent in north Australia. Age distribution of chikungunya antibody suggested that the antibody last occurred in most Indonesian localities about 30 years ago. Ross River virus-specific antibody was confined to localities of the Australian zoogeographic region. Antibodies reacting to dengue 2 and 3 viruses occurred in high frequency in the entire area of the archipelago. Antibodies specific to Murray Valley encephalitis and Kunjin viruses were also widespread although at a very low frequency. Japanese encephalitis virus-specific antibody was highly prevalent in areas west of Wallace's Line while it was absent in areas east of the line with the exception of Lombok. Antibody to Edge Hill virus was rare and confined to the Australian zoogeographic region. The distribution of arthropod vectors, vertebrate hosts, and of arboviruses are discussed in relation to zoogeographic divisions.     

The viruses of Australia and the risk to tourists

Australia is a climatically diverse country varying from a tropical climate in the north to arid central desert and grassland regions, and to temperate climates in the south. There are many viral infections found in Australia that are common to developed countries worldwide, but this article will focus on those that pose a special risk for travellers to Australia, especially the mosquito-borne viruses. The commonest are the members of the alphavirus genus, particularly Ross River virus and Barmah Forest virus, which cause predominantly arthralgia with or without fever or rash. Less frequent but more serious illness is seen with the encephalitic flaviviruses, Murray Valley encephalitis virus, and the Kunjin strain of West Nile virus. In addition dengue occurs intermittently on the northern part of Queensland, and in recent years Japanese encephalitis virus has been found in the Torres Strait Islands and the tip of far north Queensland. Also of interest, but with a much lower risk, are the bat-borne viruses, Hendra virus and Australian bat lyssavirus, that have caused a small number of human infections. However, it is important to remember that most tourists pass through other countries in the Asia/Pacific region on their way to and from Australia and may therefore have acquired infections prior to or after leaving Australia.     

Transmission potential of two chimeric Chikungunya vaccine candidates in the urban mosquito vectors, Aedes aegypti and Ae. albopictus

Chikungunya virus (CHIKV) is an emerging, mosquito-borne alphavirus that has caused major epidemics in Africa and Asia. We developed chimeric vaccine candidates using the non-structural protein genes of either Venezuelan equine encephalitis virus (VEEV) attenuated vaccine strain TC-83 or a naturally attenuated strain of eastern equine encephalitis virus (EEEV) and the structural genes of CHIKV. Because the transmission of genetically modified live vaccine strains is undesirable because of the potentially unpredictable evolution of these viruses as well as the potential for reversion, we evaluated the ability of these vaccines to infect the urban CHIKV vectors, Aedes aegypti and Ae. albopictus. Both vaccine candidates exhibited significantly lower infection and dissemination rates compared with the parent alphaviruses. Intrathoracic inoculations indicated that reduced infectivity was mediated by midgut infection barriers in both species. These results indicate a low potential for transmission of these vaccine strains in the event that a vaccinee became viremic.     

Dengue and other emerging flaviviruses

Flaviviruses are among the most important emerging viruses known to man. Most are arboviruses (arthropod-borne) being transmitted by mosquitoes or ticks. They derived from a common ancestor 10-20000 years ago and are evolving rapidly to fill new ecological niches. Many are spreading to new geographical areas and causing increased numbers of infections. Traditionally, three clinical syndromes are recognized: fever-arthralgia-rash, viral haemorrhagic fever, and neurological disease, though for some flaviviruses the disease pattern is changing. Dengue, the most important flavivirus, is transmitted between humans by Aedes mosquitoes. Recent work is elucidating the pathogenesis of its most severe form, dengue haemorrhagic fever. Yellow fever, which has epidemiological similarities to dengue, was under control in the mid-20th century, but is once again increasing. Japanese encephalitis virus is numerically the most important cause of epidemic encephalitis; its geographical area is expanding despite the availability of vaccines. Other mosquito-borne neurotropic flaviviruses with clinical and epidemiological similarities are found across the globe. These include St Louis encephalitis virus, Murray Valley encephalitis virus, and West Nile virus, which recently reached the Americas for the first time. In cooler northern climates ticks are more important vectors. Tick-borne encephalitis virus occurs across large parts of Eastern Europe and the Commonwealth of Independent states. The tick-borne haemorrhagic flaviviruses, Omsk haemorrhagic fever and Kyasanur Forrest disease are localized in small areas.     

Adaptive Evolution as a Driving Force of the Emergence and Re-Emergence of Mosquito-Borne Viral Diseases

Emerging and re-emerging mosquito-borne viral diseases impose a significant burden on global public health. The most common mosquito-borne viruses causing recent epidemics include flaviviruses in the family Flaviviridae, including Dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV) and West Nile virus (WNV) and Togaviridae viruses, such as chikungunya virus (CHIKV). Several factors may have contributed to the recent re-emergence and spread of mosquito-borne viral diseases. Among these important causes are the evolution of mosquito-borne viruses and the genetic mutations that make them more adaptive and virulent, leading to widespread epidemics. RNA viruses tend to acquire genetic diversity due to error-prone RNA-dependent RNA polymerases, thus promoting high mutation rates that support adaptation to environmental changes or host immunity. In this review, we discuss recent findings on the adaptive evolution of mosquito-borne viruses and their impact on viral infectivity, pathogenicity, vector fitness, transmissibility, epidemic potential and disease emergence.     

Innate Immune Antagonism of Mosquito-Borne Flaviviruses in Humans and Mosquitoes

Mosquito-borne viruses of the Flavivirus genus (Flaviviridae family) pose an ongoing threat to global public health. For example, dengue, Japanese encephalitis, West Nile, yellow fever, and Zika viruses are transmitted by infected mosquitoes and cause severe and fatal diseases in humans. The means by which mosquito-borne flaviviruses establish persistent infection in mosquitoes and cause disease in humans are complex and depend upon a myriad of virus-host interactions, such as those of the innate immune system, which are the main focus of our review. This review also covers the different strategies utilized by mosquito-borne flaviviruses to antagonize the innate immune response in humans and mosquitoes. Given the lack of antiviral therapeutics for mosquito-borne flaviviruses, improving our understanding of these virus-immune interactions could lead to new antiviral therapies and strategies for developing refractory vectors incapable of transmitting these viruses, and can also provide insights into determinants of viral tropism that influence virus emergence into new species.     

Distribution of mosquitoes and mosquito-borne arboviruses in Yunnan Province near the China-Myanmar-Laos border

Economic development and increased tourism in the southern region of Yunnan Province in China, adjacent to several countries in Southeast Asia, has increased the likelihood of import and export of vectors and vector-borne diseases. We report the results of surveillance of mosquitoes and mosquito-borne arboviruses along the border of China-Myanmar-Laos in 2005 and 2006, and information associating several arboviruses with infections and possibly disease in local human populations. Seventeen mosquito species representing four genera were obtained, and 14 strains of mosquito-borne viruses representing six viruses in five genera were isolated from Culex tritaeniorhynchus. In addition, IgM against Japanese encephalitis virus, Sindbis virus, Yunnan orbivirus and novel Banna virus was detected in acute-phase serum samples obtained from hospitalized patients with fever and encephalitis near the areas where the viruses were isolated. This investigation suggests that Japanese encephalitis virus, Sindbis virus, and lesser-known arboviruses circulate and may be infecting humans in the China-Myanmar-Laos border region.     

Vector competence of Culex pipiens quinquefasciatus for Murray Valley encephalitis, Kunjin, and Ross River viruses from Australia

Australian populations of Culex pipiens quinquefasciatus Say from Brisbane, Charleville, Cairns, Kowanyama (Queensland), Darwin (Northern Territory), Mildura (Victoria), and Port Hedland (Western Australia) proved to be either poorly susceptible or refractory to oral infection with low passage level Murray Valley encephalitis, Kunjin, and Ross River viruses. With respect to past or future epidemics of Murray Valley encephalitis or Kunjin (both known to cause clinical encephalitis in man), and of epidemic polyarthritis, this mosquito is viewed as an unlikely vector.     

Influence of hosts on the ecology of arboviral transmission: potential mechanisms influencing dengue, Murray Valley encephalitis, and Ross River virus in Australia

Ecological interactions are fundamental to the transmission of infectious disease. Arboviruses are particularly elegant examples, where rich arrays of mechanisms influence transmission between vectors and hosts. Research on host contributions to the ecology of arboviral diseases has been undertaken within multiple subdisciplines, but significant gaps in knowledge remain and multidisciplinary approaches are needed. Through our multidisciplinary review of the literature we have identified five broad areas where hosts may influence the ecology of arboviral transmission: host immunity; cross-protective immunity and antibody-dependent enhancement; host abundance; host diversity; and pathogen spillover and dispersal. Herein we discuss the known and theoretical roles of hosts within these topics and then apply this knowledge to three epidemiologically important mosquito-borne arboviruses that occur in Australia: dengue virus (DENV), Murray Valley encephalitis virus (MVEV), and Ross River virus (RRV). We argue that the underlying mechanisms by which hosts influence arboviral activity are numerous and attempts to delineate these mechanisms further are needed. Investigations that focus on hosts of vector-borne diseases are likely to be rewarding, particularly where the ecology of vectors is relatively well understood. From an applied perspective, enhanced knowledge of host influences upon vector-borne disease transmission is likely to enable better management of disease burden. Finally, we suggest a framework that may be useful to identify and determine host contributions to the ecology of arboviruses.     

Changes in range of mosquito-borne diseases affected by global climatic fluctuations

Climate models suggest the strong possibility of range increase of the diseases transmitted by parasitic arthropods, mostly mosquitoes. In predicting processes of malaria and Dengue diseases dispersion the estimation of risk is based mostly on reproduction rate of vector species. These models allow to calculate the critical threshold of host density which is necessary to maintain parasites and pathogens transmission. Such studies based on integrated mathematical modelling indicate widespread increase of risk due to expansion of the areas suitable for mosquito-borne diseases transmission. This predicted increase is the most pronounced at the borders of the endemic areas and at higher altitudes within malaria and Dengue areas. The simulated change in mosquito-borne diseases risk must be interpreted on the basis of local environmental conditions as well as the effects of socio-economic developments and control disease programs. Apart from mathematical models the sequencing of proteins and DNA of vectors and their pathogens as well as satellite technology (GIS) are taken into consideration. It is supposed that potential impact of global climate change on malaria and Dengue risk can be reduced by constant warning system based on biological monitoring of mosquito vector species and their pathogens. Efficient care system connected with full diagnosis, treatment and prophylaxis of transmission diseases are also required.     

Investigation of the southern limits of Murray Valley encephalitis activity in Western Australia during the 2000 wet season

Western Australia experienced its worst-ever outbreak of the mosquito-borne Murray Valley encephalitis (MVE) virus during the 2000 wet season. Highest-on-record rainfall throughout much of the state during the 2000 wet season gave rise to extensive mosquito breeding and increased MVE virus transmission, resulting in nine cases of encephalitis. Activity of MVE virus in Western Australia is monitored by detecting MVE virus-specific antibodies in serum from sentinel chickens, located at towns and communities throughout the north of the state. However, during 2000, all 28 flocks of chickens seroconverted to MVE virus, including a flock located >600 km further south than MVE virus activity had ever previously been recorded. Furthermore, the majority of the nine cases of encephalitis occurred outside the enzootic Kimberley region. We therefore undertook a major serosurvey of domestic chicken flocks both south and east of the previously defined regions of virus activity. The results suggest that MVE virus activity extended as far south as the Midwest and northern Goldfields during 2000. A new southern limit of activity of MVE virus is therefore proposed. The results have implications for managing outbreaks of MVE virus in Western Australia and have enabled us to locate additional sentinel flocks as part of the MVE surveillance program for future years.     

Incubation Periods of Mosquito-Borne Viral Infections: A Systematic Review

Mosquito-borne viruses are a major public health threat, but their incubation periods are typically uncited, non-specific, and not based on data. We systematically review the published literature on six mosquito-borne viruses selected for their public health importance: chikungunya, dengue, Japanese encephalitis, Rift Valley fever, West Nile, and yellow fever viruses. For each, we identify the literature''s consensus on the incubation period, evaluate the evidence for this consensus, and provide detailed estimates of the incubation period and distribution based on published experimental and observational data. We abstract original data as doubly interval-censored observations. Assuming a log-normal distribution, we estimate the median incubation period, dispersion, 25th and 75th percentiles by maximum likelihood. We include bootstrapped 95% confidence intervals for each estimate. For West Nile and yellow fever viruses, we also estimate the 5th and 95th percentiles of their incubation periods.     

Epizootic activity of Murray Valley encephalitis virus in an aboriginal community in the southeast Kimberley region of Western Australia: results of cross-sectional and longitudinal serologic studies

Murray Valley encephalitis (MVE) virus is a mosquito-borne flavivirus causing severe encephalitis with a resultant high morbidity and mortality. In the period 1989-1993, we undertook a cross-sectional and longitudinal study by annually screening members of a small remote Aboriginal community in northwestern Australia for MVE virus antibodies. Of the estimated 250-300 people in the community, 249 were tested, and 52.6% had positive serology to MVE. The proportion testing positive increased with increasing age group, and males were slightly more likely to be positive than females. During the study period, a high proportion of the population seroconverted to MVE; the clinical/subclinical ratio seems to be lower than previously reported. Although MVE is mostly asymptomatic, the devastating consequences of clinical illness indicate that advice should be provided regarding the avoidance of mosquito bites. Our longitudinal study showed that the risk of seroconversion was similar for each age group, not just the young.     

Mosquito-Borne Viruses and Suppressors of Invertebrate Antiviral RNA Silencing

The natural maintenance cycles of many mosquito-borne viruses require establishment of persistent non-lethal infections in the invertebrate host. While the mechanisms by which this occurs are not well understood, antiviral responses directed by small RNAs are important in modulating the pathogenesis of viral infections in disease vector mosquitoes. In yet another example of an evolutionary arms race between host and pathogen, some plant and insect viruses have evolved to encode suppressors of RNA silencing (VSRs). Whether or not mosquito-borne viral pathogens encode VSRs has been the subject of debate. While at first there would seem to be little evolutionary benefit to mosquito-borne viruses encoding proteins or sequences that strongly interfere with RNA silencing, we present here a model explaining how the expression of VSRs by these viruses in the vector might be compatible with the establishment of persistence. We also discuss the challenges associated with interrogating these viruses for the presence of suppressor proteins or sequences, as well as the candidates that have been identified in the genomes of mosquito-borne pathogens thus far.     

Chikungunya virus: a novel and potentially serious threat to New Zealand and the South Pacific islands

There has never been a locally transmitted outbreak of mosquito-borne disease in New Zealand, but the risk of an outbreak occurring is increasing with on-going interceptions of exotic mosquito vectors across its border, increasing traffic of goods and passengers, higher numbers of viremic travelers arriving, and local, regional, and global environmental change. The risk posed to New Zealand by chikungunya virus is potentially high because of the transmissibility of this virus in subtropical climates, compounded by a population that is predominantly immunologically naive to exotic arboviruses. However, risk reduction in New Zealand should not be considered in isolation but must be viewed within a wider South Pacific context. In this report, we discuss the potential threat posed by chikungunya to the region, focusing in particular on New Zealand, and re-emphasizing the need for a South Pacific-wide approach towards mosquito-borne disease prevention.     

Further observations on the mechanism of vertical transmission of flaviviruses by Aedes mosquitoes

As previously observed for dengue viruses, vertical (i.e., transgenerational) transmission of Japanese and St. Louis encephalitis viruses by Aedes albopictus takes place when the fully formed egg, enclosed in the chorion, is oviposited. The demonstration of such a mechanism for three flaviviruses suggests that vertical transmission of all mosquito-borne flaviviruses may occur in the same manner.     

Australian encephalitis in the Northern Territory: clinical and epidemiological features, 1987–1996

Background: The last epidemic of Australian encephalitis occurred in 1974. Since then, cases have been reported from the Kimberley of Western Australia (WA).
Aims: To describe the epidemiology and clinical features of Australian encephalitis in the Northern Territory (NT) of Australia.
Methods: Review of cases of Australian encephalitis presenting to Royal Darwin Hospital from 1987–1996 and review of sentinel chicken surveillance for Australian encephalitis viruses.
Results: Sixteen patients were identified; ten from the NT and six from WA. Cases occurred in the years 1987, 1988, 1991 and 1993. Infection was acquired throughout northern NT below latitude 20°S in the months March to July. All infections were due to Murray Valley encephalitis (MVE) virus. Eleven of the patients were children. Distinguishing features were spinal cord and brainstem involvement and the absence of seizures in adults. CT scanning was normal and EEG showed no focal activity. Five died (31%) and four (25%) have residual neurological disability. Sentinel chicken surveillance since 1992 shows yearly seroconversion to MVE virus throughout northern NT; human cases occurred simultaneously with chicken seroconversion in 1993.
Conclusions: Australian encephalitis is endemic in the NT; the areas at risk are norm of Tennant Creek. Outbreaks are seasonal and occur every few years. Young children are most at risk. Mortality and morbidity are high. Prevention of disease is by avoidance of mosquito exposure and vector control measures.     

Isolation of Japanese encephalitis virus from mosquitoes (Diptera: Culicidae) collected in the Western Province of Papua New Guinea, 1997-1998

After Japanese encephalitis (JE) virus emerged in the Torres Strait in Australia in 1995, investigations were initiated into the origin of the incursion. New Guinea was considered the most likely source, given its proximity to islands of the Torres Strait. Almost 400,000 adult mosquitoes were processed for virus isolation from 26 locations in the Western Province of Papua New Guinea (PNG) between February 1996 and February 1998, yielding three isolates of JE virus. Two isolates of Murray Valley encephalitis, 17 isolates of Sindbis, and 1 each of Sepik and Ross River viruses were also obtained. Nucleic acid sequences of the PNG JE isolates were determined in the prM region, and in a region overlapping a part of the fifth nonstructural protein and the 3' untranslated region. The PNG isolates belonged to genotype II, and shared > 99.2% identity with isolates from humans and mosquitoes from the Torres Strait, suggesting that PNG is the source of incursions of JE virus into Australia.     

Bunyavirus infections in North Carolina white-tailed deer (Odocoileus virginianus)

We analyzed serum from white-tailed deer (Odocoileus virginianus) collected in southeastern North Carolina in 1991 for neutralizing antibodies to six mosquito-borne bunyaviruses (Lacrosse, Jamestown Canyon, Keystone,Cache Valley, Potosi, and Tensaw), including several of public health importance. Evidence was found for all six to be locally transmitted, although greatest seroprevalence was found for Potosi, Jamestown Canyon, and Cache Valley viruses.