Emerging infectious encephalitides.

PURPOSE OF REVIEW: The COVID-19 pandemic has cast increased attention on emerging infections. Clinicians and public health experts should be aware of emerging infectious causes of encephalitis, mechanisms by which they are transmitted, and clinical manifestations of disease. RECENT FINDINGS: A number of arthropod-borne viral infections -- transmitted chiefly by mosquitoes and ticks -- have emerged in recent years to cause outbreaks of encephalitis. Examples include Powassan virus in North America, Chikungunya virus in Central and South America, and tick-borne encephalitis virus in Europe. Many of these viruses exhibit complex life cycles and can infect multiple host animals in addition to humans. Factors thought to influence emergence of these diseases, including changes in climate and land use, are also believed to underlie the emergence of the rickettsial bacterium Orientia tsutsugamushi, now recognized as a major causative agent of acute encephalitis syndrome in South Asia. In addition, the COVID-19 pandemic has highlighted the role of bats as carriers of viruses. Recent studies have begun to uncover mechanisms by which the immune systems of bats are poised to allow for viral tolerance. Several bat-borne infections, including Nipah virus and Ebola virus, have resulted in recent outbreaks of encephalitis. SUMMARY: Infectious causes of encephalitis continue to emerge worldwide, in part because of climate change and human impacts on the environment. Expansion of surveillance measures will be critical in rapid diagnosis and limiting of outbreaks in the future.

Climate change and mosquito-borne disease: knowing the horse before hitching the cart.

Speculations on the potential impacts of climate change on human health often focus on the mosquito-borne diseases but ignore the complex interplay of the multitude of factors that are generally dominant in the dynamics of their transmission. A holistic view of this complexity - particularly the ecology and behaviour of the host and the ecology and behaviour of the vector - is the only valid starting point for assessing the significance of climate in the prevalence and incidence of these diseases.

Comparison of immune responses of brown-headed cowbird and related blackbirds to west Nile and other mosquito-borne encephalitis viruses.

The rapid geographic spread of West Nile virus (family Flaviviridae, genus Flavivirus, WNV) across the United States has stimulated interest in comparative host infection studies to delineate competent avian hosts critical for viral amplification. We compared the host competence of four taxonomically related blackbird species (Icteridae) after experimental infection with WNV and with two endemic, mosquito-borne encephalitis viruses, western equine encephalomyelitis virus (family Togaviridae, genus Alphavirus, WEEV), and St. Louis encephalitis virus (family Flaviviridae, genus Flavivirus, SLEV). We predicted differences in disease resistance among the blackbird species based on differences in life history, because they differ in geographic range and life history traits that include mating and breeding systems. Differences were observed among the response of these hosts to all three viruses. Red-winged Blackbirds were more susceptible to SLEV than Brewer's Blackbirds, whereas Brewer's Blackbirds were more susceptible to WEEV than Red-winged Blackbirds. In response to WNV infection, cowbirds showed the lowest mean viremias, cleared their infections faster, and showed lower antibody levels than concurrently infected species. Brown-headed Cowbirds also exhibited significantly lower viremia responses after infection with SLEV and WEEV as well as coinfection with WEEV and WNV than concurrently infected icterids. We concluded that cowbirds may be more resistant to infection to both native and introduced viruses because they experience heightened exposure to a variety of pathogens of parenting birds during the course of their parasitic life style.

The ecology and epidemiology of Ross River and Murray Valley encephalitis viruses in Western Australia: examples of One Health in Action.

Arboviruses are maintained and transmitted through an alternating biological cycle in arthropods and vertebrates, with largely incidental disease in humans and animals. As such, they provide excellent examples of One Health, as their health impact is inextricably linked to their vertebrate hosts, their arthropod vectors and the environment. Prevention and control requires a comprehensive understanding of these interactions, and how they may be effectively and safely modified. This review concentrates on human disease due to Ross River and Murray Valley encephalitis viruses, the two major arboviral pathogens in Australia. It describes how their pattern of infection and disease is influenced by natural climatic and weather patterns, and by anthropogenic activities. The latter includes human-mediated environmental manipulations, such as water impoundment infrastructures, human movements and migration, and community and social changes, such as urban spread into mosquito larval habitats. Effective interventions need to be directed at the environmental precursors of risk. This can best be achieved using One Health approaches to improve collaboration and coordination between different disciplines and cross-sectoral jurisdictions in order to develop more holistic mitigation and control procedures, and to address poorly understood ecological issues through multidisciplinary research.

A review of West Nile and Usutu virus co-circulation in Europe: how much do transmission cycles overlap?

Due to the increasing global spread of arboviruses, the geographic extent of virus co-circulation is expanding. This complicates the diagnosis of febrile conditions and can have direct effects on the epidemiology. As previously demonstrated, subsequent infections by two closely related viruses, such as those belonging to the Japanese encephalitis virus (JEV) serocomplex, can lead to partial or complete cross-immunity, altering the risk of infections or the outcome of disease. Two flaviviruses that may interact at population level are West Nile virus (WNV) and Usutu virus (USUV). These pathogens have antigenic cross-reactivity and affect human and animal populations throughout Europe. This systematic review investigates the overlap of WNV and USUV transmission cycles, not only geographically but also in terms of host and vector ranges. Co-circulation of WNV and USUV was reported in 10 countries and the viruses were found to infect 34 common bird species belonging to 11 orders. Moreover, four mosquito species are potential vectors for both viruses. Taken together, these data suggest that WNV and USUV transmission overlaps substantially in Europe and highlight the importance of further studies investigating the interactions between the two viruses within host and vector populations.

Clinical and laboratory findings on the first imported case of Murray Valley encephalitis in Europe.

Murray Valley encephalitis (MVE) is an important mosquitoborne flavivirus infection endemic to Australia and Papua New Guinea. We report the first imported case of MVE in Europe. A 23-year-old tourist developed severe encephalitis after having returned to Germany from a long-term trip across the Australian continent. The diagnosis was suspected on the basis of clinical findings and the patient's travel history and was confirmed by serological findings. The patient made a prolonged but complete recovery. Our case coincides with a recently reported spread of MVE virus in Australia. This emphasizes the need for continuous surveillance in areas of endemicity and appropriate protection when traveling through regions in which the MVE virus is endemic.

Mosquito-borne arboviruses in Australia: the current scene and implications of climate change for human health.

Of the mosquito-borne arboviruses, the encephalitic Murray Valley encephalitis and Kunjin viruses are a major public health concern, but the arthritides Ross River and Barmah Forest viruses are more important in a public health sense, being responsible for a far greater number of infections. Reported cases of Ross River totalled approximately 30,000 during 1991-1996; there have been several widely separated outbreaks of Barmah Forest in recent years and case reports are increasing annually. Surveillance programmes have increased our understanding of the geographic regions, climatic conditions and vector factors associated with viruses. Virus activity is widespread but is often localised, is driven primarily by mosquito abundance and various species are involved; host factors are involved also, but are not well understood. Typically, mosquito populations are governed by availability of habitat and environmental conditions. Models of climate change predict increases in rainfall, tides and temperature for parts of Australia, and such changes have the potential to increase the risk of arbovirus transmission by increasing the distribution and abundance of vectors, and duration of mosquito and arbovirus seasons. However, the amplitude of climate change is uncertain and the ecology of arbovirus transmission is complex. It is likely that some areas will have increases in arbovirus activity and human infection with predicted climate change, but risk of increased transmission will vary with locality, vector, host and human factors.

Emergence of eastern encephalitis in Massachusetts.

The 20th century emergence in Massachusetts of zoonotic eastern encephalitis was interpreted in terms of recorded environmental change. The main mosquito vector of the infection, Cs. melanura, appears to have been scarce in eastern North America before the 1930s. Its relative scarcity resulted from destruction of the swamps that had been lumbered or drained for farming in the 18th and 19th centuries. When swamps matured once again early in the 1900s, the formation of subsurface pools of water beneath mature trees would have increased the availability of breeding sites for this mosquito. Transmission would have further been enhanced by the simultaneous proliferation of wetland-roosting robins and the extinction of such vagile birds as the passenger pigeon. Although numerous horses were maintained in Massachusetts at the time, no outbreaks of "equine sleeping sickness" came to public notice between the 1830s and the 1930s, when mature trees were scarce and the fauna was most disturbed. The severity of the first major outbreak in 1938 may have been potentiated by the absence of herd-immunity in a rapidly proliferating population of reservoir birds. These considerations suggest that recent landscape and faunal changes caused zoonotic EE to emerge in Massachusetts after waning for a century.

Emergence and virulence of encephalitogenic arboviruses.

Each arbovirus that causes encephalitis is geographically restricted by the availability of appropriate vectors and reservoir hosts. These viruses evolve regionally by recombination, reassortment and point mutation and can "emerge" as causes of human encephalitis through extension to new geographic regions or by selection of more virulent or more efficiently transmitted virus variants. The properties of arboviruses that result in encephalitis involve efficient replication in peripheral tissues after initiation of infection, production of a viremia, entry into the central nervous system and efficient replication in neurons with spread to additional populations of neurons. Many of these steps are determined by properties of the envelope glycoproteins responsible for cellular attachment, but changes in noncoding regions of the genome, as well as in other structural and nonstructural proteins, also contribute to neurovirulence.

Experimental transmission of trivittatus virus (California virus group) by Aedes trivittatus.

The mosquito, Aedes trivittatus, when fed through a membrane a trivittatus virus dosage of 10(3.4) to 10(5.5) suckling mouse LD50/0.03 ml of blood, transmitted the virus to suckling mice. Virus multiplication indicative of a biological vector occurred in this species. When Aedes vexans and A. triseriatus ingested similar doses of trivittatus virus, both the infection and transmission rates were low and virus multiplication was poor. These results, added to evidence based on virus isolations from mosqito populations in nature, indicate that A. trivittatus is the primary vector of trivittatus virus in the north central United States.

Natural transmission of Keystone virus to sentinel rabbits on the Delmarva Peninsula.

Domestic rabbits were exposed in the Pocomoke Cypress Swamp from early May through October 1973, to act as sentinel indicators of Keystone (KEY) virus transmission on the Delaware-Maryland-Virginia (DelMarVa) Peninsula. Rabbits were bled weekly and their sera were tested for the presence of neutralizing antibody to both KEY and James-town Canyon (JC) viruses. Adult mosquito activity was monitored concurrently by CDC miniature light traps with Dry Ice. Of 100 rabbits exposed, 20 rabbits acquired neutralizing antibody to KEY virus as a result of their exposure; none acquired antibody to JC virus. Eighty-three percent of susceptible rabbits exposed converted immediately after the emergence of Aedes atlanticus adult mosquitoes in early September. Rabbit seroconversions were not limited to any particular habitat within the swamp. The conversion of a large proportion of sentinel rabbits immediately following emergence of A. atlanticus, and the previous demonstration of transovarial transmission of KEY virus by A. atlanticus, suggest that vertically infected individuals are capable of viral transmission at their initial engorgement. Such transmission provides the initial step in a vertebrate amplification cycle.

Stabilized infection of California encephalitis virus in Aedes dorsalis, and its implications for viral maintenance in nature.

Three populations of Aedes dorsalis were selected which transmitted California encephalitis (CE) virus vertically to over 90% of their progeny. Infected progeny in these subpopulations transmitted virus at similar rates through five generations; females from the last generation transmitted virus by bite to suckling mice. These high rates of vertical transmission appeared to be due to the development of a stabilized infection with CE virus rather than to genetic selection for a more efficient transmitter or for a mutant strain of virus. In developed nonstabilized infections and transmitted virus vertically to approximately 20% of their progeny. The existence of stabilized infections of CE virus in vector populations and its implications for the natural history of CE virus and on the Fine and LeDuc model are discussed.

Virus-vector-host relationships of Aedes stimulans and Jamestown Canyon virus in a northern Indiana enzootic focus.

Collections of hematophagous Diptera at the Kingsbury State Fish and Wildlife Area in northern Indiana between 1982 and 1984 yielded 118,972 mosquitoes from which 5 isolates of Jamestown Canyon virus and 3 isolates of trivittatus virus were obtained. All Jamestown Canyon isolates were from Aedes stimulans, including 1 from a pool of newly emerged males and 2 from pools of newly emerged females. These 3 isolates suggest that Jamestown Canyon virus is transovarially transmitted by Ae. stimulans. All isolates of trivittatus virus came from pools of Ae. trivittatus. No isolates were obtained from greater than 4,000 tabanids collected along with the mosquitoes those years. Transmission trials with field-collected newly emerged adult female Ae. stimulans demonstrated a mean midgut infection rate of 44%, a disseminated infection rate of 16%, and an oral transmission rate of 12% to suckling mice. Precipitin tests of field-collected bloodfed female mosquitoes indicated that white-tailed deer were the preferred host for numerous mosquito species including Ae. stimulans. The results of this study suggest that Ae. stimulans is a primary vector of Jamestown Canyon virus and that transovarial transmission is the probable overwintering mechanism for this California group virus.

La Crosse viremias in juvenile, subadult and adult chipmunks (Tamias striatus) following feeding by transovarially-infected Aedes triseriatus.

Viremia and antibody responses to La Crosse (LAC) virus were determined for juvenile, subadult and adult chipmunks (Tamias striatus). Viremia was detected in 16 of 16 juveniles, 13 of 17 subadults and 21 of 29 adults fed upon by transovarially (TO)-infected Aedes triseriatus. Mean viremia titers for juvenile, subadult and adult chipmunks responding to LAC infection were 3.0, 2.9 and 3.2 log10SMICLD50/0.025 ml, respectively. The average duration of viremia with LAC virus was 2.4, 2.3 and 2.4 days for juveniles, subadults and adults, respectively. Mean viremia titers and durations did not differ significantly among chipmunk age-classes. Neutralizing antibodies to LAC virus were detected in viremic chipmunks at day 5 and day 20 post-infection. Observations of TO-infected Ae. triseriatus and their sibling controls refeeding on restrained chipmunks indicated that a significant number of infected (34/54) and uninfected (37/59) females probed multiple times to obtain a second bloodmeal. Data indicate that chronological age or time between successive bloodmeals affects feeding behaviors. No relationship between probing or ability to refeed and infection was found.

Oral infection and transmission of La Crosse virus by an enzootic strain of Aedes triseriatus feeding on chipmunks with a range of viremia levels.

The susceptibility of Aedes triseriatus to oral infection with La Crosse (LAC) virus resulting from feeding on chipmunks with viremia titers of 0.6 to 4.6 log10SMICLD50/0.025 ml was determined. Results indicated that viremia titers must exceed 3.2 log10SMICLD50/0.025 ml before a significant proportion (greater than or equal to 50%) of mosquitoes are infected and capable of transmitting LAC virus. Mosquitoes which fed on chipmunk blood-LAC virus mixtures through a membrane feeder had significantly lower infection rates at virus titers of 1.8 to 4.4 log10SMICLD50/0.025 ml and transmission was also significantly reduced. Application of these data to LAC viremia titers measured in chipmunks in an earlier study indicate that viremias sufficiently high to ensure transmission by the mosquitoes becoming orally infected average only about 1 day per infective bite delivered to the susceptible portion of the amplifier population. Oral infection and transmission rates were also determined for Ae. triseriatus feeding on chipmunk blood containing LAC virus neutralizing (N) antibodies and for Ae. triseriatus feeding on deer blood containing Jamestown Canyon (JC) virus N antibodies. Infection rates were similar to those observed in mosquitoes imbibing blood free of N antibody at the virus titers tested, but, oral transmission was reduced in females feeding on chipmunk blood-LAC virus mixtures containing LAC N antibodies and there was no transmission by females feeding on deer blood-LAC virus mixtures containing JC N antibodies. These data suggest that high LAC antibody prevalences in chipmunk populations and high LAC or JC antibody prevalences in deer populations may be antagonistic to horizontal LAC virus transmission.

Experimental infection of birds with epidemic Venezuelan encephalitis virus.

Sixty-three birds representing 13 species were inoculated with a strain of epidemic Venezuelan encephalitis (VE) virus from the 1971 Texas outbreak. More than 95% of the birds became infected. Mortality which could be attributed to infection with VE virus was very low. Viremia persisted 2-6 days. Peak viremia levels ranged from 10(3.2) to 10(8.2) suckling mouse intracranial 50% lethal doses per milliliter (SMICLD50/ml). Blood virus levels were highest in juvenile Louisiana Herones, adult Robins and adult Mockingbirds and were lowest in juvenile Common Egrets. Most bird species had blood virus levels about 10(5) SMICLD50/ml (high vector infection potential) for 2-3 days. Neutralizing antibody response was more uniform and frequent in herons (95%) than in passerines (56%). The role of birds in the epidemiology of Venezuelan is discussed.

Towards a quantitative understanding of the epidemiology of Keystone virus in the eastern United States.

The implications of the Keystone virus--Aedes atlanticus transmission cycle are explored in the context of a quantitative model. Among the variables considered are the vertical transmission rate, the effect of the virus upon vector fertility and survival, vector densities and distributions, the proportion susceptible in the vertebrate population, the attractiveness of different vertebrates to the vector and vector survival rates. The logical relationships between these several variables are explored. It is concluded that the current view of Keystone virus maintenance is quantitatively feasible, and that certain predictions may be made as to the magnitude of several parameters which have not yet been measured. Such predictions allow direct testing of the model. The general structure of the model is such that it may prove useful in describing the epidemiology of other vector-borne infections in which vertical transmission is essential for infection maintenance at certain periods of the year.

Bloodmeal sources of Aedes triseriatus and Aedes vexans in a southern Wisconsin forest endemic for La Crosse encephalitis virus.

The micro enzyme-linked immunosorbent assay (ELISA) was used to specifically identify bloodmeal sources of Aedes triseriatus Say and Aedes vexans Meigen collected at a site endemic for La Crosse (LAC) encephalitis virus. Deer were the source of 65% of Ae. triseriatus and 94% of Aedes vexans bloodmeals, respectively. Chipmunks and tree squirrels, which are considered to be the major vertebrate amplifying hosts of LAC virus, were the sources of 8% and 16%, respectively, of the bloodmeals of Ae. triseriatus, the vector of LAC virus. The relatively small proportion of vector bloodmeals taken from the amplifying hosts raises further doubts as to the significance of vertebrate amplification in perpetutation of La Crosse virus in nature, i.e. whether vertebrate amplification alone is sufficient to make up for the shortfall of virus infection that occurs during vertical transmission.

Infection rates of Ascocystis-infected Aedes triseriatus following ingestion of La Crosse virus by the larvae.

The La Crosse (LAC) virus infection rate of Aedes triseriatus larvae that ingest LAC virus does not appear to be increased by concomitant infection of larvae by the gregarine parasite, Ascocystis barretti. Infection rates ranged only from 0--2.6% in adult Ae. triseriatus reared from groups of A. barretti-infected larvae that had ingested LAC virus (California encephalitis group) at dosages of 2.0--7.7 log10 SMICLD50/ml. Females resulting from orally infected larvae transmitted LAC virus to suckling mice. Larvae that were infected with A. barretti and devoured carcasses of adult mosquitoes containing 4.7 log10 SMICLD50/ml failed to become infected. A. barretti spores developing in transovarially infected mosquitoes did not harbor LAC virus; thus, A. barretti does not appear to be a mechanism for virus dispersal.

Two possible mechanisms for survival and initiation of Murray Valley encephalitis virus activity in the Kimberley region of Western Australia.

Two possible mechanisms are described for the initiation of Murray Valley encephalitis (MVE) virus activity in arid, epizootic regions of tropical Australia. Virus isolations were made from mosquitoes trapped shortly after the first heavy wet season rains and flooding in the east Kimberley, which followed approximately nine months of drought. A number of isolates of MVE virus were obtained, including isolates from pools of blood-engorged Culex annulirostris mosquitoes and from a single pool of male Aedes tremulus mosquitoes. The results strongly suggested that MVE virus activity was due both to its introduction in viremic vertebrate hosts, from which first-generation mosquitoes became infected following blood meals, and also to reactivation of vertically transmitted virus from desiccation-resistant eggs of Ae. tremulus. Both mechanisms are discussed with respect to environmental conditions.