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mosquito-borne - Top 30 Publications

Bacterial diversity of cosmopolitan Culex pipiens and invasive Aedes japonicus from Germany.

Symbiotic bacteria have gained significant attention in recent years. For example, microbiota of some mosquito species seems to influence the development and transmission of pathogens. Furthermore, several attempts using bacteria as a paratransgenetic tool have been made in order to assist the control of mosquito-borne diseases. In this study, we examined the bacterial diversity of wild-caught adult Culex (Cx.) pipiens and laboratory-reared adult Aedes japonicus (Ae. japonicus) in Germany using a culture-independent method. Genomic DNA was extracted from each specimen and submitted to PCR amplification of eubacterial 16S rDNA. After the cloning reaction, 28 bacterial transformants per sample containing the 16S rDNA inserts were selected per each sample for sequencing. The analysed specimens of Cx. pipiens as well as of Ae. japonicus showed a diverse bacterial community including some common bacterial genera. Blast analysis allowed to identify 21 bacterial genera belonging to 2 phyla among the 23 specimens of Cx. pipiens. The 14 analysed Ae. japonicus revealed 11 bacterial genera belonging to 3 phyla. In both mosquito species, identified isolates were mainly Proteobacteria. Only 4 of the bacterial genera were found in both mosquito species, with the most prevalent genera Sphingomonas and Rahnella in Cx. pipiens and in Ae. japonicus respectively. Most of the bacterial genera found in our study have been identified in other mosquito species before. Due to the currently scarce data situation, ongoing examinations on the very abundant bacterial genera or species are strongly required to determine their relevance for the biology and adaptiveness of mosquitoes including pathogen-host relationship.

The paradigm of eave tubes: scaling up house improvement and optimizing insecticide delivery against disease-transmitting mosquitoes.

Control of mosquito-borne diseases is greatly compromised by spread of insecticide resistance, high implementation costs and sub-optimal compliance among users. Improved housing has potential to reduce malaria transmission nearly as much as long-lasting insecticide-treated nets (LLINs), while also preventing other arthropod-borne diseases and improving overall well-being. Yet, it is hardly promoted as mainstream intervention, partly because of high costs, minimal communal benefits to people in non-improved houses, and low scalability. By exploiting biological observations of mosquito behaviours around dwellings, scientists have developed a new approach that integrates effective vector control into housing developments. The technique involves blocking eave spaces in local houses, leaving a few cylindrical holes into which plastic tubes with insecticide-laden electrostatic nettings are inserted. Where houses already have blocked eaves, these cylindrical holes are drilled and the tubes inserted. The eave tube technology, as it is called, is an innovative new approach for implementing housing improvements, by creating a new scalable product that can be integrated in houses during or after construction. It takes away insecticides from proximity of users, and instead puts them where mosquitoes are most likely to enter houses, thereby reducing insecticidal exposure among household occupants, while maximizing exposure of mosquitoes. This way, lower quantities of insecticides are used, better house ventilation achieved, intervention costs reduced, and mass communal benefits achieved even were vectors are resistant to similar insecticides when delivered conventionally. There are however still some critical pieces missing, notably epidemiological, social and economic evidence that the above assertions are true and sustainable. Besides, there also some technical limitations to be considered, namely: (1) need for extensive house modifications before eave tubes are inserted, (2) ineligibility of poorest and highest-risk households living in housing structures not amenable to eave tubes, and (3) poor synergies when eave tubes are combined with LLINs or IRS in same households. Overall, this paradigm significantly improves delivery of insecticides against disease-transmitting mosquitoes, and provides opportunities for scaling-up the long-neglected concept of house improvement as a malaria intervention.

High Frequency of Mayaro Virus IgM among Febrile Patients, Central Brazil.

Mayaro virus (MAYV), an Aedes mosquito-borne alphavirus, is endemic to Brazil and other South America countries. We investigated dengue- and chikungunya-negative febrile patients visiting rural areas near Goiânia, Goiás, and found a high proportion (55%) of MAYV IgM. Our findings suggest the presence of highly endemic foci of MAYV in central Brazil.

Georgia's collaborative approach to expanding mosquito surveillance in response to Zika virus: a case study.

Zika virus (ZIKV) was declared an international public health emergency by the World Health Organization on February 1, 2016. Due to the known and estimated range of the ZIKV mosquito vectors, southern and central US states faced increased risk of ZIKV transmission. With the state of Georgia hosting the world's busiest international airport, a climate that supports the ZIKV vectors, and limited surveillance (13 counties) and response capacity, the Department of Public Health (DPH) was challenged to respond and prevent ZIKV transmission. This case study describes and evaluates the state's surveillance capacity before and after the declaration of ZIKV as a public health emergency.

Antiviral activity of nordihydroguaiaretic acid and its derivative tetra-O-methyl nordihydroguaiaretic acid against West Nile virus and Zika virus.

Flaviviruses are positive strand RNA viruses distributed all over the world that infect millions of people every year, and for which no specific antiviral agents have been approved. These viruses include the mosquito-borne West Nile virus (WNV) responsible for outbreaks of meningitis and encephalitis. Considering that nordihydroguaiaretic acid (NDGA) has been previously shown to inhibit the multiplication of the related dengue virus and hepatitis C virus, we have evaluated the effect of NDGA, and its methylated derivative tetra-O-methyl nordihydroguaiaretic (M4N), on the infection of WNV. Both compounds inhibited the infection of WNV likely by impairing viral replication. Since flavivirus multiplication is highly dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism probably by interfering with the sterol regulatory element binding proteins (SREBP) pathway. Remarkably, we observed that other structurally unrelated inhibitors of the SREBP pathway, such as PF-429242 and Fatostatin, also reduced WNV multiplication, supporting that the SREBP pathway could constitute a druggable target suitable for antiviral intervention against flavivirus infection. Moreover, treatment with NDGA, M4N, PF-429242, and Fatostatin also inhibited the multiplication of the mosquito-borne flavivirus Zika virus (ZIKV), which has been recently associated with birth defects (microcephaly) and neurological disorders. Our results point to SREBP inhibitors such as NDGA and M4N as potential candidates for further antiviral development against medically relevant flaviviruses.

Dissecting the human serum antibody response to secondary dengue virus infections.

Dengue viruses (DENVs) are mosquito-borne flaviviruses and the causative agents of dengue fever and dengue hemorrhagic fever. As there are four serotypes of DENV (DENV1-4), people can be infected multiple times, each time with a new serotype. Primary infections stimulate antibodies that mainly neutralize the serotype of infection (type-specific), whereas secondary infections stimulate responses that cross-neutralize 2 or more serotypes. Previous studies have demonstrated that neutralizing antibodies induced by primary infections recognize tertiary and quaternary structure epitopes on the viral envelope (E) protein that are unique to each serotype. The goal of the current study was to determine the properties of neutralizing antibodies induced after secondary infection with a different (heterotypic) DENV serotypes. We evaluated whether polyclonal neutralizing antibody responses after secondary infections consist of distinct populations of type-specific antibodies to each serotype encountered or a new population of broadly cross-neutralizing antibodies. We observed two types of responses: in some individuals exposed to secondary infections, DENV neutralization was dominated by cross-reactive antibodies, whereas in other individuals both type-specific and cross-reactive antibodies contributed to neutralization. To better understand the origins of type-specific and cross-reactive neutralizing antibodies, we analyzed sera from individuals with well-documented sequential infections with two DENV serotypes only. These individuals had both type-specific and cross-reactive neutralizing antibodies to the 2 serotypes responsible for infection and only cross-reactive neutralizing antibodies to other serotypes. Collectively, the results demonstrate that the quality of neutralizing (and presumably protective) antibodies are different in individuals depending on the number of previous exposures to different DENV serotypes. We propose a model in which low affinity, cross-reactive antibody secreting B-cell clones induced by primary exposure evolve during each secondary infection to secrete higher affinity and more broadly neutralizing antibodies.

The mosquito fauna of the western region of Spain with emphasis on ecological factors and the characterization of Culex pipiens forms.

This study updates the diversity, distribution, and seasonal trends of mosquitoes in a western region of Spain, assesses ecological determinants of Culex pipiens s.l., and determines form composition of Cx. pipiens s.s.

Mosquito distribution in a saltmarsh: determinants of eggs in a variable environment.

Two saltmarsh mosquitoes dominate the transmission of Ross River virus (RRV, Togoviridae: Alphavirus), one of Australia's most prominent mosquito-borne diseases. Ecologically, saltmarshes vary in their structure, including habitat types, hydrological regimes, and diversity of aquatic fauna, all of which drive mosquito oviposition behavior. Understanding the distribution of vector mosquitoes within saltmarshes can inform early warning systems, surveillance, and management of vector populations. The aim of this study was to identify the distribution of Ae. camptorhynchus, a known vector for RRV, across a saltmarsh and investigate the influence that other invertebrate assemblage might have on Ae. camptorhynchus egg dispersal. We demonstrate that vegetation is a strong indicator for Ae. camptorhynchus egg distribution, and this was not correlated with elevation or other invertebrates located at this saltmarsh. Also, habitats within this marsh are less frequently inundated, resulting in dryer conditions. We conclude that this information can be applied in vector surveillance and monitoring of temperate saltmarsh environments and also provides a baseline for future investigations into understanding mosquito vector habitat requirements.

Zoonotic intestinal parasites and vector-borne pathogens in Italian shelter and kennel dogs.

This study investigated the presence of zoonotic parasites and vector-borne pathogens in dogs housed in kennels and shelters from four sites of Italy. A total of 150 adoptable dogs was examined with different microscopic, serological and molecular methods. Overall 129 dogs (86%) were positive for one or more parasites and/or pathogens transmitted by ectoparasites. Forty-eight (32%) were positive for one infection, while 81 (54%) for more than one pathogen. The most common zoonotic helminths recorded were hookworms, roundworms and Capillaria aerophila, followed by mosquito-borne Dirofilaria spp. and Dipylidium caninum. One hundred and thirteen (77.9%), 6 (4.1%) and 2 (1.4%) dogs were positive for Rickettsia spp., Leishmania infantum and Anaplasma spp., respectively. The results show that dogs living in rescue facilities from the studied areas may be infected by many zoonotic internal parasites and vector-borne pathogens, and that control measures should be implemented.

First molecular detection of Dirofilaria immitis (Spirurida: Onchocercidae) infection in dogs from Northern Algeria.

Dirofilaria immitis and Dirofilaria repens are mosquito-borne filarioid nematodes that affect dogs and other domestic and wild carnivores, causing heartworm disease and subcutaneous dirofilariosis, respectively. In Algeria, the data about the epidemiology of these infections is largely unknown. The present study was designed to establish the occurrence of D. immitis and D. repens in dogs in Algeria using molecular tools. In 2014 and 2015, a total of 209 dogs over one year of age of different breed and sex, living in Northern Algeria, were examined and blood samples were collected from each dog. The presence of D. immitis and D. repens in these samples was detected by real-time PCR followed by standard PCR and sequencing. Overall, the blood of 209 dogs from two departments was collected and only 3 (1.4%) of the blood samples were found positive for D. immitis DNA. Sequencing of the corresponding amplicon displayed a 99.8% identity to D. immitis, confirming the presence of this mosquito-borne nematode in Algeria. Furthermore, all tested samples were negative for D. repens.

Bilateral optic neuritis with maculopathy: A rare manifestation of dengue fever.

Dengue fever is a common mosquito-borne disease, which is endemic in tropical and subtropical countries. Bilateral optic neuropathy is a relatively unusual dengue-related ocular complication. Here, we present a case of bilateral optic neuritis with maculopathy complicating dengue infection.

Detection of West Nile virus in human samples: follow-up studies during the 2015 seasonal period.

West Nile virus, a mosquito-borne viral zoonosis is responsible for human infections in Hungary. Laboratory diagnosis is based on serological tests, however the application of molecular methods has been appreciated.

Interaction of Flavivirus with their mosquito vectors and their impact on the human health in the Americas.

Some of the major arboviruses with public health importance, such as dengue, yellow fever, Zika and West Nile virus are mosquito-borne or mosquito-transmitted Flavivirus. Their principal vectors are from the family Culicidae, Aedes aegypti and Aedes albopictus being responsible of the urban cycles of dengue, Zika and yellow fever virus. These vectors are highly competent for transmission of many arboviruses. The genetic variability of the vectors, the environment and the viral diversity modulate the vector competence, in this context, it is important to determine which vector species is responsible of an outbreak in areas where many vectors coexist. As some vectors can transmit several flaviviruses and some flaviviruses can be transmitted by different species of vectors, through this review we expose importance of yellow fever, dengue and Zika virus in the world and the Americas, as well as the updated knowledge about these flaviviruses in their interaction with their mosquito vectors, guiding us on what is probably the beginning of a new stage in which the simultaneity of outbreaks will occur more frequently.

Zika's Long Haul: Tackling the Causes of Human Vulnerability to Mosquito-Borne Viruses.

Comparison of the tracheal systems of Anopheles sinensis and Aedes togoi larvae using synchrotron X-ray microscopic computed tomography (respiratory system of mosquito larvae using SR-╬╝CT).

Mosquito-borne diseases, such as malaria, dengue fever, and Zika virus, are serious global health issues. Vector control may be an important strategy in reducing the mortality caused by these diseases. The respiratory system of mosquito larvae in the water has to inhale atmospheric oxygen as aquatic organisms. In this study, the three-dimensional (3D) structures of the dorsal longitudinal trunks (DLTs) of the tracheal systems of Anopheles sinensis and Aedes togoi were compared using synchrotron X-ray microscopic computed tomography. DLT respiratory frequencies were also investigated. Interestingly, the larvae of the two mosquito species exhibit tracheal systems that are both morphologically and functionally distinct. A. sinensis hangs horizontally under the water surface, and has a smaller DLT volume than A. togoi. In contrast, A. togoi hangs upside down using a siphon by fixing its tip to the water surface. The frequency of peristaltic movement in A. togoi is higher than that of A. sinensis. These differences in the structures and breathing behaviors of the respiratory systems of mosquito larvae provide new insights into the tracheal systems of mosquito larvae, which should help develop novel effective control strategies targeting mosquito larvae.

RNA Interference Restricts Rift Valley Fever Virus in Multiple Insect Systems.

The emerging bunyavirus Rift Valley fever virus (RVFV) is transmitted to humans and livestock by a large number of mosquito species. RNA interference (RNAi) has been characterized as an important innate immune defense mechanism used by mosquitoes to limit replication of positive-sense RNA flaviviruses and togaviruses; however, little is known about its role against negative-strand RNA viruses such as RVFV. We show that virus-specific small RNAs are produced in infected mosquito cells, in Drosophila melanogaster cells, and, most importantly, also in RVFV vector mosquitoes. By addressing the production of small RNAs in adult Aedes sp. and Culex quinquefasciatus mosquitoes, we showed the presence of virus-derived Piwi-interacting RNAs (piRNAs) not only in Aedes sp. but also in C. quinquefasciatus mosquitoes, indicating that antiviral RNA interference in C. quinquefasciatus mosquitoes is similar to the described activities of RNAi in Aedes sp. mosquitoes. We also show that these have antiviral activity, since silencing of RNAi pathway effectors enhances viral replication. Moreover, our data suggest that RVFV does not encode a suppressor of RNAi. These findings point toward a significant role of RNAi in the control of RVFV in mosquitoes. IMPORTANCE Rift Valley fever virus (RVFV; Phlebovirus, Bunyaviridae) is an emerging zoonotic mosquito-borne pathogen of high relevance for human and animal health. Successful strategies of intervention in RVFV transmission by its mosquito vectors and the prevention of human and veterinary disease rely on a better understanding of the mechanisms that govern RVFV-vector interactions. Despite its medical importance, little is known about the factors that govern RVFV replication, dissemination, and transmission in the invertebrate host. Here we studied the role of the antiviral RNA interference immune pathways in the defense against RVFV in natural vector mosquitoes and mosquito cells and draw comparisons to the model insect Drosophila melanogaster. We found that RVFV infection induces both the exogenous small interfering RNA (siRNA) and piRNA pathways, which contribute to the control of viral replication in insects. Furthermore, we demonstrate the production of virus-derived piRNAs in Culex quinquefasciatus mosquitoes. Understanding these pathways and the targets within them offers the potential of the development of novel RVFV control measures in vector-based strategies.

Facilitating State-Wide Collaboration around Family Planning Care in the Context of Zika.

Family planning providers have an important role to play in the response to the public health challenge posed by Zika. In the United States, there are high rates of unintended pregnancy, especially in states most at risk for mosquito-borne transmission of the Zika virus. This paper describes efforts by eight of these states (Arizona, California, Florida, Georgia, Louisiana, Mississippi, South Carolina, and Texas) to build capacity for quality family planning care in the context of Zika.

Mosquito Biting Modulates Skin Response to Virus Infection.

Mosquito-borne infections are increasing in number and are spreading to new regions at an unprecedented rate. In particular, mosquito-transmitted viruses, such as those that cause Zika, dengue, West Nile encephalitis, and chikungunya, have become endemic or have caused dramatic epidemics in many parts of the world. Aedes and Culex mosquitoes are the main culprits, spreading infection when they bite. Importantly, mosquitoes do not act as simple conduits that passively transfer virus from one individual to another. Instead, host responses to mosquito-derived factors have an important influence on infection and disease, aiding replication and dissemination within the host. Here, we discuss the latest research developments regarding this fascinating interplay between mosquito, virus, and the mammalian host.

Observational evidence of a long-term increase in precipitation due to urbanization effects and its implications for sustainable urban living.

Although projected precipitation increases in East Asia due to future climate change have aroused concern, less attention has been paid by the scientific community and public to the potential long-term increase in precipitation due to rapid urbanization. A ten-year precipitation dataset was analysed for both a rapidly urbanized megacity and nearby suburban/rural stations in southern China. Rapid urbanization in the megacity was evident from satellite observations. A statistically significant, long-term, increasing trend of precipitation existed only at the megacity station (45.6mm per decade) and not at the other stations. The increase was attributed to thermal and dynamical modifications of the tropospheric boundary layer related to urbanization, which was confirmed by the results of our WRF-SLUCM simulations. The results also suggested that a long-term regional increase in precipitation, caused by greenhouse gas-induced climate change, for instance, was not evident within the study period. The urbanization-induced increase was found to be higher than the precipitation increase (18.3mm per decade) expected from future climate change. The direct climate impacts due to rapid urbanization is highlighted with strong implications for urban sustainable development and the planning of effective adaptation strategies for issues such as coastal defenses, mosquito-borne disease spread and heat stress mortality.

Distribution and phylogeny of Wolbachia strains in wild mosquito populations in Sri Lanka.

Wolbachia are a group of maternally inherited intracellular bacteria known to be widespread among arthropods. Infections with Wolbachia cause declines of host populations, and also induce host resistance to a wide range of pathogens. Over the past few decades, researchers were curious to use Wolbachia as a biological tool to control mosquito vectors. During the present study, assessment of the prevalence of Wolbachia infections among wild mosquito populations in Sri Lanka where mosquito-borne diseases are a major health concern, was carried out for the first time. DNA was extracted from the abdomens of mosquitoes, collected from seven provinces, and screened for the presence of Wolbachia by PCR using wsp and groE primers. Group-specific and strain-specific primers were used to classify Wolbachia into the supergroups A and B, and into the strains Mel, AlbA and Pip.

Isolation of a novel orthobunyavirus from bat flies (Eucampsipoda africana).

The Bunyaviridae family comprises viruses causing diseases of public and veterinary health importance, including viral haemorrhagic and arboviral fevers. We report the isolation, identification and genome characterization of a novel orthobunyavirus, named Wolkberg virus (WBV), from wingless bat fly ectoparasites (Eucampsipoda africana) of Egyptian fruit bats (Rousettus aegyptiacus) in South Africa. Complete genome sequence data of WBV suggests it is most closely related to two bat viruses (Mojuí dos Campos and Kaeng Khoi viruses) and an arbovirus (Nyando virus) previously shown to infect humans. WBV replicates to high titres in VeroE6 and C6-36 cells, characteristic of mosquito-borne arboviruses. These findings expand our knowledge of the diversity of orthobunyaviruses and their insect vector host range.

Prevention and Control of Worldwide Mosquito-Borne Illnesses: Nurses as Teachers

Humoral cross-reactivity between Zika and dengue viruses: implications for protection and pathology.

Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that has recently caused extensive outbreaks in Central and South America and the Caribbean. Given its association with Guillain-Barré syndrome in adults and neurological and ocular malformities in neonates, ZIKV has become a pathogen of significant public health concern worldwide. ZIKV shares a considerable degree of genetic identity and structural homology with other flaviviruses, including dengue virus (DENV). In particular, the surface glycoprotein envelope (E), which is involved in viral fusion and entry and is therefore a chief target for neutralizing antibody responses, contains regions that are highly conserved between the two viruses. This results in immunological cross-reactivity, which in the context of prior DENV exposure, may have significant implications for the generation of immune responses to ZIKV and affect disease outcomes. Here we address the issue of humoral cross-reactivity between DENV and ZIKV, reviewing the evidence for and discussing the potential impact of this cross-recognition on the functional quality of antibody responses against ZIKV. These considerations are both timely and relevant to future vaccine design efforts, in view of the existing overlap in the distribution of ZIKV and DENV and the likely spread of ZIKV to additional DENV-naive and experienced populations.

Mapping the ecoepidemiology of Zika virus infection in urban and rural areas of Pereira, Risaralda, Colombia, 2015-2016: Implications for public health and travel medicine.

Geographical information systems (GIS) have been demonstrated earlier to be of great use to inform public health action against vector-borne infectious diseases.

Zika virus-like particle (VLP) based vaccine.

The newly emerged mosquito-borne Zika virus poses a major public challenge due to its ability to cause significant birth defects and neurological disorders. The impact of sexual transmission is unclear but raises further concerns about virus dissemination. No specific treatment or vaccine is currently available, thus the development of a safe and effective vaccine is paramount. Here we describe a novel strategy to assemble Zika virus-like particles (VLPs) by co-expressing the structural (CprME) and non-structural (NS2B/NS3) proteins, and demonstrate their effectiveness as vaccines. VLPs are produced in a suspension culture of mammalian cells and self-assembled into particles closely resembling Zika viruses as shown by electron microscopy studies. We tested various VLP vaccines and compared them to analogous compositions of an inactivated Zika virus (In-ZIKV) used as a reference. VLP immunizations elicited high titers of antibodies, as did the In-ZIKV controls. However, in mice the VLP vaccine stimulated significantly higher virus neutralizing antibody titers than comparable formulations of the In-ZIKV vaccine. The serum neutralizing activity elicited by the VLP vaccine was enhanced using a higher VLP dose and with the addition of an adjuvant, reaching neutralizing titers greater than those detected in the serum of a patient who recovered from a Zika infection in Brazil in 2015. Discrepancies in neutralization levels between the VLP vaccine and the In-ZIKV suggest that chemical inactivation has deleterious effects on neutralizing epitopes within the E protein. This along with the inability of a VLP vaccine to cause infection makes it a preferable candidate for vaccine development.

Molecular phylogeny of Anopheles hyrcanus group (Diptera: Culicidae) based on mtDNA COI.

The Anopheles hyrcanus group, which includes at least 25 species, is widely distributed in the Oriental and Palearctic regions. Some group members have been incriminated as vectors of malaria and other mosquito-borne diseases. It is difficult to identify Hyrcanus Group members by morphological features. Thus, molecular phylogeny has been proposed as an important complementary method to traditional morphological taxonomy.

Immunogenicity & safety of a single dose of live-attenuated Japanese encephalitis vaccine SA 14-14-2 in adults.

Japanese encephalitis (JE) caused by mosquito-borne Flavivirus is one of the leading causes of viral encephalitis in Asia. Control strategies include vector control and human vaccination. Due to lack of immunization programmes in endemic regions, there are still high mortality and morbidity. A live-attenuated SA 14-14-2 JE vaccine (LAJEV) has been licensed and used in Asian countries, including India. We report the assessment of immunogenicity and safety of the vaccine in adults during the first mass adult vaccination campaign carried out in Assam, India.

Phenotypic characterisation of cell populations in the brains of horses experimentally infected with West Nile Virus.

West Nile Virus (WNV), a mosquito borne member of the Flaviviridae, is one of the most commonly diagnosed agents of viral encephalitis in horses and people worldwide.

Antibody preparations from human transchromosomic cows exhibit prophylactic and therapeutic efficacy versus Venezuelan equine encephalitis virus.

Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne RNA virus that causes low mortality but high morbidity in humans. In addition to natural outbreaks, there is potential for exposure to VEEV via aerosolized virus particles. There are currently no FDA-licensed vaccines or antiviral therapies for VEEV. Passive immunotherapy is an approved method used to treat individuals against several pathogens and toxins. Human polyclonal antibodies (pAbs) are ideal, but this is dependent upon serum from convalescent human donors, which is in limited supply. Non-human derived pAbs can have serious immune-reactivity complications, and when "humanized" these antibodies may exhibit reduced neutralization efficiency. To address these issues, transchromosomic (Tc) bovines have been created that can produce potent neutralizing human antibodies in response to hyperimmunization. In the current studies, we have immunized these bovines with different VEEV immunogens and evaluated the protective efficacy of purified preparations of the resultant human polyclonal antisera against low and high dose VEEV challenge. The studies demonstrate that prophylactic or therapeutic administration of the polyclonal antibody preparations (TcpAbs) can protect mice against lethal subcutaneous or aerosol challenge with VEEV. Furthermore, significant protection can be conferred against unrelated co-infecting viral pathogens by combining individual virus-specific TcpAb preparations.IMPORTANCE With the globalization and spread or potential aerosol release of emerging infectious diseases, it will be critical to develop platforms able to produce therapeutics in a short time-frame. Using a transchromosomic (Tc) bovine platform, it is theoretically possible to produce antigen-specific highly neutralizing therapeutic polyclonal human antibody (TcpAb) preparations in six months or less. In this study, we demonstrate that Tc bovine-derived Venezuelan equine encephalitis virus (VEEV)-specific TcpAb are highly effective against VEEV infection that mimics not only the natural route of infection, but also infection via an aerosol exposure. Additionally, we show that combinatorial TcpAb preparations can be used to treat co-infections with divergent pathogens, demonstrating that the Tc bovine platform could be beneficial in areas where multiple infectious diseases contemporaneously or in the case of multipathogen release.

Historical Perspectives on Flavivirus Research.

The flaviviruses are small single-stranded RNA viruses that are typically transmitted by mosquito or tick vectors. These "arboviruses" are found around the world and account for a significant number of cases of human disease. The flaviviruses cause diseases ranging from mild or sub-clinical infections to lethal hemorrhagic fever or encephalitis. In many cases, survivors of neurologic flavivirus infections suffer long-term debilitating sequelae. Much like the emergence of West Nile virus in the United States in 1999, the recent emergence of Zika virus in the Americas has significantly increased the awareness of mosquito-borne viruses. The diseases caused by several flaviviruses have been recognized for decades, if not centuries. However, there is still a lot that is unknown about the flaviviruses as the recent experience with Zika virus has taught us. The objective of this review is to provide a general overview and some historical perspective on several flaviviruses that cause significant human disease. In addition, available medical countermeasures and significant gaps in our understanding of flavivirus biology are also discussed.