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Research and Development

Host-Virus Interactions

Arboviruses are unique in that they require infection, replication and transmission from taxonomically diverse vertebrate and invertebrate hosts.  Characterizing the complexity of these diverse interactions is critical to our understanding of arbovirus emergence and maintenance and is therefore among the primary research goals of the Wadsworth Center Arbovirus Laboratory. 

West Nile virus is maintained primarily by Culex species mosquitoes and the focus of studies in this area is characterizing interactions in this system.  Studies in recent years have begun to reveal the complexity and specificity of mosquito-virus interactions.  Particular areas of interest include assessing temporal and spatial variability in vector competence, quantifying the effect of arbovirus infection on mosquito life history traits, identifying mechanisms of resistance, and characterizing interactions between arboviruses and the mosquito microbiome.

  • Ciota AT, Bialosuknia SM, Zink SD, Brecher M, Ehrbar DJ, Morrissette MN, Kramer LD. Effects of Zika Virus Strain and Aedes Mosquito Species on Vector Competence. Emerging Infectious Diseases. 2017;23(7):1110-1117.
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  • Ciota AT, Bialosuknia SM, Ehrbar DJ, Kramer LD. Vertical Transmission of Zika Virus by Aedes aegypti and Ae. albopictus Mosquitoes. Emerg Infect Dis. 2017;23(5):880-882.
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  • Kilpatrick AM, Peters RJ, Dupuis AP, Jones MJ, Daszak P, Marra PP, Kramer LD. Predicted and observed mortality from vector-borne disease in wildlife: West Nile virus and small songbirds. Biological Conservation. 2013;16579-85.
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  • Ciota AT, Chin PA, Kramer LD. The effect of hybridization of Culex pipiens complex mosquitoes on transmission of West Nile virus. Parasite Vectors. 2013;6(1):305.
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  • Ciota AT, Ehrbar DJ, Van Slyke GA, Payne AF, Willsey GG, Viscio RE, Kramer LD. Quantification of intrahost bottlenecks of West Nile virus in Culex pipiens mosquitoes using an artificial mutant swarm. Infection, Genetics & Evolution. 2012;12(3):557-564.
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  • Ciota AT, Styer LM, Meola MA and Kramer LD. The costs of infection and resistance as determinants of West Nile virus susceptibility in Culex mosquitoes. BMC Ecology. 2011;(11):23.
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  • Kilpatrick, AM, Fonseca, DM, Ebel, GD, Reddy, MR and Kramer, LD. Spatial and Temporal Variation in Vector Competence of Culex pipiens and Cx. restuans Mosquitoes for West Nile Virus. American Journal of Tropical Medicine & Hygiene. 2010;83(3):607-613.
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Arbovirus Evolution & Adaptation

Studies investigating the causes and consequences of genomic change of arboviruses are a focus of the Wadsworth Center Arbovirus Laboratory.  Arboviruses are almost exclusively RNA viruses which replicate rapidly and genomic replication is exceedingly error-prone.  The resultant genetic diversity affords these pathogens vast evolutionary and adaptive potential that can have direct implications for their capacity to spread and cause human disease. Although arboviruses are often noted as being remarkably genetically stable, they are in fact in constant flux both within and among hosts.

Ongoing studies utilizing both natural virus isolates and laboratory-adapted strains combine traditional and next-generation sequencing and molecular tools with experimental infections and passaging to advance our understanding of evolutionary pressures and arbovirus fitness.  Included in this are experimental evolution studies in both cell culture and natural hosts, phylogenetic studies assessing both geographic and temporal genetic change, studies assessing the phenotypic importance of intra-host diversity, and studies assessing host-specific selective pressures and the potential for host-range expansion.  Although this work has focused on West Nile virus, additional studies have been completed or are ongoing with St. Louis encephalitis virus, Eastern equine encephalitis virus, Powassan virus, La Crosse virus and Dengue virus.

  • Kuo L, Jaeger AS, Banker EM, Bialosuknia SM, Mathias N, Payne AF, Kramer LD, Aliota MT, Ciota AT. Reversion to ancestral Zika virus NS1 residues increases competence of Aedes albopictus. PLoS Pathog. 2020;16(10):e1008951.
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  • Caldwell HS, Ngo K, Pata JD, Kramer LD, Ciota AT. West Nile Virus fidelity modulates the capacity for host cycling and adaptation. J Gen Virol. 2020;101(4):410-419.
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  • Bialosuknia SM, Tan Y, Zink SD, Koetzner CA, Maffei JG, Halpin RA, Muller E, Novatny M, Shilts M, Fedorova NB, Amedeo P, Das SR, Pickett B, Kramer LD, Ciota AT. Evolutionary dynamics and molecular epidemiology of West Nile virus in New York State: 1999-2015. Virus Evol. 2019;5(2):vez020.
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  • Tan Y, Lam TT, Heberlein-Larson LA, Smole SC, Auguste AJ, Hennigan S, Halpin RA, Fedorova N, Puri V, Stockwell TB, Shilts MH, Andreadis T, Armstrong PM, Tesh RB, Weaver SC, Unnasch TR, Ciota AT, Kramer LD, Das SR. Large-Scale Complete-Genome Sequencing and Phylodynamic Analysis of Eastern Equine Encephalitis Virus Reveals Source-Sink Transmission Dynamics in the United States. J Virol. 2018;92(12):e00074-18.
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  • Ehrbar DJ, Ngo KA, Campbell SR, Kramer LD, Ciota AT. High levels of local inter- and intra-host genetic variation of West Nile virus and evidence of fine-scale evolutionary pressures. 2017;
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  • Van Slyke GA, Arnold JJ, Lugo AJ, Griesemer SB, Moustafa IM, Kramer LD, Cameron CE, Ciota AT. Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes. PLoS Pathogens. 2015;11(6):e1005009.
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  • Ciota AT, Payne AF, Kramer LD. West Nile virus adaptation to ixodid tick cells is associated with phenotypic trade-offs in primary hosts. Virology. 2015;482(NULL):128-132.
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  • Ciota AT, Ehrbar DJ, Matacchiero AC, Van Slyke GA, Kramer LD. The evolution of virulence of West Nile virus in a mosquito vector: implications for arbovirus adaptation and evolution - art. no. 71. BMC Evolutionary Biology. 2013;13(71):20.
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  • Ciota AT, Ehrbar DJ, Van Slyke GA, Willsey GG, Kramer LD. Cooperative interactions in the West Nile virus mutant swarm. BMC Evolutionary Biology. 2012;12(58):27.
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  • Ciota AT, Lovelace AO, Jia Y, Davis LJ, Young DS, Kramer LD. Characterization of mosquito-adapted West Nile virus. J Gen Virol. 2008;89(7):1633-42.
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Impact of Temperature on Arbovirus Transmission

Among the most important consequences of climate change are alterations in patterns of pathogen transmission. Arboviruses and invertebrate vectors are particularly sensitive to the effects of temperature and therefore studies assessing the effects of temperature on viral and mosquito fitness are a focus of the Wadsworth Center Arbovirus laboratory. 

Current areas of interest include quantifying species and population-specific effects of temperature on West Nile and Dengue virus transmission in Culex and Aedes mosquitoes and assessing the capacity for mosquito populations to adapt to rising temperatures.  The overarching goal of these studies is to gain insight into how changing temperatures alter the vectorial capacity of mosquito populations.

  • Onyango MG, Bialosuknia SM, Payne AF, Mathias N, Kuo L, Vigneron A, DeGennaro M, Ciota AT, Kramer LD. Increased temperatures reduce the vectorial capacity of Aedes mosquitoes for Zika virus. Emerg Microbes Infect. 2020;9(1):67-77.
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  • Ciota AT, Keyel AC. The Role of Temperature in Transmission of Zoonotic Arboviruses. Viruses. 2019;11(11):1013.
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  • Ciota AT, Chin PA, Ehrbar DJ, Micieli MV, Fonseca DM, Kramer LD. Differential Effects of Temperature and Mosquito Genetics Determine Transmissibility of Arboviruses by Aedes aegypti in Argentina. Am J Trop Med Hyg. 2018;99(2):417-424.
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  • Ciota AT, Matacchiero AC, Kilpatrick AM, Kramer LD. The effect of temperature on life history traits of Culex mosquitoes. Parasite Vectors. 2014;51(1):55-62.
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  • M. T. Aliota, S. A. Jones, A. P. Dupuis, 2nd, A. T. Ciota, Z. Hubalek and L. D. Kramer. Characterization of Rabensburg virus, a flavivirus closely related to West Nile virus of the Japanese encephalitis antigenic group. PLoS ONE [Electronic Resource]. 2012;7(6):e39387.
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  • Aliota MT, Kramer LD. Replication of West Nile virus, Rabensburg lineage in mammalian cells is restricted by temperature. Parasite Vectors. 2012;14(5):293.
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  • Dodson BL, Kramer LD, Rasgon JL. Effects of larval rearing temperature on immature development and West Nile virus vector competence of Culex tarsalis. Parasite Vectors. 2012;11(5):199.
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  • Lambrechts L, Paaijmans KP, Fansiri T, Carrington LB, Kramer LD, Thomas MB and Scott TW. Impact of daily temperature fluctuations on dengue virus transmission by Aedes aegypti. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(18):7460-7465.
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  • Kilpatrick AM, Meola MA, Moudy RM, Kramer LD. Temperature, viral genetics, and the transmission of West Nile virus by Culex pipiens mosquitoes. PLoS Pathog. 2008;4(6):e1000092.
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Antivirals

Despite the global disease burden associated with arboviruses, there are very few therapeutics approved for the treatment of arboviral infections. The Arbovirus Laboratory is involved in testing novel antiviral compounds, including toxicity and efficacy studies against a range of arboviruses including: West Nile virus, Yellow fever virus, Japanese Encephalitis virus, Dengue viruses, Powassan virus, Western Equine Encephalitis virus, and Vesicular Stomatitis virus. These studies are performed both on cell culture and using vertebrate models of disease.

  • Li Z, Lang Y, Sakamuru S, Samrat S, Trudeau N, Kuo L, Rugenstein N, Tharappel A, D'Brant L, Koetzner CA, Hu S, Zhang J, Huang R, Kramer LD, Butler D, Xia M, Li H. Methylene blue is a potent and broad-spectrum inhibitor against Zika virus in vitro and in vivo. Emerg Microbes Infect. 2020;201-37.
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  • Li Z, Xu J, Lang Y, Fan X, Kuo L, D'Brant L, Hu S, Samrat SK, Trudeau N, Tharappel AM, Rugenstein N, Koetzner CA, Zhang J, Chen H, Kramer LD, Butler D, Zhang QY, Zhou J, Li H. JMX0207, a Niclosamide Derivative with Improved Pharmacokinetics, Suppresses Zika Virus Infection Both In Vitro and In Vivo. ACS Infect Dis. 2020;6(10):2616-2628.
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  • Kim SY, Koetzner CA, Payne AF, Nierode GJ, Yu Y, Wang R, Barr E, Dordick JS, Kramer LD, Zhang F, Linhardt RJ. Glycosaminoglycan Compositional Analysis of Relevant Tissues in Zika Virus Pathogenesis and in Vitro Evaluation of Heparin as an Antiviral against Zika Virus Infection. Biochemistry. 2019;58(8):1155-1166.
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  • Griesemer SB, Kramer LD, Van Slyke GA, Pata JD, Gohara DW, Cameron CE, Ciota AT. Mutagen resistance and mutation restriction of St. Louis encephalitis virus. Journal of General Virology. 2017;98201-211.
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  • Chen H, Liu LH, Jones SA, Banavali N, Kass J, Li Z, Zhang J, Kramer LD, Ghosh AK,Li HM. Selective inhibition of the West Nile virus methyltransferase by nucleoside analogs. Antiviral Research. 2013;97(3):232-239.
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  • Chen H, Zhou B, Brecher M, Banavali N, Jones SA, Li Z, Zhang J, Nag D, Kramer LD, Ghosh AK, Li H. S-adenosyl-homocysteine is a weakly bound inhibitor for a flaviviral methyltransferase. PLoS One. 2013;8(10):e76900.
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Tick Research

New York State is a major focus of tick-borne pathogens.  The etiologic agents responsible for Lyme disease, Anaplasmosis, Babesiosis, and Powassan encephalitis are transmitted by Ixodes scapularis (black-legged or “deer” ticks).  The ticks and pathogens they transmit are expanding north- and west-ward from the original epicenter of the lower Hudson River Valley.  Recently, Amblyomma americanum (lone-star) ticks have been expanding their range from the southeastern and midwestern United States and into Long Island and southern NYS.  This tick is capable of transmitting the agent responsible for Ehrlichiosis as well as Heartland Virus.  In 2014, a newly discovered virus (Bourbon virus), thought to be vectored by ticks, was implicated in the death of a man in Kansas. 

The laboratory has maintained capacity for confirmatory testing of clinical encephalitis cases including Powassan encephalitis, but has augmented the surveillance and research program in response to these public health concerns. The Arbovirus Laboratory has partnered with the Bureau of Communicable Disease Control to establish a surveillance and research program to understand the geographic distribution of Powassan virus (Deer Tick virus, DTV) in NYS by testing ticks collected in the spring and fall each year and testing vertebrate sera for the presence of antibody.  The laboratory has documented DTV throughout the Hudson River Valley, determined co-infection rates of DTV and bacterial pathogens in adult and nymphal ticks collected in Dutchess and Putnam Counties, and through a collaboration with the United States Army Medical Research Institute of Infectious Diseases has led to the discovery of novel viral agents in ticks collected across NYS.  The laboratory has acquired the necessary reagents to begin to assess whether Heartland virus is present in ticks beyond the current range of Missouri and Iowa and to detect/isolate novel viruses from ticks in a preemptive measure to ascertain risk.  The Arbovirus Laboratory’s tick research and surveillance component complements our proficient mosquito-borne virus program. 

  • Frost HM, Schotthoefer AM, Thomm AM, Dupuis AP 2nd, Kehl SC, Kramer LD, Fritsche TR, Harrington YA, Knox KK. Serologic Evidence of Powassan Virus Infection in Patients with Suspected Lyme Disease. Emerg Infect Dis. 2017;23(8):1384-1388.
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  • Aliota MT, Dupuis AP, Wilczek MP, Peters RJ, Ostfeld RS, Kramer LD. The Prevalence of Zoonotic Tick-Borne Pathogens in Ixodes Scapularis Collected in the Hudson Valley, New York State. Vector Borne Zoonotic Diseases. 2014;14(4):245-250.
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  • Dupuis AP, Peters RJ, Prusinski MA, Falco RC, Ostfeld RS, Kramer LD. Isolation of deer tick virus (Powassan virus, lineage II) from Ixodes scapularis and detection of antibody in vertebrate hosts sampled in the Hudson Valley, New York State. Parasite & Vectors. 2013;(6):185.
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