{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/137823"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/137823","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"Cache Valley Virus: A Comparison Across Both Lineages and Reassortant Strains Using in vitro and in vivo Models","abstract":"Cache Valley virus (CVV) is an emerging mosquito-borne orthobunyavirus of significant concern to One Health. CVV was first isolated from Culiseta inornata mosquitoes in Cache Valley, Utah in 1956 and has sporadically emerged to cause epizootics in livestock, particularly affecting small ruminants. CVV is a known teratogenic virus, and its infection has been associated with spontaneous abortions and several birth defects in ruminants such as sheep, goats, and cattle. Seven human cases have been reported to date, presenting symptoms such as headache, fever, nausea and in severe cases, neurological disease such as encephalitis, meningitis, and organ failure. Four human fatalities have been documented to date. CVV is endemic to North America and has been detected in mosquito, wildlife, and human samples across Canada, United States, and Mexico. CVV strains are phylogenetically classified into two genetic lineages. Recent mosquito surveillance studies indicated that lineage II strains originating from Mexico have displaced lineage I isolates in Connecticut, New York, and Canada, since 2010. Furthermore, as a result of coinfection and segment reassortment between CVV lineages, reassortant isolates have emerged and has increased the genetic diversity of this virus. Importantly, recent case reports in humans have been associated with infection by these reassortant CVV strains. Pathogenesis studies in immune-compromised mice showed significant disease including weight loss, encephalitis, and mortality. To expand on our previous murine model studies and gain a better understanding of the pathogenicity of CVV isolates from both lineages as well as reassortant isolates, we explored pathogenesis with an emphasis on neuropathogenesis in several murine models. Herein, we explored the pathogenesis of three CVV strains from lineage I, lineage II, and reassortant viruses in immune-competent and immune-compromised murine models, as well as different inoculation routes. Our results show significant strain-specific differences in pathogenesis with clear differences in weight loss, viremia, organ loads, and mortality, among our models used. Considering our comparative pathogenesis data as a surrogate for understanding differences in human pathogenesis, our data suggests increased neuropathogenesis among the lineage II and one of the reassortant viruses studied. Our studies identify a unique and highly neurovirulent reassortant strain of CVV that presents significantly more disease than lineage I and II strains in several murine models. Altogether, our results suggest significant strain- and lineage-specific differences in CVV neuropathogenesis and suggests a plausible increased risk of neurological disease may be associated with currently circulating lineage II strains. CVV continues to remain an important agricultural and human pathogen and further research is needed to understand its ecology, the factors that may contribute to its risk of emergence, and intervention strategies to prevent its emergence and/or diminish its disease burden are urgently needed.","abstract_html":"Cache Valley virus (CVV) is an emerging mosquito-borne orthobunyavirus of significant concern to One Health. CVV was first isolated from Culiseta inornata mosquitoes in Cache Valley, Utah in 1956 and has sporadically emerged to cause epizootics in livestock, particularly affecting small ruminants. CVV is a known teratogenic virus, and its infection has been associated with spontaneous abortions and several birth defects in ruminants such as sheep, goats, and cattle. Seven human cases have been reported to date, presenting symptoms such as headache, fever, nausea and in severe cases, neurological disease such as encephalitis, meningitis, and organ failure. Four human fatalities have been documented to date. CVV is endemic to North America and has been detected in mosquito, wildlife, and human samples across Canada, United States, and Mexico. CVV strains are phylogenetically classified into two genetic lineages. Recent mosquito surveillance studies indicated that lineage II strains originating from Mexico have displaced lineage I isolates in Connecticut, New York, and Canada, since 2010. Furthermore, as a result of coinfection and segment reassortment between CVV lineages, reassortant isolates have emerged and has increased the genetic diversity of this virus. Importantly, recent case reports in humans have been associated with infection by these reassortant CVV strains. Pathogenesis studies in immune-compromised mice showed significant disease including weight loss, encephalitis, and mortality. To expand on our previous murine model studies and gain a better understanding of the pathogenicity of CVV isolates from both lineages as well as reassortant isolates, we explored pathogenesis with an emphasis on neuropathogenesis in several murine models. Herein, we explored the pathogenesis of three CVV strains from lineage I, lineage II, and reassortant viruses in immune-competent and immune-compromised murine models, as well as different inoculation routes. Our results show significant strain-specific differences in pathogenesis with clear differences in weight loss, viremia, organ loads, and mortality, among our models used. Considering our comparative pathogenesis data as a surrogate for understanding differences in human pathogenesis, our data suggests increased neuropathogenesis among the lineage II and one of the reassortant viruses studied. Our studies identify a unique and highly neurovirulent reassortant strain of CVV that presents significantly more disease than lineage I and II strains in several murine models. Altogether, our results suggest significant strain- and lineage-specific differences in CVV neuropathogenesis and suggests a plausible increased risk of neurological disease may be associated with currently circulating lineage II strains. CVV continues to remain an important agricultural and human pathogen and further research is needed to understand its ecology, the factors that may contribute to its risk of emergence, and intervention strategies to prevent its emergence and/or diminish its disease burden are urgently needed.","abstract_has_math":false,"creators":["Shrestha, Marissa"],"institution":"Virginia Tech","degree_name":"Master of Science in Life Sciences","degree_level":"masters","degree_discipline":"Entomology","degree_department":"Entomology","school":null,"contributors":[],"advisors":[],"committee_chairs":["Auguste, Albert Jonathan"],"committee_members":["Bertke, Andrea S.","Kehn-Hall, Kylene Wesley"],"year":2025,"date_issued":"2025-09-22","date_published":"2025-09-22","updated_at":"2026-07-22T22:20:40Z","subjects":["Orthobunyavirus","Cache Valley virus","comparative pathogenesis","neurovirulence","neuropathogenesis","in vitro","in vivo","murine models","reassortant viruses"],"languages":["en"],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:44614"],"render_values":[{"text":"vt_gsexam:44614","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/10919/137823","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Auguste, Albert Jonathan"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Bertke, Andrea S.","Kehn-Hall, Kylene Wesley"]},{"key":"dc:contributor.department","label":"Department","values":["Entomology"]},{"key":"dc:creator","label":"Author","values":["Shrestha, Marissa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-09-24T08:00:28Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2025-09-24T08:00:28Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-09-22"]},{"key":"dc:publisher","label":"Institution","values":["Virginia Tech"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Entomology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["masters"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science in Life Sciences"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Virginia Polytechnic Institute and State University"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Orthobunyavirus","Cache Valley virus","comparative pathogenesis","neurovirulence","neuropathogenesis","in vitro","in vivo","murine models","reassortant viruses"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["In Copyright"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://rightsstatements.org/vocab/InC/1.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:44614"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10919/137823"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Cache Valley virus (CVV) is an emerging mosquito-borne orthobunyavirus of significant concern to One Health. CVV was first isolated from Culiseta inornata mosquitoes in Cache Valley, Utah in 1956 and has sporadically emerged to cause epizootics in livestock, particularly affecting small ruminants. CVV is a known teratogenic virus, and its infection has been associated with spontaneous abortions and several birth defects in ruminants such as sheep, goats, and cattle. Seven human cases have been reported to date, presenting symptoms such as headache, fever, nausea and in severe cases, neurological disease such as encephalitis, meningitis, and organ failure. Four human fatalities have been documented to date. CVV is endemic to North America and has been detected in mosquito, wildlife, and human samples across Canada, United States, and Mexico. CVV strains are phylogenetically classified into two genetic lineages. Recent mosquito surveillance studies indicated that lineage II strains originating from Mexico have displaced lineage I isolates in Connecticut, New York, and Canada, since 2010. Furthermore, as a result of coinfection and segment reassortment between CVV lineages, reassortant isolates have emerged and has increased the genetic diversity of this virus. Importantly, recent case reports in humans have been associated with infection by these reassortant CVV strains. Pathogenesis studies in immune-compromised mice showed significant disease including weight loss, encephalitis, and mortality. To expand on our previous murine model studies and gain a better understanding of the pathogenicity of CVV isolates from both lineages as well as reassortant isolates, we explored pathogenesis with an emphasis on neuropathogenesis in several murine models. Herein, we explored the pathogenesis of three CVV strains from lineage I, lineage II, and reassortant viruses in immune-competent and immune-compromised murine models, as well as different inoculation routes. Our results show significant strain-specific differences in pathogenesis with clear differences in weight loss, viremia, organ loads, and mortality, among our models used. Considering our comparative pathogenesis data as a surrogate for understanding differences in human pathogenesis, our data suggests increased neuropathogenesis among the lineage II and one of the reassortant viruses studied. Our studies identify a unique and highly neurovirulent reassortant strain of CVV that presents significantly more disease than lineage I and II strains in several murine models. Altogether, our results suggest significant strain- and lineage-specific differences in CVV neuropathogenesis and suggests a plausible increased risk of neurological disease may be associated with currently circulating lineage II strains. CVV continues to remain an important agricultural and human pathogen and further research is needed to understand its ecology, the factors that may contribute to its risk of emergence, and intervention strategies to prevent its emergence and/or diminish its disease burden are urgently needed."]},{"key":"dc:description.abstractgeneral","label":"General Abstract","values":["Cache Valley virus (CVV) is a mosquito-borne pathogen of great significance to One Health, as it has been known to infect ruminants, humans, and other vertebrates. This virus is widely distributed across the Americas and is known to cause fetal abnormalities and birth defects in ruminants. Several outbreaks of the virus have been reported in sheep herds. Although human cases are rare, there is mounting evidence that CVV may be a greater threat to public health, particularly when its vector range is expanded by ecological and climatic conditions. Throughout Canada, the United States, and Mexico, CVV has been found in human, wildlife, and mosquito samples. It is endemic to North America. According to phylogenetic analysis, there are two genetic lineages of CVV strains. According to recent studies on mosquito monitoring, since 2010, lineage II strains from Mexico have replaced lineage I isolates in Connecticut, New York, and Canada. A phenomenon known as reassortment takes place when 2 strains of CVV of different lineages, coinfect the same host and subsequently exchange genome segments. Reassortant isolates have arisen as a result of coinfection and segment reassortment between CVV lineages, which has enhanced this virus' genetic diversity. Crucially, infection by these reassortant CVV strains has been linked to subsequent human case reports. Pathogenesis studies in immune-compromised mice revealed severe illness, including weight loss, encephalitis, and death. To build on our earlier murine model investigations and acquire a better knowledge of the pathogenicity of CVV isolates from both lineages and reassortant isolates, we investigated pathogenesis in multiple murine models, focusing on neuropathogenesis. Our findings point to a possible elevated risk of neurological illness associated with currently circulating lineage II strains. Further research is required to understand the ecology of CVV, the factors that may increase its risk of emergence, and the urgent need for intervention techniques to stop its emergence and/or reduce its disease burden."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Master of Science in Life Sciences"]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["ETD"]},{"key":"dc:title","label":"Title","values":["Cache Valley Virus: A Comparison Across Both Lineages and Reassortant Strains Using in vitro and in vivo Models"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Auguste, Albert Jonathan"],"dc:contributor.committeemember":["Bertke, Andrea S.","Kehn-Hall, Kylene Wesley"],"dc:contributor.department":["Entomology"],"dc:creator":["Shrestha, Marissa"],"dc:date.accessioned":["2025-09-24T08:00:28Z"],"dc:date.available":["2025-09-24T08:00:28Z"],"dc:date.issued":["2025-09-22"],"dc:description.abstract":["Cache Valley virus (CVV) is an emerging mosquito-borne orthobunyavirus of significant concern to One Health. CVV was first isolated from Culiseta inornata mosquitoes in Cache Valley, Utah in 1956 and has sporadically emerged to cause epizootics in livestock, particularly affecting small ruminants. CVV is a known teratogenic virus, and its infection has been associated with spontaneous abortions and several birth defects in ruminants such as sheep, goats, and cattle. Seven human cases have been reported to date, presenting symptoms such as headache, fever, nausea and in severe cases, neurological disease such as encephalitis, meningitis, and organ failure. Four human fatalities have been documented to date. CVV is endemic to North America and has been detected in mosquito, wildlife, and human samples across Canada, United States, and Mexico. CVV strains are phylogenetically classified into two genetic lineages. Recent mosquito surveillance studies indicated that lineage II strains originating from Mexico have displaced lineage I isolates in Connecticut, New York, and Canada, since 2010. Furthermore, as a result of coinfection and segment reassortment between CVV lineages, reassortant isolates have emerged and has increased the genetic diversity of this virus. Importantly, recent case reports in humans have been associated with infection by these reassortant CVV strains. Pathogenesis studies in immune-compromised mice showed significant disease including weight loss, encephalitis, and mortality. To expand on our previous murine model studies and gain a better understanding of the pathogenicity of CVV isolates from both lineages as well as reassortant isolates, we explored pathogenesis with an emphasis on neuropathogenesis in several murine models. Herein, we explored the pathogenesis of three CVV strains from lineage I, lineage II, and reassortant viruses in immune-competent and immune-compromised murine models, as well as different inoculation routes. Our results show significant strain-specific differences in pathogenesis with clear differences in weight loss, viremia, organ loads, and mortality, among our models used. Considering our comparative pathogenesis data as a surrogate for understanding differences in human pathogenesis, our data suggests increased neuropathogenesis among the lineage II and one of the reassortant viruses studied. Our studies identify a unique and highly neurovirulent reassortant strain of CVV that presents significantly more disease than lineage I and II strains in several murine models. Altogether, our results suggest significant strain- and lineage-specific differences in CVV neuropathogenesis and suggests a plausible increased risk of neurological disease may be associated with currently circulating lineage II strains. CVV continues to remain an important agricultural and human pathogen and further research is needed to understand its ecology, the factors that may contribute to its risk of emergence, and intervention strategies to prevent its emergence and/or diminish its disease burden are urgently needed."],"dc:description.abstractgeneral":["Cache Valley virus (CVV) is a mosquito-borne pathogen of great significance to One Health, as it has been known to infect ruminants, humans, and other vertebrates. This virus is widely distributed across the Americas and is known to cause fetal abnormalities and birth defects in ruminants. Several outbreaks of the virus have been reported in sheep herds. Although human cases are rare, there is mounting evidence that CVV may be a greater threat to public health, particularly when its vector range is expanded by ecological and climatic conditions. Throughout Canada, the United States, and Mexico, CVV has been found in human, wildlife, and mosquito samples. It is endemic to North America. According to phylogenetic analysis, there are two genetic lineages of CVV strains. According to recent studies on mosquito monitoring, since 2010, lineage II strains from Mexico have replaced lineage I isolates in Connecticut, New York, and Canada. A phenomenon known as reassortment takes place when 2 strains of CVV of different lineages, coinfect the same host and subsequently exchange genome segments. Reassortant isolates have arisen as a result of coinfection and segment reassortment between CVV lineages, which has enhanced this virus' genetic diversity. Crucially, infection by these reassortant CVV strains has been linked to subsequent human case reports. Pathogenesis studies in immune-compromised mice revealed severe illness, including weight loss, encephalitis, and death. To build on our earlier murine model investigations and acquire a better knowledge of the pathogenicity of CVV isolates from both lineages and reassortant isolates, we investigated pathogenesis in multiple murine models, focusing on neuropathogenesis. Our findings point to a possible elevated risk of neurological illness associated with currently circulating lineage II strains. Further research is required to understand the ecology of CVV, the factors that may increase its risk of emergence, and the urgent need for intervention techniques to stop its emergence and/or reduce its disease burden."],"dc:description.degree":["Master of Science in Life Sciences"],"dc:format.medium":["ETD"],"dc:identifier.other":["vt_gsexam:44614"],"dc:identifier.uri":["https://hdl.handle.net/10919/137823"],"dc:language.iso":["en"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["Orthobunyavirus","Cache Valley virus","comparative pathogenesis","neurovirulence","neuropathogenesis","in vitro","in vivo","murine models","reassortant viruses"],"dc:title":["Cache Valley Virus: A Comparison Across Both Lineages and Reassortant Strains Using in vitro and in vivo Models"],"dc:type":["Thesis"],"thesis:degree_discipline":["Entomology"],"thesis:degree_level":["masters"],"thesis:degree_name":["Master of Science in Life Sciences"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:20:40Z"}