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Principal Investigator: Tian Wang
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2024
Award: $247,852
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Chikungunya virus (CHIKV), a mosquito-borne RNA virus, causes chikungunya fever (CHIKF), typically
accompanied by severe, debilitating and often chronic arthralgia. The virus was first associated with human
disease in the 1950s in Tanzania, and has re-emerged, causing epidemics in Africa, Asia, Europe, and
Americas over the last decade. Neither antiviral treatment nor vaccines are available for CHIKV infection.
Animal models have been used to understand CHIKV infection and virus-induced acute and persistent
arthralgia. CHIKV infection induces viremia, acute and chronic arthralgia in immunocompetent mice and severe
lethal diseases in mice deficient of interferon (IFN)-I signaling. The limitation of murine models of CHIKV
infection is that they do not recapitulate human CHIKV diseases completely, in particular CHIKV-induced
chronic arthralgia and maternal/neonatal transmission. Thus, development of other feasible small animal
models to recapitulate CHIKV-induced human diseases is in high need. The golden Syrian hamster has been
used in studying many human viral infections. CHIKV infection in wild-type hamsters induced viremia, rapid
virus dissemination to major organs, and histopathologic lesions in limbs and joints as reported in human
patients. Nevertheless, infectious virus was cleared within 4 days. Investigation of viral RNA persistence and
chronic tissue injury in wild-type and optimized mutant hamsters will be critical for further development of a
hamster model of CHIKV infection. Type I and III IFNs contribute to the control of CHIKV infection in mice and
cell culture models. Both signaling pathways result in activation of signal transducer and activator of
transcription 2 (STAT2). By utilizing the CRISPR/Cas9 system to conduct gene targeting in hamsters, we
previously produced STAT2 knockout (KO) hamsters. STAT2 KO hamsters have been used in several other
viral disease models to increase viral replication and severity of viral diseases and to recapitulate Zika virus
vertical transmission in humans. SARS-CoV-2 replication was also enhanced in hamsters defective of IL28Rα,
a subunit of type III IFN receptor compared to wild-type hamsters. Furthermore, adaptive immunity has been
shown to play critical roles in controlling CHIKV infection in mice and humans. To further define the hamster as
a model for CHIKV infection, we hypothesize that type I and/or III IFNs contribute to control of CHIKV
infection, virus-induced tissue inflammation and vertical transmission, and protect host from CHIKV-
induced chronic disease via modulating adaptive immune responses in hamsters. We will first determine
viral infection, tissue inflammation, and vertical transmission following CHIKV infection in STAT2 KO and
IL28Rα KO hamsters. We will also identify the role of humoral and T cell- mediated immune responses in
CHIKV-induced chronic diseases in hamsters. Results from this study will not only refine a novel hamster
model of CHIKV-induced chronic arthralgia, but also increase our understanding of the pathogenesis of CHIKV
infection and vertical transmission.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><Acute Disease><Africa><Age><Americas><Animal Model><Animal Models and Related Studies><Antibodies><Arthralgia><Arthritis><Asia><Body Tissues><Brain><Brain Nervous System><CHIKV><CHIKV fever><CHIKV infection><COVID-19 virus><COVID19 virus><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cells Placenta-Tissue><Chikungunya fever><Chikungunya virus><Chronic><Chronic Disease><Chronic Illness><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><CoV-2><CoV2><Cricetinae><Development><Disease><Disorder><Encephalon><Epidemic><Europe><Extremities><Fever><Gene Targeting><Goals><Golden Hamsters><Golden Syrian Hamsters><Hamsters><Hamsters Mammals><Human><IFN><Immune><Immune response><Immunes><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Inbred Mouse><Infection><Inflammation><Injury><Interferon Receptor><Interferons><Intracellular Communication and Signaling><Investigation><Joint Pain><Joints><Knock-out><Knockout><Lesion><Licensing><Limb structure><Limbs><Measures><Mesocricetus auratus><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Muscle><Muscle Tissue><Neonatal><Non-Trunk><Normal Placentoma><Organ><Pathogenesis><Patients><Phosphorylation><Placenta><Placenta Embryonic Tissue><Placentome><Play><Predisposition><Protein Phosphorylation><Pyrexia><RNA Viruses><Reporting><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Pathway><Signal Transducer and Activator of Transcription 2><Signal Transduction><Signal Transduction Systems><Signaling><Stat2 protein><Susceptibility><Synovia><Synovial Fluid><Syrian Hamsters><System><T-Cells><T-Lymphocyte><Tanzania><Tissues><Transmission><Vaccines><Vertical Transmission><Viral><Viral Arthritis><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Viremia><Virus><Virus Diseases><Virus Replication><Work><Wuhan coronavirus><ZIKV><ZIKV infected><ZIKV infection><ZIKV positive><Zika Virus><Zika virus infection><access to vaccination><access to vaccines><acute disease/disorder><acute disorder><adaptive immune response><adaptive immunity><ages><arthritic><biological signal transduction><cell culture><cell cultures><cell mediated immune response><chikungunya><chikungunya infection><chikungunya virus infection><chronic disorder><coronavirus disease 2019 virus><coronavirus disease-19 virus><cost><cytokine><developmental><disease model><disorder model><febrile><febris><fetal><hCoV19><host response><human disease><immune competent><immune system response><immunoresponse><infected with CHIKV><infected with ZIKV><infected with chikungunya><infected with zika><injuries><injury to tissue><lymph organ><lymphatic organ><lymphoid organ><model of animal><mosquito-borne><mosquitoborne><mouse model><murine model><muscular><mutant><nCoV2><non-human primate><nonhuman primate><novel><pregnant><respiratory infection virus><response><social role><thymus derived lymphocyte><tissue injury><transmission process><vaccination access><vaccination availability><vaccine access><vaccine availability><viraemia><viral RNA><viral infection><viral multiplication><viral replication><viral sepsis><virus RNA><virus infection><virus multiplication><virus-induced disease><virusemia><zika infected><zika infection><zika viral infection><zikav>