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Principal Investigator: James D Weger
Organization: VIRGINIA POLYTECHNIC INST AND ST UNIV
Fiscal Year: 2022
Award: $190,284
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
Chikungunya virus (CHIKV), an NIAID category B pathogen, causes a debilitating arthritic
disease that can last for years. A massive outbreak of CHIKV occurred throughout the Americas in 2013,
with an estimated 39.9 million people infected. Closely related viruses include Ross River virus (RRV) and
Mayaro virus (MAYV), which produce thousands of annual cases of arthritic disease in Australia and South
America, respectively. While previous research demonstrates that the host immune response mediates the
disease caused by these viruses, little is known about the host cofactors that act as risk factors for severe disease
caused by these viruses. One host cofactor—obesity, which affects 42.4% of Americans and 1 in 8 people
worldwide—has been associated with disease severity during infection with several viruses; including,
Influenza virus, SARS-CoV-2, and dengue virus. Similarly, our recent experimental data suggest that obese mice
infected with either CHIKV, RRV, or MAYV experience more severe disease outcomes. Furthermore, we
have identified several cytokines and chemokines that correlate strongly with obesity in our mouse model during
infection.
Our long-term goals are: (i) to identify novel therapeutic targets to treat severe alphavirus disease and
(ii) to increase our fundamental knowledge regarding the underlying mechanisms associated with the increased
disease severity in obese people caused by several viral pathogens towards reducing illness and disability. The
objectives of this proposal, directed towards attaining our long-term goal, are to (i) define the role of obesity-
associated immune genes on alphavirus pathogenesis in lean and obese hosts and (ii) define the interplay
between macrophages, NK cells, and neutrophils with obesity in the context of alphavirus infection. Our central
hypothesis is that pro-inflammatory cytokines induced by obesity promote an increase in disease severity upon
alphavirus infection by altering infiltration and activation of several immune cell populations. These studies'
rationale is two-fold: (i) to define obesity's impact on alphavirus disease severity and (ii) to use obesity to
identify host gene candidates to develop novel therapeutics. In Aim 1, we will use knockout mice, depletion, and
cytokine treatment to determine the impact of several cytokines that strongly correlate with bodyweight in
infected mice, which we expect will lead to a better understanding of alphavirus pathogenesis and identify
therapeutic targets. In Aim 2, we will use flow cytometry and transcriptomics to define the impact of obesity on
immune cell infiltration and activation during alphavirus infection, which we expect will provide novel insight
into immune mediators of pathogenesis in lean and obese hosts, which can be targeted by therapeutics. The
proposed studies seek to provide insight into the fundamental relationship between obesity and alphavirus
pathogenesis and identify novel therapeutic targets towards reducing alphavirus disease.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><ACT2><AT744.1><Act-2><Adult><Adult Human><Affect><Alpha Virus><Alphavirus><Alphavirus Infections><American><Americas><Antibodies><Antiviral Agents><Antiviral Drugs><Antivirals><Arthritis><Australia><Biological Response Modifiers><Biomodulators><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood leukocyte><Body Tissues><Body Weight decreased><Breakbone Fever Virus><C-C CKR-5><C-C CKR-5 Gene><C-C Chemokine Receptor Type 5><C-C Chemokine Receptor Type 5 Gene><CC Chemokine Receptor 5><CC-CKR-5><CC-CKR-5 Gene><CC-CKR5><CCCKR5><CCCKR5 Gene><CCL2><CCL2 gene><CCL4><CCL4 gene><CCR-5><CCR-5 Gene><CCR5><CCR5 Protein><CCR5 Receptors><CCR5 gene><CD195 Antigen><CD195 Antigen Gene><CHEMR13><CHEMR13 Gene><CHIKV><CHIKV infection><CKR-5><CKR-5 Gene><CKR5><CKR5 Gene><CKR5 Receptors><CMKBR5><CMKBR5 Gene><COVID-19 virus><COVID19 virus><CSF3><CSF3 gene><Candidate Disease Gene><Candidate Gene><Category B pathogen><Category B priority pathogen><Cell Body><Cells><Chemokine (C-C Motif) Ligand 4><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Chemokine, CC Motif, Ligand 2><Chemokine, CC Motif, Ligand 4><Chemotactic Cytokines><Chikungunya virus><Chronic><CoV-2><CoV2><Cytotoxic cell><Data><Dengue Virus><Dengue fever virus><Disease><Disease Outbreaks><Disease Outcome><Disorder><ELISA><Enzyme-Linked Immunosorbent Assay><Epidemiology><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><G-CSF><GCSF><Gamma interferon><Gene Expression><Genes><Goals><Group A Arboviruses><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><Homologous Chemotactic Cytokines><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Activation 2><Immune Cell Activation><Immune Interferon><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune response><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Infection><Infiltration><Inflammation><Inflammatory><Influenza A><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Intercrines><Interferon Gamma><Interferon Type II><Interferon-gamma><Investigators><K lymphocyte><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Leanness><Leukocytes><Leukocytes Reticuloendothelial System><MCAF><MCP-1><MCP1><MGC45931><MIP1B><MIP1B1><Macrophage Activation><Macrophage Inflammatory Protein 1-Beta><Marrow Neutrophil><Marrow leukocyte><Mayaro virus><Measures><Mediating><Mice><Mice Mammals><Modern Man><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Murine><Mus><Mφ><NIAID><NK Cells><National Institute of Allergy and Infectious Disease><Natural Killer Cells><Neutrophil Activation><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Null Mouse><Obese Mice><Obesity><Orthomyxovirus Type A><Outbreaks><Pathogenesis><Pathogenicity><Pathology><Persons><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Public Health><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><RNA Seq><RNA sequencing><RNAseq><Recombinant Cytokines><Research><Research Personnel><Researchers><Risk Factors><Role><Ross river virus><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><SCYA2><SCYA4><SIS cytokines><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Small Inducible Cytokine A2><Small Inducible Cytokine A4><South America><Swelling><Testing><Therapeutic><Thinness><Tissues><Togaviridae><Togaviruses><Transgenic Mice><Type A Influenza><Viral Diseases><Viral Pathogenesis><Virus><Virus Diseases><Virus Replication><Weight Loss><Weight Reduction><White Blood Cells><White Cell><Work><Wuhan coronavirus><access to vaccination><access to vaccines><adiposity><adulthood><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><arthritic><body weight loss><cell type><chemoattractant cytokine><chemokine><chikungunya><chikungunya infection><chikungunya virus infection><cofactor><coronavirus disease 2019 virus><coronavirus disease-19 virus><corpulence><cytokine><design><designing><disability><disease severity><enzyme linked immunoassay><epidemiologic><epidemiological><experience><experiment><experimental research><experimental study><flow cytophotometry><hCoV19><high risk><host response><human disease><immune activation><immune system response><immunomodulatory biologics><immunoresponse><infected with CHIKV><infected with chikungunya><influenzavirus><innovate><innovation><innovative><insight><lFN-Gamma><macrophage><mouse model><murine model><nCoV2><neutrophil><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ob/ob mouse><obese individuals><obese people><obese person><obese population><obese subjects><pathogen><pathogenic virus><prevent><preventing><qRTPCR><response><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><transcriptome sequencing><transcriptomics><translational impact><vaccination access><vaccination availability><vaccine access><vaccine availability><viral infection><viral multiplication><viral pathogen><viral replication><virus infection><virus multiplication><virus pathogen><virus pathogenesis><virus-induced disease><white blood cell><white blood corpuscle><wt-loss>