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Principal Investigator: SUSAN R ROSS
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $480,006
Funding agency: National Institute of Allergy and Infectious Diseases
New world hemorrhagic fever arenaviruses (NWAs), such as Junín virus, are rodent-transmitted
viruses that cause ~30% mortality when they zoonose into humans. The mechanism by the NWAs
induce disease is still not certain, although it likely includes induction of high levels of cytokines
by infected sentinel cells of the immune system, leading to endothelia and thrombocyte
dysfunction and neurological disease. Survivors of Junín infection develop strong humoral
immune responses, suggesting that controlling infection at early times post-infection is critical for
virus clearance. Although an effective Junín virus vaccine has decreased disease incidence,
sporadic cases of this as well as the other known and novel NWAs for which there are no vaccines
or effective therapeutics still occur. It is well-established that the clade B pathogenic NWAs bind
to transferrin receptor 1 and other receptors on the cell surface, but the steps leading to their entry
from an acidic cellular compartment are not well-determined. We recently performed a siRNA
screen with pseudotyped viruses bearing a pathogenic Junín glycoprotein with the goal of finding
host genes involved in entry that could serve as therapeutic targets. We found that TRIM2, a
member of the tripartite motif family that includes well-known members of the host's intrinsic
defense against viral infections, limits NWA endocytosis into cells. By probing the TRIM2
interactome for other host proteins that block NWA infection, we discovered that SIRPA, a cell
surface protein that inhibits macrophage phagocytosis of tumor and dead cells and erythrocytes,
also decreases infection. Importantly, SIRPA, unlike TRIM2, inhibits infection by various human
pathogenic viruses that require trafficking to an acidic compartment, including VSV, Zika virus,
LCMV and Ebola and SARS-Cov-2 pseudoviruses. Our data suggest that TRIM2 and SIRPA act
at the viral entry/internalization step. These finding suggests that there are common mechanisms
that regulate virus endocytosis and phagocytosis.
We propose here to further investigate the overlap between virus-mediated endocytosis
and phagocytosis in vitro, ex vivo and in vivo in three aims that will 1) investigate the overlap in
the NWA entry and phagocytosis pathways; 2) determine where TRIM2/SIRPA inhibition of
infection occurs; and 3) use TRIM2, SIRPA and other relevant knockout mice to probe the roles
of these proteins in cell-type specific and in vivo infection by replication-competent NWAs. In
addition to providing mechanistic insight into the entry of NWAs into cells, these studies have the
potential of increasing our understanding as to how host factors limit infection and could lead to
new approaches to therapeutic intervention.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Actins><Aerosols><Amino Acid Motifs><Anti-viral Response><Anti-viral Therapy><Apoptosis><Apoptosis Pathway><Arenaviridae><Arenaviridae Infections><Arenavirus><Arenavirus Infections><Arenavirus group><Argentina><Argentine hemorrhagic fever virus><Argentinian Hemorrhagic Fever Virus><Binding><Biological Function><Biological Process><Blood Platelets><Blood erythrocyte><C-terminal><CD71><COVID-19 virus><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Extracts><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell Surface Proteins><Cell surface><Cells><Cellular Matrix><Cellular Proliferation><CoV-2><CoV2><Complex><Cultured Cells><Cytoskeletal System><Cytoskeleton><Data><Disease><Disorder><Dysfunction><Ebola><Endocytosis><Endothelium><Erythrocytes><Erythrocytic><Family><Functional disorder><Genes><Genetic Alteration><Genetic Change><Genetic defect><Glycoproteins><Goals><HCPH><Hematopoietic Cell Phosphatase><Host Factor><Host Factor Protein><Human><Human Pathology><Image><Immune response><Immune system><Immunological response><In Vitro><Incidence><Infection><Infection Control><Integration Host Factors><Intracellular Communication and Signaling><Junin><Junin virus><KO mice><Knock-out Mice><Knockout Mice><LCM Viruses><LCM-Lassa Complex Viruses><LCMV><Link><Lymphocytic Choriomeningitis-Lassa Complex Viruses><Lymphocytic choriomeningitis virus><MFR gene><MFR protein><MYD-1><Macrophage><Macrophage Fusion Receptor><Marrow erythrocyte><Marrow platelet><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Mutation><Mφ><Nervous System Diseases><Nervous System Disorder><Neurologic Disorders><Neurological Disorders><New World Arenaviruses><Nonreceptor Type 6 Protein-Tyrosine Phosphatase><Null Mouse><Old World Arenaviruses><P84><PTP-1C><PTP1C><PTPN6><PTPN6 gene><PTPNS1><PTPNS1 gene><Pathogenicity><Pathway interactions><Patients><Phagocytosis><Phagocytosis Inhibition><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphorylation><Physiopathology><Platelets><Primates><Primates Mammals><Process><Programmed Cell Death><Protein Family><Protein Motifs><Protein Phosphorylation><Protein-Tyrosine Phosphatase 1C><Protein-Tyrosine Phosphatase, Nonreceptor Type, Substrate 1><Proteins><RBCC/TRIM Motif><RNA Viruses><RNA interference screen><RNAi screen><RNAi-based screen><Receptor Protein><Red Blood Cells><Red Cell><Rodent><Rodentia><Rodents Mammals><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><SHP Substrate 1><SHP-1><SHPS1><SIRP-Alpha-1><SIRPA><Sentinel><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><Short interfering RNA><Signal Regulatory Protein, Alpha Type, 1><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Small Interfering RNA><Specificity><Survivors><TAC virus><TFR gene><TFR protein><TFR1><TFRC><TFRC gene><TRFR><TRIM Motif><Tacaribe Complex Viruses><Tacaribe virus><Testing><Therapeutic Intervention><Thrombocytes><Tissue Extracts><Transferrin Receptor><Transferrin Receptor 1><Transmission><Tripartite Motif><Tumor Cell><Tyrosine Phosphatase SHP Substrate 1><Tyrosine phosphatase SHP1><Ubiquitilation><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Ubiquitination><Ubiquitinoylation><VSV><Vaccines><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Diseases><Viral Hemorrhagic Fevers><Virus><Virus Diseases><Visualization><Work><Wuhan coronavirus><ZIKV><Zika Virus><Zoonoses><Zoonotic><Zoonotic Infection><biological signal transduction><blood corpuscles><cell culture><cell cultures><cell type><cellular targeting><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><experiment><experimental research><experimental study><experiments><genome mutation><hCoV19><hemorrhagic fever><host response><imaging><immune system response><immunoresponse><in vivo><insight><intervention therapy><intracellular skeleton><knock-down><knockdown><member><mortality><nCoV2><neoplastic cell><neurological disease><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new 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