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Principal Investigator: Antonella Casola
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2024
Award: $200,000
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Several viruses have been shown to induce metabolic reprogramming of host cells to establish productive
infections. One common mechanism utilized by viruses is the stabilization of hypoxia-inducible-factors (HIF).
The HIF complex, comprised of an inducible α subunit (HIF-1α or HIF-2α) and a constitutively expressed β
subunit (HIF-1β), is known to control diverse transcriptional processes in response to hypoxia and other disease
states. The use of both HIF inhibitors and stabilizers has been investigated in models of cancer, autoimmunity,
and non-infectious acute lung injury, with several compounds for both classes currently being tested in phase 3
clinical trials for a variety of clinical disorders. However, there are no publications describing the use of a HIF
specific inhibitors or stabilizers in in vivo models of viral infections. In vitro studies have suggested that inhibiting
HIF-1α could represent an effective anti-viral strategy, including against respiratory viruses such as respiratory
syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our
preliminary data in a mouse model of RSV infection, the leading cause of severe acute lung illness in infants for
which there are no effective therapeutics or licensed vaccines, did not support this strategy, as we found that
inhibition of HIF-1α worsen clinical disease and favors viral replication, while stabilization of HIF proteins
improves clinical disease and lung function. The central hypothesis of this application is that during RSV infection
(and possibly other respiratory viruses) HIFs mediate activation and survival of key immune cells that control
antiviral responses while maintaining lung integrity and function. We will test this hypothesis in a well-established
mouse model of RSV infection. In Specific Aim 1, we will determine the contributions of HIF-1α and/or HIF-2α to
RSV-mediated clinical disease, lung function, immune modulation, and viral replication using inhibitors specific
for each of the HIF-αsubunits. In Specific Aim 2, we will test the hypothesis that HIF stabilization protects the
airways from experimental RSV infection and modulate antiviral immune responses, using similar disease and
viral outcomes. This is a novel project with a long-term goal to uncover the unique and complex contribution of
HIFs to both antiviral immunity and lung pathophysiology, and with wider relevance for human respiratory
infections. This contribution is significant as these studies will provide important new information for ongoing
clinical trials of HIF inhibitors, used in patients with cancers and other diseases who could be at higher risk for
more severe respiratory viral infections, as well the potential use of HIF stabilizers as therapeutic approach for
respiratory virus associated lung diseases.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Ab response><Acute><Acute Lung Injury><Acute Pulmonary Injury><Airway infections><Anemia><Animal Cancer Model><Animal Model><Animal Models and Related Studies><Anti-viral Response><Antibody Formation><Antibody Production><Autoimmune Status><Autoimmunity><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><BALB C Mouse><BALB/c><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Bone-Derived Transforming Growth Factor><COVID-19 virus><COVID19 virus><CSIF><CSIF-10><Cancer Model><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Metabolic Process><Child><Child Youth><Children (0-21)><Chronic><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Clinical Trials><Co(beta)-cyano-7''-(2-methyl)adeninylcobamide><CoV-2><CoV2><Collagen><Complex><Cytokine Gene><Cytokine Synthesis Inhibitory Factor><Data><Dendritic Cells><Deposit><Deposition><Development><Disease><Disorder><Drug Modulation><Drug usage><Dysfunction><Elderly><Epithelial Cells><Exhibits><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Gene Expression><Gene Transcription><Genetic><Genetic Transcription><Goals><HIF 1><HIF-1 protein><HIF1><HIF1 protein><Histopathology><Human><Hypoxia><Hypoxia Inducible Factor><Hypoxic><IL-10><IL10><IL10A><Immune><Immune Cell Activation><Immune response><Immunes><Immunological response><Immunomodulation><In Vitro><Inbred BALB C Mice><Infant><Infection><Inflammation><Interleukin 10 Precursor><Interleukin-10><Intracellular Communication and Signaling><Investigation><Kinetics><Knowledge><Laboratories><Licensing><Lower Respiratory Tract Infection><Lower respiratory infection><Lung><Lung Diseases><Lung Inflammation><Lung Respiratory System><Lung damage><Lung infections><Macrophage><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Mediating><Metabolic><Metabolic Pathway><Mice><Mice Mammals><Milk Growth Factor><Modern Man><Molecular><Mucous body substance><Mucus><Murine><Mus><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Outcome><Oxygen Deficiency><Pathogenesis><Pathogenicity><Patients><Phase 3 Clinical Trials><Phase III Clinical Trials><Phenotype><Physiopathology><Platelet Transforming Growth Factor><Play><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Process><Production><Productivity><Proteins><Publications><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Inflammation><RNA Expression><RSV infection><Respiratory Epithelium><Respiratory Infections><Respiratory Syncytial Virus Infections><Respiratory Tract Infections><Respiratory syncytial virus><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><Scientific Publication><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><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Structure of respiratory epithelium><T-Cells><T-Lymphocyte><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic><Transcription><Transcription Process><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Vaccines><Veiled Cells><Viral><Viral Diseases><Viral Pathogenesis><Viral Respiratory Tract Infection><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Work><Wuhan coronavirus><access to vaccination><access to vaccines><advanced age><airway epithelium><airway remodeling><anti-viral immunity><antibody biosynthesis><antiviral immunity><biological signal transduction><cancer type><cell metabolism><cellular metabaolism><chronic kidney disease><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><developmental><disease of the lung><disorder of the lung><drug development><drug use><experience><extracellular><factor A><flow cytophotometry><geriatric><hCoV19><high risk><host response><hypoxia inducible factor 1><immune activation><immune modulation><immune regulation><immune system response><immunoglobulin biosynthesis><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><in vivo Model><inhibitor><kids><lung disorder><lung function><lung injury><malignancy><migration><model of animal><mouse model><mucous><murine model><nCoV2><neoplasm/cancer><neutrophil><novel><pathophysiology><pharmacologic><phase III protocol><protective effect><pulmonary><pulmonary damage><pulmonary function><pulmonary infections><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><respiratory><respiratory tract epithelium><respiratory virus><response><senior citizen><side effect><social role><therapeutically effective><thymus derived lymphocyte><tissue regeneration><tissue regrowth><tissue renewal><tissue specific regeneration><vaccination access><vaccination availability><vaccine access><vaccine availability><viral infection><viral multiplication><viral replication><viral respiratory infection><virus infection><virus multiplication><virus pathogenesis><virus-induced disease><youngster>