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Principal Investigator: KIM HASENKRUG
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2021
Award: $29,973
Funding agency: National Institute of Allergy and Infectious Diseases
We have completed the testing of SARS-CoV-2-infected rhesus macaques that were depleted of CD4+ or CD8+ T cells or dually depleted of both subsets and the results have been published (Hasenkrug et al. 2021). 6 macaques in each of 4 groups including a control non-depleted group have been analyzed. Nasal, throat and rectal swabs along with blood and bronchoalveolar fluids were collected in a kinetic manner over a period of 6 weeks and the animals were then re-infected to analyze anamnestic immune responses. The animals were then studied for an additional 2 weeks and were euthanized for harvesting of tissues for immunohistochemical study. Our study produced the rather surprising findings that neither CD4+ or CD8+ T cells were essential for the resistance of macaques to SARS-CoV-2 infection, nor were they required for strong anamnestic responses. In a collaboration with Dr. Mario Santiago, we investigated the best interferon subsets to control SARS-CoV-2 infections in vitro, and found IFN alpha 8 and 14 to be the most potent mediators of virus control. Furthermore, we found that variants of concern including alpha, beta, gamma and delta, had all developed significant resistance to interferon (Guo et al. 2021). This is important because the interferon response initiates many of the downstream immune responses critical to control SARS-CoV-2 in humans. Experiments are now in the works to test the resistance of the delta variant to interferon. Vaccine studies in aged mice are also underway in our laboratory with the goal of making elderly mice more reactive to vaccination and to develop stronger protective immunity. This is a collaboration with Dr. Irving Weissman at Stanford University who has developed a method to rejuvenate the immune systems of old mice, which, like humans, become less able to respond to new infections as they age, a phenomenon known as immune senescence. The rejuvenation experiments have been partially successful in that we have improved the vaccine-induced responses of aged mice significantly, but not to the extent of young mice. Finally, our project to develop aptamers that bind to SARS-CoV-2 spike protein receptor binding domain to block interactions with human ACE-2 has yielded more than a dozen aptamers with blocking activity. Unfortunately, Dr. Leonard Evans, who was leading this project, died during the experiments and we are currently re-evaluating how to proceed.
Terms: <(IFN) α><(IFN)-α><(IFN)α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Age><Alferon><Animal Model><Animal Models and Related Studies><Animals><B.1.617.2><Binding><Blood><Blood Reticuloendothelial System><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19><COVID-19 S protein><COVID-19 infection><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 testing><COVID-19 virus><COVID19><COVID19 S protein><COVID19 infection><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 testing><COVID19 virus><CV-19><CV19><CoV-2><CoV2><Collaborations><Cricetinae><Delta variant><Disease><Disorder><Elderly><Goals><Hamsters><Hamsters Mammals><Human><IFN><IFN Alpha><IFN α><IFN-α><IFNa><IFNα><Immune><Immune response><Immune system><Immunes><Immunity><Immunological response><Immunology><In Vitro><Infection><Interferon Alfa-n3><Interferon-alpha><Interferon-α><Interferons><Kinetics><Laboratories><Leukocyte Interferon><Liquid substance><Lymphoblast Interferon><Lymphoblastoid Interferon><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Mediator><Mediator of Activation><Mediator of activation protein><Methods><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><Nasal><Nasal Passages Nose><Nose><Pharyngeal structure><Pharynx><Publishing><Recovery><Rejuvenation><Resistance><Respiratory System, Nose, Nasal Passages><Rhesus Macaque><Rhesus Monkey><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 B.1.617.2><SARS-CoV-2 S protein><SARS-CoV-2 infection><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 testing><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><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 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 coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Swab><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Throat><Tissue Harvesting><Universities><Vaccination><Vaccines><Virus><Work><Wuhan coronavirus><acute infection><adaptive immune response><advanced age><aged><ages><allergic/immunologic body system><allergic/immunologic organ system><aptamer><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 testing><coronavirus disease 2019 virus><elders><experiment><experimental research><experimental study><fluid><geriatric><hCoV19><host response><immune system response><immunoresponse><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><late life><later life><liquid><model of animal><model organism><nCoV2><non-human primate><nonhuman primate><older adult><older person><prevent><preventing><receptor binding><receptor bound><rectal><resistant><response><senescence><senescent><senior citizen><severe acute respiratory syndrome coronavirus 2 B.1.617.2><severe acute respiratory syndrome coronavirus 2 testing><therapeutic agent development><therapeutic development><vaccination study><vaccination trial><vaccine study><vaccine trial><variants of concern>