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Principal Investigator: Steven Holland
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $2,783,766
Funding agency: National Institute of Allergy and Infectious Diseases
The major activities of this research project in the past have centered around using our optimized methods and procedures for imaging rhesus macaques, NZW rabbits, and common marmosets on PET/CT scanners while conducting a variety of chemotherapy and basic immunology experiments in Mtb models. We have also optimized the imaging of mice on the LFER scanner to fulfill the need in the Tuberculosis Research Section (TRS), but because of the resolution and speed of the unit, it is not ideal for mice. The experiments in 2023 included finishing up short term Mtb infections of unvaccinated rhesus macaques with the Vaccine Research Center (VRC) as well as rabbit, marmoset, and mouse infections with Mtb with TRS to examine efficacy or penetration of potential anti-tubercular compounds into MTB lesions. Experiments involving Sars-Cov-2 infection of macaques was also completed with the T-cell biology section (TBS) and members of the LID. As the ABSL-3 closure has extended significantly, no new experiments have started although many are planned. When possible, we applied automated image analysis methods that segregate low- and high-density ranges using a whole lung technique. We have working with multiple extramural partners during this time to assist in the analysis of their Mtb-infection models imaging data.
Some specific projects where we contributed and are now published are mentioned below:
We assisted TRS in investigating the myxobacterial antibiotic myxovalargin by conducting tolerability studies in mice. Myxovalargin was not tolerable in MTB-infected mice although nave mice survived short term exposure. Myxovalargin killed MTB through inhibiting translation initiation by occluding the ribosome exit. This unique mechanism of action seemed to be a viable target, but the compound needs improvement to be used in vivo (PMID 36603206).
In collaboration with TRS and investigators at Rutgers University, we continued to use rabbits and MTB lesions from the rabbit model to elucidate the drug penetration into caseum as a mimic of human lesions and drug activity in this nutrient-limiting hypoxic condition. In 2023, we specifically examined Bedaquiline (BDQ) and 2 newer diarylquinolines TBAJ876 and TBAJ587, that target the MTB adenosine triphosphate (ATP) synthase enzyme in MTB infected rabbits and found that the new drug candidates had more rapid penetration and faster wash-out periods than BDQ. One of these achieved high enough penetration into the center of large (3-5 cm) lesions to exceed the concentration necessary to kill at least 90% of resident MTB in the 2 week assay, while the approved drug BDQ and the other compounds diffusion was inadequate in large lesions. Both of the new diarylquinolines exhibited superior bactericidal activity against caseum-resident bacteria than BDQ and were reported to be more active in regimens as substitutes for BDQ (PMID 37017524).
In Sars-CoV-2 investigations with the RNA Viruses Section of LID and TBS, they used rhesus macaques to demonstrate the activity of a live-attenuated parainfluenza-virus-vectored vaccine candidate expressing SARS-CoV-2 prefusion-stabilized spike (S) protein (B/HPIV3/S-6P) (PMID: 3642362). As we assisted the team with clinical assays of the infected macaques as they demonstrated that SARS-CoV-2 replication was undetectable in airways and lung tissues of immunized macaques. The immunized macaques made S-specific antibodies which efficiently neutralized SARS-CoV-2 variants of concern of alpha, beta, and delta lineages and induced systemic and pulmonary S-specific CD4+ and CD8+ T cell responses, including tissue-resident memory cells in the lungs.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><Adenosine Triphosphate><Adenylpyrophosphate><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antibodies><Assay><Atomic Medicine><Attenuated><Bacteria><Bioassay><Biologic Assays><Biological Assay><Body Tissues><CAT scan><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19><COVID-19 infection><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 infection><COVID19 virus><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><CV19><Callithrix><Callithrix jacchus><Callithrix jacchus jacchus><Cell Body><Cells><Cellular biology><Clinical><CoV-2><CoV2><Collaborations><Common Marmoset><Computed Tomography><Computed Tomography Scanners><Data><Development><Diffusion><Discipline of Nuclear Medicine><Disease><Disorder><Domestic Rabbit><Drugs><EXTMR><Enzyme Gene><Enzymes><Exhibits><Extramural><Extramural Activities><Goals><HPIV3><Hapale><Hemadsorption Virus 1><Human><Human Parainfluenza Virus 3><Hypoxia><Hypoxic><Image><Image Analyses><Image Analysis><Imaging Procedures><Imaging Technics><Imaging Techniques><Immunize><Immunology><Individual><Infection><Infectious Diseases / Laboratory><Infectious Diseases Research><Intramural Program><Intramural Research Program><Investigation><Investigators><Lesion><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><M mulatta><M tb><M tuberculosis><M tuberculosis infection><M. mulatta><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Macaca><Macaca mulatta><Macaque><Marmosets><Medical Imaging><Medication><Memory><Methods><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Monitor><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NIAID><National Institute of Allergy and Infectious Disease><Nuclear Medicine><Nutrient><Oryctolagus cuniculus><Oxygen Deficiency><PET><PET Scan><PET imaging><PETSCAN><PETT><Para-Influenza Virus Type 3><Penetration><Pharmaceutic Preparations><Pharmaceutical Preparations><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Preventative intervention><Procedures><Proteins><Publishing><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Viruses><Rabbits><Rabbits Mammals><Rad.-PET><Radiology / Radiation Biology / Nuclear Medicine><Regimen><Reporting><Research><Research Activity><Research Design><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Resolution><Rhesus Macaque><Rhesus Monkey><Ribosomes><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 infection><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 coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Short-Tusked Marmoset><Speed><Structure of parenchyma of lung><Study Type><T cell response><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TB infection><TB therapy><TB treatment><Techniques><Therapeutic><Therapeutic Intervention><Time><Tissues><Tomodensitometry><Translation Initiation><Translational Inhibition><Translational Repression><Tuberculosis><Universities><Vaccine Research><Wuhan coronavirus><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><attenuate><attenuates><automated image analysis><bactericidal><bactericide><catscan><cell biology><chemotherapy><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><density><determine efficacy><developmental><diffused><diffuses><diffusing><diffusions><disseminated TB><disseminated tuberculosis><drug candidate><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><hCoV19><image evaluation><image interpretation><imaging><imaging program><immunization strategy><improved><in vivo><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><infection due to Mycobacterium tuberculosis><inflammation marker><inflammatory marker><intervention for prevention><intervention therapy><member><mtb><multidisciplinary><nCoV2><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non vaccinated><non-contrast CT><noncontrast CT><noncontrast computed tomography><not vaccinated><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nuclear imaging><parainfluenza virus><parainfluenza virus type 3><plasmid vaccine><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><prevention intervention><preventional intervention strategy><preventive intervention><programs><pulmonary><quantitative imaging><resolutions><response><segregation><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><study design><thymus derived lymphocyte><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><unvaccinated><vaccination strategy><vaccine candidate><vaccine efficacy><vaccine-related research><variants of concern><vector vaccine>