Document text
Principal Investigator: Steven Holland
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $3,147,878
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 2024 included adding an additional group of unvaccinated rhesus macaques for a short term Mtb infection 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 (PMID: 38581700) and worked on the development of the [18F]2 fluor deoxy trehalose (FDT) dataset to support an IND application for the probe. Two experiments involving Mtb infection of macaques followed by immunological manipulation of the animals with the T-cell biology section (TBS) were also completed. In addition, we have worked with two extramural partners to assist in the analysis of their imaging data of Mtb-infected animals.
Some specific projects where we have contributed to the work and that have been recently published are mentioned below:
We assisted TRS in investigating if [18F]FDT could function as a mechanism-based reporter of mycobacteria-selective enzyme activity in vivo (PMID: 38937448). Administering [18F]FDT as a PET tracer successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment in two NHP species. The uptake of [18F]FDT was significantly blocked with prior administration of non-radioactive 2-deoxy trehalose and FDT uptake was decreased with drug treatment that reduced bacterial load in TB lesions more consistently that with FDG. We are completing some further characterization of the tracer to build a case for its use in clinical assessment of TB disease in clinical studies. Toward this goal, in 2024 we have monitored the disease progression with FDT and seen FDT uptake increase as disease progressed and we hope to show a clear relationship between FDT retention in tissues and their bacterial content.
Also in 2024, we shared the treatment outcome data extracted from 114 marmosets with colleagues developing a modeling pipeline, referred to as GranSim, for drug regimen ranking. They used the model to predict drug efficacies of various regimens (PMID: 38404200). The GranSim in silico model correlated well with the data from our marmoset studies, helping to validate their in silico granuloma model.
In collaboration with TRS and investigators at Mass General Hospital and Rutgers University, we continued to use rabbits and MTB lesions from the rabbit model to develop a potential host directed therapy (HDT) for tuberculosis (PMID: 38530888). We demonstrated that FDA-approved therapies (bevacizumab and losartan, respectively) could be repurposed as HDTs to normalize blood vessels and extracellular matrix improve drug delivery, and reduce bacterial loads in TB granulomas. Combining both HDTs promoted secretion of proinflammatory cytokines and improved anti-TB drug delivery under some conditions. Finally, alone and in combination with second-line antitubercular agents (moxifloxacin or bedaquiline), these HDTs significantly reduce bacterial burden. RNA sequencing analysis of HDT-treated lung and granuloma tissues implicates up-regulated antimicrobial peptide and proinflammatory gene expression as the putative mechanism of this HDT combination. As part of this work, we developed a model of oxygen, nutrient and drug transport in tuberculosis granulomas (PMID: 38335224) and reviewed the similarities tumors treatments that could inform tuberculosis treatment (trends in molecular medicine, in press).
In Sars-CoV-2 investigations with the RNA Viruses Section of LID and TBS, we assisted in the evaluation of the immunogenicity and protective efficacy of one or two doses of a live-attenuated murine pneumonia virus vector expressing SARS-CoV-2 prefusion-stabilized spike protein (MPV/S-2P), delivered intranasally/intratracheally to male rhesus macaques (PMID: 38670948). It was determined that one dose induces substantial protection against SARS-CoV-2 challenge, and two doses of MPV/S-2P are fully protective against SARS-CoV-2 challenge virus replication in the airways. In addition, we assisted TBS to examine the roles of the prototypic pro- and anti-inflammatory cytokines IFNγ and IL-10 using the rhesus macaque model of mild COVID-19 (PMID: 38950078). It was found that IFNγ drove the development of [18F]fluorodeoxyglucose (FDG)-avid lesions in the lungs as measured by PET/CT imaging but was not required for suppression of viral replication. In contrast, IL-10 limited the duration of acute pulmonary lesions, serum markers of inflammation and the magnitude of virus-specific T cell expansion but did not impair viral clearance. An unexpected role for IL-10 in promoting airway memory T cells during SARS-CoV-2 infection of macaques was also found.
Terms: <18-FDG><18F- FDG><18FDG><2 Fluoro 2 deoxy D glucose><2-Fluoro-2-deoxyglucose><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-VEGF><Anti-VEGF Humanized Monoclonal Antibody><Anti-VEGF RhuMAb><Anti-inflammatory><Antitubercular Agents><Antitubercular Drugs><Atomic Medicine><Attenuated><Blood Vessels><Body Tissues><CAT scan><COVID-19><COVID-19 infection><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CSIF><CSIF-10><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><Callithrix><Callithrix jacchus><Callithrix jacchus jacchus><Cell-Extracellular Matrix><Cellular biology><Clinical Research><Clinical Study><Clinical assessments><CoV-2><CoV2><Collaborations><Combined Modality Therapy><Common Marmoset><Computed Tomography><Computed Tomography Scanners><Coronavirus Infectious Disease 2019><Cytokine Synthesis Inhibitory Factor><Data><Data Set><Development><Discipline of Nuclear Medicine><Disease><Disease Progression><Disorder><Domestic Rabbit><Dose><Drug Delivery><Drug Delivery Systems><Drug Therapy><Drug Transport><Drugs><ECM><EXTMR><Evaluation><Extracellular Matrix><Extramural><Extramural Activities><FDA approved><Gene Expression><General Hospitals><Genus Mycobacterium><Goals><Granuloma><Granulomatous Lesion><Hapale><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-10><IL10><IL10A><Image><Image Analyses><Image Analysis><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune Interferon><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Immunology><Individual><Infection><Infectious Diseases / Laboratory><Infectious Diseases Research><Inflammatory><Interferon Gamma><Interferon Type II><Interleukin 10 Precursor><Interleukin-10><Intramural Program><Intramural Research Program><Investigation><Investigators><Lesion><Losartan><Lung><Lung Respiratory System><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><Measures><Mediating><Medical Imaging><Medication><Methods><Mice><Mice Mammals><MoAb VEGF><Modeling><Molecular Medicine><Monitor><Monoclonal Antibody Anti-VEGF><Moxifloxacin><Multimodal Therapy><Multimodal Treatment><Murine><Murine pneumonia virus><Mus><Mycobacterium><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NIAID><National Institute of Allergy and Infectious Disease><Nuclear Medicine><Nutrient><O element><O2 element><Oryctolagus cuniculus><Oxygen><PET><PET Scan><PET imaging><PETSCAN><PETT><Penetration><Pharmaceutical Preparations><Pharmacotherapy><Pneumonia Virus of Mice><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 Seq><RNA Viruses><RNA sequencing><RNAseq><Rabbits><Rabbits Mammals><Rad.-PET><Radiology / Radiation Biology / Nuclear Medicine><Recombinant Humanized Anti-VEGF Monoclonal Antibody><Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor><Regimen><Reporter><Research><Research Activity><Research Design><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Resolution><Rhesus Macaque><Rhesus Monkey><RhuMAb VEGF><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><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><Serum Markers><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><Study Type><T memory cell><T-Cells><T-Lymphocyte><TB drugs><TB granuloma><TB infection><TB therapy><TB treatment><Therapeutic><Therapeutic Intervention><Tissues><Tomodensitometry><Tracer><Treatment outcome><Trehalose><Tuberculosis><Tuberculostatic Agents><Universities><Vaccine Research><Viral><Virus><Virus Replication><Work><Wuhan coronavirus><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><anti-TB><anti-TB drugs><anti-microbial peptide><anti-tuberculosis><anti-tuberculosis drugs><antiTB><attenuate><attenuates><bevacizumab><catscan><cell biology><chemotherapy><combination therapy><combined modality treatment><combined treatment><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><cytokine><determine efficacy><developmental><disseminated TB><disseminated tuberculosis><drug efficacy><drug treatment><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><enzyme activity><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><fluorodeoxyglucose><hCoV19><image evaluation><image interpretation><imaging><imaging program><immunization strategy><immunogenicity><improved><in silico><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><lFN-Gamma><lozartan><lung lesion><male><memory T lymphocyte><mtb><multi-modal therapy><multi-modal treatment><multidisciplinary><nCoV2><non vaccinated><non-contrast CT><noncontrast CT><noncontrast computed tomography><not vaccinated><novel><nuclear imaging><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><prevention intervention><preventional intervention strategy><preventive intervention><programs><protective efficacy><prototype><pulmonary><pulmonary lesion><quantitative imaging><resolutions><response><rhuMabVEGF><social role><study design><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><treatment effect><trend><tuberculosis drugs><tuberculosis granuloma><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><tumor><unvaccinated><uptake><vaccination strategy><vaccine candidate><vaccine efficacy><vaccine-related research><vascular><vector><viral multiplication><viral replication><virus multiplication>