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Principal Investigator: Vitaly V. Ganusov
Organization: TEXAS BIOMEDICAL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $634,089
Funding agency: National Institute of Allergy and Infectious Diseases
Research Summary
Tuberculosis (TB), a disease caused by the bacteria Mycobacterium tuberculosis (Mtb), remains a major infec-
tious disease of humans in the world. After the initial local infection of one site in the lung Mtb somehow dissem-
inates in the lung and often spreads beyond the lung. In fact, extrapulmonary TB is a hallmark of the disease in
young children and immunocompromised adults that is difficult to diagnose and treat. Our understanding of Mtb
dissemination, both within the lung and beyond, remains limited, however. In this proposal we assembled a team
of scientists with expertise in computational biology (Ganusov, Aitchison, Duffy, Langston) and TB pathogenesis
(Urdahl, Sherman, Behar) to provide quantitative understanding of mechanisms of Mtb dissemination the lung
and systemically. To this end, we will be using a number of highly innovative techniques such as i) a novel animal
model of TB: infection of mice with an ultra low dose (ULD, 1-3 colony forming units, CFU) of Mtb along with a set
of 50 barcoded Mtb strains, ii) an Mtb strain H37Rv-pBP10 with the replication clock plasmid, allowing to estimate
how quickly bacteria are eliminated in vivo, and iii) mRNA-based gene signatures predicting bacterial numbers in
murine lungs and TB disease progression risk in humans. With three complementary specific aims we will pro-
vide detailed, quantitative understanding of fundamental processes of how Mtb disseminates from the deposition
in lung alveoli to the whole lung and systemically. In Aim 1 we will determine the pathway of Mtb dissemination
within the lung using a novel model of ULD-infected mice that mimics better human infection than many other
animal models. In particular, we will discriminate between alternative hypotheses of Mtb spread in the lungs
such the “bubble model” (in which Mtb spreads locally between lung lobes) and the “reseeding model” (in which
Mtb spreads hematogenously to different parts of the lung after disseminating systemically). In Aim 2 we will
determine the contribution of different cell populations, including Mtb-specific CD4 T cell response, to kinetics of
Mtb dissemination systemically in mice infected with conventional doses (CD, 150 CFU) of Mtb. To parameterize
best fit models we will use data from experiments with Mtb H37Rv carrying the replication clock plasmid pBP10.
Finally, in Aim 3 we will attempt to improve on our recently derived mRNA-based gene signatures predicting
CFU in murine lungs using cutting-edge graph theory-based methods of data dimensionality reduction. We will
also perform experiments and define a new signature predicting disseminated TB in mice, and test its accuracy
using data from monkeys and humans. Taken together, by combining experimental data from highly innovative
experiments involving novel techniques (ultra low dose infections, barcoded strains, replication clock plasmid,
microarray-based gene signatures) we will provide a quantitative understanding of how Mtb disseminates in the
lung and systemically in the body.
Terms: <0-11 years old><21+ years old><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adult><Adult Human><Advocate><Animal Model><Animal Models and Related Studies><Bacteria><Bar Codes><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Sample><Blood specimen><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cells><Cessation of life><Child><Child Youth><Children (0-21)><Clinical><Colony-forming units><Communicable Diseases><Computational Biology><Data><Data Analyses><Data Analysis><Death><Deposit><Deposition><Diagnosis><Disease><Disease Progression><Disorder><Dose><Experimental Models><Expression Signature><Focal Infection><Gene Expression Profile><Genetic Markers><Goals><Granuloma><Granulomatous Lesion><HIV><Health><Hematogenous><Hematogenous Spread><Human><Human Immunodeficiency Viruses><Immune><Immunes><Immunity><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Kinetics><LAV-HTLV-III><Licensing><Lung><Lung Diseases><Lung Respiratory System><Lung infections><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic nodes><M tb><M tuberculosis><M tuberculosis H37Rv><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis H37Rv><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><MTB vaccine><Macrophage><Marrow Neutrophil><Math Models><Mediating><Messenger RNA><Methods><Mice><Mice Mammals><Micro Array Data><Modeling><Modern Man><Monkeys><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis H37Rv><Mycobacterium tuberculosis infection><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Pathogenesis><Pathology><Pathway interactions><Patients><Plasmids><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Probability><Process><Protocol><Protocols documentation><Pulmonary Alveoli><Pulmonary Diseases><Pulmonary Disorder><Pulmonary alveolar structure><Repression><Research><Risk><Scientist><Site><Spleen><Spleen Reticuloendothelial System><Supporting Cell><System><T cell response><T4 Cells><T4 Lymphocytes><TB infection><TB vaccine><Techniques><Testing><Time><Tissues><Tuberculosis><Tuberculosis Vaccines><Vaccine for TB><Vaccine for Tuberculosis><Vaccines><Virus-HIV><Whole Blood><adulthood><anti-TB vaccine><barcode><computer biology><conventional dosage><conventional dosing><data interpretation><design><designing><develop a vaccine><develop vaccines><development of a vaccine><dimension reduction><dimensionality reduction><disease of the lung><disorder of the lung><disseminated TB><disseminated tuberculosis><experiment><experimental research><experimental study><experiments><gene biomarker><gene expression biomarker><gene expression pattern><gene expression signature><gene marker><gene signature biomarker><gene signatures><genetic biomarker><genetic signature><graph theory><human disease><immunosuppressed patient><improved><in vivo><infection due to Mycobacterium tuberculosis><infection localized><innovate><innovation><innovative><insight><kids><local infection><lung alveolus><lung disorder><lung lobe><lung upper lobe><lymph gland><lymph nodes><lymphnodes><mRNA><mathematic model><mathematical model><mathematical modeling><model of animal><mortality><mtb><neutrophil><new marker><novel><novel biomarker><novel marker><pathogen><pathway><predictive signature><progression risk><pulmonary><pulmonary infections><reduce data dimension><reduce dimensionality><traditional dosage><traditional dosing><transcriptional profile><transcriptional signature><tuberculosis infection><tuberculous spondyloarthropathy><vaccine against M. tuberculosis><vaccine against Mtb><vaccine against Mycobacterium tuberculosis><vaccine against TB><vaccine against tuberculosis><vaccine candidates against tuberculosis><vaccine development><youngster>