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Principal Investigator: JoAnne L. Flynn
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $739,545
Funding agency: National Institute of Allergy and Infectious Diseases
Despite major advances in global health care, there were an estimated 1.5 millions deaths and 10 million new
cases of tuberculosis (TB) in 2018. Nearly 1 million people living with HIV developed tuberculosis (TB). Co-
infection with HIV and TB is associated with high morbidity and mortality and treatment with TB drugs and anti-
retroviral (ART) therapy is now universally available. TB drug treatment followed by ART improves long term
survival, particularly among those whose immune systems are severely suppressed from HIV infection. Signs
and symptoms of disease improve soon after treatment is started but, in many cases, disease can recur and
appear clinically worse as the immune system is being re-established from ART. This is known as TB-
associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and is more common among patients
with severely suppressed immune systems before treatment and those who have a short time interval between
starting TB treatment and ART. Very little is known about how or why TB-IRIS occurs and how to best to treat
or even prevent it. We hypothesize that symptoms of TB-IRIS are driven by the dynamic interaction between
the immune system, Mycobacterium tuberculosis (Mtb, the bacteria that causes TB) and HIV deep within
infected tissues in the body such as the lung granuloma. Virtually nothing is known about what happens in the
tissues where both Mtb and HIV interact during TB-IRIS. This proposal will develop an animal model of TB-
IRIS by taking advantage of our pre-existing model of HIV-TB co-infection in which animals with SIV-Mtb co-
infection undergo TB drug treatment and ART just like humans. We will use sophisticated imaging,
immunology and microbiologic tools to better understand how and why TB-IRIS develops and what factors can
predict its emergence. Aim 1 will determine how often TB-IRIS occurs in this model and to what extent Mtb and
SIV remain in the tissues during treatment. We will also perform a detailed examination of the changes that
occur in the tissues but especially the lungs (granulomas) and lymph nodes through serial in vivo images to
better understand the events that lead to TB-IRIS and its predictors. In Aim 2, we will perform a detailed
examination of the immunologic events in the tissues and blood during TB-IRIS. Tissue specific (lung
granulomas and lymph nodes) immune responses will be correlated with the amount of Mtb bacteria and virus
with the imaging findings so that we can better understand the causes of TB-IRIS. Our short term goal is to
better understand the pathogenesis of TB-IRIS in this proposal and these findings will ultimately lead to better
treatment and prevention of TB-IRIS which is our long term goal.
Terms: <1, 2-Dehydrocortisone><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adverse effects><After Care><After-Treatment><Aftercare><Animal Model><Animal Models and Related Studies><Animals><Anti-Retroviral Agents><Antitubercular Agents><Antitubercular Drugs><Autopsy><Bacteria><Biological><Blood><Blood Plasma><Blood Reticuloendothelial System><Body Tissues><CD4 Lymphocyte Count><CD4+ Cell Counts><CD4+ Counts><Cell Body><Cells><Cellular Immune Function><Cessation of life><Characteristics><Clinical><Collaborations><Complex><Country><Data><Death><Dehydrocortisone><Delta(1)-Cortisone><Deltacortisone><Deltadehydrocortisone><Development><Diagnostic Findings><Disease><Disorder><Drug Therapy><Drugs><Early treatment><Event><Goals><Granuloma><Granulomatous Lesion><HIV><HIV Infections><HIV/Mtb><HIV/TB><HIV/mycobacterium tuberculosis><HIV/tuberculosis><HTLV-III Infections><HTLV-III-LAV Infections><Healthcare><Heterogeneity><Hospital Admission><Hospitalization><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Image><Immune><Immune response><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Improve Access><Incidence><Infection><Inflammation><Inflammatory><Investigators><Knowledge><LAV-HTLV-III><Lung><Lung Granuloma><Lung Respiratory System><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic nodes><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M. tuberculosis/HIV><M.tb infection><M.tuberculosis infection><MTB infection><Measures><Medical Research><Medication><Metacortandracin><Mission><Modality><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><Nature><PET/CT><PET/CT scan><Pathogenesis><Pathology><Patients><Persons><Pharmaceutical Preparations><Pharmacotherapy><Plasma><Plasma Serum><Prednisone><Prednisonum><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Process><Radiography><Recurrence><Recurrent><Research Infrastructure><Research Personnel><Research Resources><Researchers><Resources><Reticuloendothelial System, Serum, Plasma><Risk><Roentgenography><SIV><Signs and Symptoms><Simian Immunodeficiency Viruses><Site><Symptoms><Syndrome><T4 Lymphocyte Count><TB drugs><TB infection><TB therapy><TB treatment><Technology><Therapeutic><Time><Tissues><Tuberculosis><Tuberculostatic Agents><United States National Institutes of Health><Vaccines><Virus><Virus-HIV><adaptive immune response><anti-TB><anti-TB drugs><anti-retroviral><anti-tuberculosis><anti-tuberculosis drugs><antiTB><antiretroviral therapy><antiretroviral treatment><biologic><biological heterogeneity><biomarker identification><clinical predictors><co-infection><coinfection><compare to control><comparison control><death risk><delta-Cortisone><developmental><disease model><disorder model><disseminated TB><disseminated tuberculosis><drug treatment><drug/agent><early therapy><global health><health care><high risk><host response><human disease><human model><identification of biomarkers><identification of new biomarkers><imaging><imaging in vivo><immune function><immune reconstitution><immune system response><immunoresponse><improved><in vivo imaging><infection due to Mycobacterium tuberculosis><insight><lymph gland><lymph nodes><lymphnodes><marker identification><model of animal><model of human><mortality><mortality risk><mtb><necropsy><new technology><non-human primate><nonhuman primate><novel technologies><pathogen><positron emission computed tomography><post treatment><postmortem><prevent><preventing><programs><pulmonary><pulmonary granuloma><radiologic imaging><radiological imaging><response><synergism><time interval><tool><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><tuberculosis drugs><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><virtual>