A5038934486- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Infectious Diseases and Tuberculosis
- Xenotransplantation and immune response
- Immune responses and vaccinations
- Immune Cell Function and Interaction
- Immunodeficiency and Autoimmune Disorders
- T-cell and B-cell Immunology
- Animal Genetics and Reproduction
- Immune Response and Inflammation
- Cardiac Arrest and Resuscitation
- Tracheal and airway disorders
- Virus-based gene therapy research
- Thermal Regulation in Medicine
- HIV Research and Treatment
- Pluripotent Stem Cells Research
- Microscopic Colitis
- Veterinary Oncology Research
- Immunotherapy and Immune Responses
- Diagnosis and treatment of tuberculosis
- Clostridium difficile and Clostridium perfringens research
- Veterinary medicine and infectious diseases
- SARS-CoV-2 and COVID-19 Research
- Tissue Engineering and Regenerative Medicine
- Organ Transplantation Techniques and Outcomes
University of Pittsburgh
2015-2025
Vanderbilt University Medical Center
2025
The University of Texas Health Science Center at Houston
2023
University of Pittsburgh Medical Center
2015
Laerdal (Norway)
2004
United States Army
2004
Ashland (United States)
2004
UPMC Hillman Cancer Center
1988-1999
UPMC Presbyterian
1987-1993
Wilford Hall Ambulatory Surgical Center
1993
ABSTRACT Understanding the physical characteristics of local microenvironment in which Mycobacterium tuberculosis resides is an important goal that may allow targeting metabolic processes to shorten drug regimens. Pimonidazole hydrochloride (Hypoxyprobe) imaging agent bioreductively activated only under hypoxic conditions mammalian tissue. We employed this probe evaluate oxygen tension tuberculous granulomas four animal models disease: mouse, guinea pig, rabbit, and nonhuman primate....
Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide
Nonhuman primates were used to develop an animal model that closely mimics human Mycobacterium tuberculosis infection. Cynomolgus macaques infected with low doses of virulent M. via bronchoscopic instillation into the lung. All monkeys successfully infected, based on tuberculin skin test conversion and peripheral immune responses antigens. Progression infection in 17 studied was variable. Active-chronic infection, observed 50 60% monkeys, characterized by clear signs or disease serial...
We previously described that low-dose Mycobacterium tuberculosis infection in cynomolgus macaques results a spectrum of disease similar to human infection: primary disease, latent infection, and reactivation (S. V. Capuano III, D. A. Croix, S. Pawar, Zinovik, Myers, P. L. Lin, Bissel, C. Fuhrman, E. Klein, J. Flynn, Infect. Immun. 71:5831-5844, 2003). This is the only established model it provides unique opportunity understand host pathogen differences across range states. Here, we provide...
Abstract CD4 T cells are important in the protective immune response against tuberculosis. Two mouse models deficient were used to examine mechanism by which these participate protection Mycobacterium tuberculosis challenge. Transgenic mice either MHC class II or molecules demonstrated increased susceptibility M. tuberculosis, compared with wild-type mice. II−/− more susceptible than CD4−/− mice, as measured survival following challenge, but relative resistance of did not appear be due...
Abstract Macrophages in granulomas are both antimycobacterial effector and host cell for Mycobacterium tuberculosis, yet basic aspects of macrophage diversity function within the complex structures remain poorly understood. To address this, we examined myeloid phenotypes expression enzymes correlated with defense macaque human granulomas. Macaque had upregulated inducible endothelial NO synthase (iNOS eNOS) arginase (Arg1 Arg2) enzyme activity compared nongranulomatous tissue....
It is estimated that one-third of the world's population infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, bovis bacillus Calmette-Guérin (BCG), largely ineffective, and ways enhance its efficacy are being developed. Of note, candidate booster vaccines currently under development have been designed improve BCG not prevent reactivation latent infection. Here, we demonstrate administering a...
Genetically engineered pigs could provide a source of kidneys for clinical transplantation. The two longest kidney graft survivals reported to date have been 136 and 310 days, but survival >30 days has unusual until recently.
Abstract The longest survival of a non‐human primate with life‐supporting kidney graft to date has been 90 days, although > 30 days unusual. A baboon received from an α‐1,3‐galactosyltransferase gene‐knockout pig transgenic for two human complement‐regulatory proteins and three coagulation‐regulatory (although only one was expressed in the kidney). Immunosuppressive therapy ATG +anti‐ CD 20mAb (induction) anti‐ 40mAb+rapamycin+corticosteroids (maintenance). Anti‐ TNF ‐α IL ‐6R were...
Mycobacterium tuberculosis lung infection results in a complex multicellular structure: the granuloma. In some granulomas, immune activity promotes bacterial clearance, but others, bacteria persist and grow. We identified correlates of control cynomolgus macaque granulomas by co-registering longitudinal positron emission tomography computed imaging, single-cell RNA sequencing, measures clearance. Bacterial persistence occurred enriched for mast, endothelial, fibroblast, plasma cells,...
Tuberculosis (TB) is a major health burden worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the route and dose from 5 × 105 CFUs ID to 107 i.v. resulted prevention of Mycobacterium tuberculosis (Mtb) infection TB disease highly susceptible nonhuman primates. Identifying immune mechanisms protection following will facilitate development more effective vaccines against TB. Here, we depleted lymphocyte subsets prior during Mtb...
Little is known regarding the early events of infection humans with Mycobacterium tuberculosis. The cynomolgus macaque a useful model tuberculosis, strong similarities to human In this study, eight macaques were infected bronchoscopically low-dose M. tuberculosis; clinical, immunologic, microbiologic, and pathologic assessed 3 6 weeks postinfection. Gross pathological abnormalities observed as weeks, including Ghon complex formation by 5 Caseous granulomas in lung 4 Only caseous lungs at...
An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor alpha (TNFalpha)-neutralizing agents. In murine models, impaired signaling by TNF causes exacerbation both acute and chronic infection associated aberrant granuloma formation maintenance. This study was undertaken to investigate immune modulation the setting neutralization primary latent a non-human primate model.Cynomolgus macaques 4 years age or older were infected Mycobacterium subjected...
Trials to test new drugs currently in development against tuberculosis humans are impractical. All animal models prioritize regimens imperfect, but nonhuman primates (NHPs) infected with Mycobacterium develop active (TB) disease a full spectrum of lesion types seen humans. Serial 2-deoxy-2-[18F]-fluoro-d-glucose (FDG) positron emission tomography (PET) computed (CT) imaging was performed on cynomolgus macaques during infection and chemotherapy individual agents or the four-drug combination...
HIV-infected individuals with latent Mycobacterium tuberculosis (Mtb) infection are at significantly greater risk of reactivation (TB) than HIV-negative TB, even while CD4 T cell numbers well preserved. Factors underlying high rates poorly understood and investigative tools limited. We used cynomolgus macaques TB co-infected SIVmac251 to develop the first animal model reactivated in humans better explore these factors. All animals developed following SIV infection, a variable time (up 11...
CD4 T cells are believed to be important in protection against Mycobacterium tuberculosis, but the relative contribution control of initial or latent infection is not known. Antibody-mediated depletion M. tuberculosis-infected cynomolgus macaques was used study role during acute and infection. Anti-CD4 antibody severely reduced levels blood, airways, lymph nodes. Increased pathology bacterial burden were observed CD4-depleted monkeys first 8 weeks compared controls. had greater interferon...
Vaccines are urgently needed to combat the global coronavirus disease 2019 (COVID-19) pandemic, and testing of candidate vaccines in an appropriate non-human primate (NHP) model is a critical step process. Infection African green monkeys (AGM) with low passage human isolate SARS-CoV-2 by aerosol or mucosal exposure resulted mild clinical infection transient decrease lung tidal volume. Imaging clinical-grade 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) co-registered...
ABSTRACT Cynomolgus macaques infected with low-dose Mycobacterium tuberculosis develop both active and latent infection similar to those of humans, providing an opportunity study the clinically silent early events in infection. 18 Fluorodeoxyglucose radiotracer positron emission tomography coregistered computed (FDG PET/CT) provides a noninvasive method measure disease progression. We sought determine temporal patterns granuloma evolution that distinguished active-disease outcomes. Macaques...
PET/CT imaging in macaques and humans with TB shows a beneficial therapeutic response to linezolid new oxazolidinone antibiotic, AZD5847.
Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential shorten therapy for active (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. infection, equal proportions cynomolgus macaques develop disease or infection latently infected animals reactivated neutralization TNF. Using this model we now show chemoprophylaxis with 6 mo isoniazid (INH) effectively...
Mycobacterium tuberculosis infection presents across a spectrum in humans, from latent to active tuberculosis. Among those with tuberculosis, it is now recognized that there also of and this likely contributes the variable risk reactivation Here, functional imaging 18F-fluorodeoxygluose positron emission tomography computed (PET CT) cynomolgus macaques M. was used characterize features after tumor necrosis factor (TNF) neutralization determine which characteristics before TNF distinguish...
Abstract Background Three costimulation blockade‐based regimens have been explored after transplantation of hearts from pigs varying genetic backgrounds to determine whether CTLA 4‐Ig (abatacept) or anti‐ CD 40mAb+ (belatacept) can successfully replace 154mAb. Methods All were on an α1,3‐galactosyltransferase gene‐knockout/ 46 transgenic ( GTKO . 46) background. Hearts transplanted into Group A baboons (n = 4) expressed additional 55, and those B 3) human thrombomodulin TBM )....
The aims of this study were to evaluate the efficacy US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation compare results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen.Ten life-supporting transplants carried out baboons α1,3-galactosyltransferase gene-knockout/CD46 pigs various other genetic manipulations aimed at controlling coagulation dysregulation. Eight resulted informative data. Immunosuppressive...