Project Grant R24AI186591

A GLOBAL RESEARCH RESOURCE FOR HUMAN TUBERCULOSIS - ABSTRACT THERE IS A FUNDAMENTAL GAP IN OUR CURRENT UNDERSTANDING OF HOW MYCOBACTERIUM TUBERCULOSIS (MTB) CAUSES DISEASE IN THE HUMAN LUNG, AND SEVERAL REASONS ARE RESPONSIBLE FOR THIS LACK OF KNOWLEDGE. FIRSTLY, THE AVAILABILITY OF TUBERCULOUS HUMAN LUNG TISSUES PLUMMETED WITH THE INTRODUCTION OF ANTIBIOTICS IN THE 1940S AND 1950S. SECONDLY, TB RESEARCH USING ANIMALS RAPIDLY PROGRESSED AND NOVEL TECHNOLOGIES WERE APPLIED TO THESE MODEL SYSTEMS. HOWEVER, IT IS WELL KNOWN THAT NO ANIMAL MODEL REPRODUCES THE FULL SPECTRUM OF DISEASE AS IT OCCURS IN HUMANS, OR NATURALLY MEDIATES TRANSMISSION TO NEW HOSTS. NOT SURPRISINGLY, INTEREST IN HUMAN PULMONARY TB WAS REVIVED DECADES LATER WHEN IT WAS REALIZED THAT THE DISEASE HAD NEVER BEEN ERADICATED. DESPITE THIS, THERE ARE FEW STUDIES FOCUSED ON ELUCIDATING THE FUNDAMENTAL MECHANISMS OF ACTIVE, SUBCLINICAL, AND LATENT HUMAN TB, WHICH IS LIKELY DUE TO LIMITED ACCESS TO HUMAN TB LUNG TISSUE. WE BELIEVE THE TB FIELD CAN NO LONGER RELY ON ANIMAL MODELS THAT YIELD FINDINGS OF LIMITED CLINICAL RELEVANCE. THUS, THERE IS AN URGENT NEED TO BETTER UNDERSTAND HUMAN PULMONARY TB IN ORDER TO DEVELOP CLINICALLY RELEVANT THERAPEUTIC STRATEGIES. THE OVERALL GOAL OF THIS R24 PROPOSAL IS TO TRANSFORM THE GLOBAL LANDSCAPE OF TB RESEARCH BY ACCELERATING THE STUDY OF HUMAN TB TISSUE. WE WILL ACCOMPLISH THIS BY PROVIDING USER-REQUESTED SERVICES COMPRISED OF TWO COMPONENTS: (I) THE PATHOLOGICAL, CELLULAR, STRUCTURAL, AND/OR GENETIC ANALYSIS OF RESECTED HUMAN TB OR POSTMORTEM (PM) TISSUE AND (II), THE DISSEMINATION OF TISSUE TO THE GLOBAL TB RESEARCH COMMUNITY. WE HAVE SEVERAL UNIQUE ADVANTAGES SINCE AHRI, LOCATED IN DURBAN, SOUTH AFRICA, HAS ACCESS TO A CONTINUOUSLY GROWING COLLECTION OF ACTIVE TB/HIV AND PM SAMPLES, INCLUDING ENTIRE LUNGS/LOBES. THIS R24 PROPOSAL IS BUILT UPON SUBSTANTIAL PUBLISHED DATA FROM OUR GROUP THAT CLEARLY DEMONSTRATE OUR CAPACITY TO EXAMINE RESECTED AND PM LUNG TISSUE FROM MTB/HIV-INFECTED HUMAN SUBJECTS. THE RATIONALE FOR THIS PROPOSAL ARE (I) THAT BY PROVIDING THIS DEDICATED SERVICE TO THE TB RESEARCH COMMUNITY, NUMEROUS LABORATORIES WORLDWIDE WILL BE ABLE TO RAPIDLY ASCERTAIN THE CLINICAL RELEVANCE OF THEIR BASIC SCIENCE DISCOVERIES, WHICH WILL HELP REFINE THE FOCUS OF THEIR RESEARCH TO HAVE TRANSLATIONAL IMPACT, AND (II) OUR SERVICES WILL DRIVE THE DISCOVERY OF NEW HUMAN TB PARADIGMS, OR CHALLENGE EXISTING PARADIGMS, ULTIMATELY LEADING TO THE DEVELOPMENT OF CLINICALLY RELEVANT DIAGNOSTICS, ANTI-TB DRUGS, AND/OR VACCINES. THIS PROPOSAL IS SIGNIFICANT BECAUSE IT IS THE FIRST STEP IN A PROGRESSION OF INNOVATIVE SERVICES TO THE GLOBAL TB RESEARCH COMMUNITY THAT IS EXPECTED TO BOLSTER AND ACCELERATE TRANSLATIONAL AND CLINICAL RESEARCH TO EXPEDITE THE DISCOVERY OF INNOVATIVE NEW STRATEGIES TO IMPROVE DIAGNOSIS, PREVENTION, AND TREATMENT OF TB.