Tuberculosis

Listening to the lungs of a TB patient in South Africa

Listening to the lungs of a TB patient in South Africa

Tuberculosis, or TB, is an infectious bacterial disease caused by Mycobacterium tuberculosis, which most commonly affects the lungs. It is transmitted from person to person via droplets from the throat and lungs of people with the active respiratory disease. One third of the world’s population is believed infected with Mycobacterium tuberculosis. In 2011, 8.7 million people worldwide became infected with TB and 1.4 million died from the disease.

The Institute for Global Health & Infectious Diseases at UNC is committed to research and global leadership in the study of tuberculosis. We hope that our work is able to influence and develop evidence-based policies and standards to help inform tuberculosis prevention strategies, as well as to find a cure for the disease.

Clinical Research

China TB Clinical Trials Consortium (2013 –Present)

In partnership with FHI 360,  UNC is part of a multi-site, national clinical trials consortium dedicated to building research infrastructure for multinational clinical trial research collaboration in China. UNC experts will provide guidance and scientific input. Key UNC personnel include Joseph Tucker (infectious diseases), Linda Manor (pharmacy), Melissa Miller (pathology and laboratory medicine), and Annelies Van Rie (epidemiology).

Innovative approaches to integrate primary care for marginalized, at-risk populations in informal settlements in urban South Africa (2012 – 2016)

This USAID funded study will evaluate innovative approaches to primary care, including novel approaches to pediatric TB/HIV diagnosis, and intensified case finding for TB and HIV at clinic and community level. Contact: Annelies Van Rie

Optimizing the impact of Xpert MTB/RIF on treatment outcomes of drug resistant TB (2011-2014)

This NIH funded study will compare important patient outcomes of rifampicin resistant tuberculosis in patients diagnosed with drug resistant TB by culture-based method and the Xpert MTB/RIF assay. Xpert MTB/RIF is a novel TB diagnostic that is able to rapidly (within 2 hours) identify the presence of M tuberculosis and rifampicin drug resistance. The study is a collaboration between the University of the Witwatersrand, Johannesburg, South Africa and UNC. Contact: Annelies Van Rie

Optimal dosing of 1st line antituberculosis and antiretroviral drugs in children- a pharmacokinetic study (2011 – 2015)

This NIH funded study led by Dr Helen McIlleron of the University of Cape Town, will evaluate the 2010 WHO dosing recommendations for first line anti-tuberculosis drugs in HIV-infected and uninfected children in South Africa and Malawi. The study is a collaboration between the University of Cape Town, Malawi Wellcome Trust Clinical Research Center in Blantyre and UNC. Contact: Annelies Van Rie

Improving treatment for TB is a focus of UNC researchers.

Improving treatment for TB is a focus of UNC researchers.

Operational Research to Assess Impact of Routine Implementation of Xpert MTB/RIF (2011-2013)

This USIAD funded study will assess the use of Xpert in extrapulmonary tuberculosis (including disseminated tuberculosis, and tuberculosis of lymph nodes, pleura, central nervous system and the abdomen). The study will also assess the value of the Xpert assay at point of care and in rural areas with poor access to standard mycobacteriological laboratories.  The study is a collaboration between Right to Care, Johannesburg, South Africa and UNC. Contact: Annelies Van Rie

Impact of malnutrition on TB-IRIS and pharmacokinetics of TB and ARV cotreatment  (2008-2013)

This NIH funded cohort study in collaboration with the University of the Witwatersrand, Johannesburg, South Africa, aims to determine the incidence of paradoxical and unmasking TB IRIS in children, and studies the immunological pathogenesis of pediatric TB IRIS. In addition, a phase II dose finding study of Rifabutin when used concommitantly with protease inhibitors in young children is performed. Contact: Annelies Van Rie

Laboratory Research

The Braunstein Lab aims to understand the basic biology and pathogenesis of M. tuberculosis as a step toward developing new tuberculosis control and prevention strategies. M. tuberculosis is an intracellular pathogen able to survive and grow in macrophages. Our understanding of how M. tuberculosis subverts normal macrophage defenses and causes disease is limited. The proteins that M. tuberculosis exports to its bacterial cell surface or into the host environment are ideally positioned for host interactions and roles promoting growth in macrophages. As a way to better understand the virulence mechanisms of M. tuberculosis, the Braunstein Lab studies these exported proteins and the M. tuberculosis systems that export them.

The Abel Lab is exploring a novel pediatric combination HIV-TB vaccine in the infant macaque model of SIV infection.  HIV and TB infections greatly overlap in many regions of the world, and particularly in sub-Saharan Africa.  Infants are especially vulnerable to both diseases.  The only TB vaccine available, the live attenuated BCG, can cause disseminated BCG disease in HIV infected children that is associated with a 75% mortality rate.  Thus, a new TB vaccine is urgently needed and needs to be effective in infants at risk or already infected with HIV.  The lab has already demonstrated that an auxotroph M. tuberculosis strain is safe in immunosuppressed SIV infected neonatal macaques (Jensen, 2012).  Recently, they confirmed these findings in a larger study.  In addition, the lab demonstrated that an oral prime with attenuated M. tuberculosis-SIV followed by an intramuscular MVA-SIV regimen could induce immune responses to both SIV and M. tuberculosis antigens in infant macaques (Jensen, 2013).  The Abel lab in collaboration with researchers at the Albert Einstein College of Medicine in New York will continue these studies to further optimize this novel pediatric vaccine candidate.

Training

UMJT Fogarty Global Health Fellows Program

Doris Duke International Clinical Research Fellowship

Pathogenesis Training Program in Infectious Diseases

Who’s Involved

Annelies Van Rie

Kristina Abel

Mina Hosseinipour

Joe Tucker

Miriam Braunstein

Melissa Miller

Selected Recent Publications

Van Rie A, Patel M, Mbonze N, VandenDriessche K, Tabala M, Yotebieng M, Behets F.  Integration and task-shifting for TB/HIV care and treatment in highly resource-scarce settings: one size may not fit all. (JAIDS, in press).

Soeters HM, Poole, C, Patel M, Van Rie A. The effect of prevalent tuberculosis on mortality following combination antiretroviral therapy initiation: a systematic review and meta-analysis. (PlosOne, in press).

Conradie F, Mabiletsa T, Sefoka M, Mabaso S, Louw R, Evans D Van Rie A.  Prevalence and incidence of Symmetrical Symptomatic Peripheral Neuropathy in patients with Multidrug-Resistant TB (South African Medical Journal, in press).

Van Rie A, Scott L, McCarthy K, Dow A, Tellie, Venter F, Stevens W. Prevalence, risk factors and risk perception of tuberculosis infection among medical students and health care workers in Johannesburg, South Africa (South African Medical Journal, in press).

Soeters H, Napravnick S, Patel M, Eron J, Van Rie A. The effect of tuberculosis treatment on virologic and CD4 count response to combination antiretroviral therapy: a systematic review (AIDS, in press).

Henegar C, Behets F, Vanden Driessche K, Tabala M, Van Rie A. Impact of HIV on clinical presentation and outcome of tuberculosis treatment at primary care level in Kinshasa, Democratic Republic of the Congo (International Journal of Tuberculosis and Lung Disease, in press).

Patel MR, Yotebieng M, Behets F, Vanden Driessche K, Nana M, Van Rie A. Outcomes of integrated treatment for tuberculosis and HIV in children at the primary health care level (The International Journal of Tuberculosis and Lung Disease, 2013).

Van Rie A, Page-Shipp L, Mellet K, Scott L, Mkhwnazi M, Jong E, et al. Diagnostic accuracy and effectiveness of the Xpert MTB/RIF assay for the diagnosis of HIV-associated lymph node tuberculosis (European Journal of Clinical and Microbiology and Infectious Diseases, 2013).

Van Rie A, Page-Shipp L, Hanrahan CF, Schnippel K, Dansey H, et al. Point-of-care Xpert® MTB/RIF for smear-negative tuberculosis suspects at a primary care clinic in South Africa (The International Journal of Tuberculosis and Lung Disease, 2013).

Allen IC, McElvania-TeKippe E, Wilson JE, Lich JD, Arthur JC, Sullivan JT, Braunstein M, et al. Characterization of NLRP12 during the in vivo host immune response to Klebsiella pneumoniae and Mycobacterium tuberculosis (PLoS One, 2013).

Trott KA, Richardson A, Hudgens MA, Abel K. Immune activation and regulation in simian immunodeficiency virus-Plasmodium fragile-coinfected rhesus macaques (Journal of Virology, 2013).

Gunawardena HP, Feltcher ME, Wrobel JA, Gu S, Braunstein M, Chen X. Comparison of the Membrane Proteome of Virulent Mycobacterium tuberculosis and the Attenuated Mycobacterium bovis BCG Vaccine Strain by Label-free Quantitative Proteomics (Journal of Proteom Research, 2013).

Sullivan JT, Young EF, McCann JR, Braunstein M. The Mycobacterium tuberculosis SecA2 system subverts phagosome maturation to promote growth in macrophages (Infection and Immunity, 2013).

Fenner L, Reid SE, Fox MP, Garone D, Wellington M, Prozesky H, et al. Tuberculosis and the risk of opportunistic infections and cancers in HIV-infected patients starting ART in Southern Africa (Journal for Tropical Medicine and International Health, 2013).

Topp SM, Chipukuma JM, Chiko MM, Matongo E, Bolton-Moore C, Reid SE. Integrating HIV treatment with primary care outpatient services: opportunities and challenges from a scaled-up model in Zambia (Health Policy Planning, 2013).

Jensen K, dela Pena MG, Wilson RL, Ranganathan UDK, Jacobs Jr. WR, et al. A neonatal oral Mycobacterium tuberculosis-SIV prime/ intramuscular MVA-SIV boost combination vaccine induces both SIV and M. tuberculosis-specific immune responses in infant macaques (Trials in Vaccinology, 2013).

Voss De Lime Y, Evans D, Page-Shipp L, Barnard A, Sanne I, Menezes CN, Van Rie A. Linkage to TB and HIV care and treatment following referral from a hospital-based TB focal point. (PLoS One, 2013.)

Jong E, Sanne I, Van Rie A, Menezes C. A hospital-based tuberculosis focal point to improve tuberculosis care in a very high burden setting (Public Health Action. 2013).

Ligon LS, Rigel NW, Romanchuk A, Jones CD, Braunstein M. Suppressor analysis reveals a role for SecY in the SecA2-dependent protein export pathway of Mycobacteria (Journal of Bacteriology, 2013).

Hayden JD, Brown LR, Gunawardena HP, Perkowski EF, Chen X, Braunstein M. Reversible acetylation regulates acetate and propionate metabolism in Mycobacterium smegmatis (Journal of Bacteriology, 2013).

Feltcher ME, Gibbons HS, Ligon LS, Braunstein M. Protein export by the mycobacterial SecA2 system is determined by the preprotein mature domain (Journal of Bacteriology, 2013).

Van Rie A,  Page-Shipp L, Harrahan C, Bistline K, Dansey H, Bassett J, Clouse K, Scott L, Stevens W, Sanne I. Point-of-care Xpert MTB/RIF for smear-negative tuberculosis suspects at a primary care clinic in South Africa. (International Journal of Tuberculosis and Lung Disease, 2013).

Jensen K, Ranganathan UD, Van Rompay KK, Canfield DR, Khan I, Ravindran R, Luciw PA, Jacobs WR Jr, Fennelly G, Larsen MH, Abel K. A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed simian immunodeficiency virus-infected infant macaques (Clinical Vaccine Immunology, 2012).

Vorkas C, Kayira D, van der Horst C, Hoffman I, Hosseinipour M, et al. Tuberculosis Drug Resistance and Outcomes among Tuberculosis Inpatients in Lilongwe, Malawi (Malawi Medical Journal: the journal of Medical Association of Malawi, 2012).

Henegar C, Behets F, Vanden Driessche K, Tabala M, Bahati E, Bola V, Van Rie A. Mortality among tuberculosis patients in the Democratic Republic of Congo (The International Journal of Tuberculosis and Lung Disease, 2012).

Ligon LS, Hayden JD, Braunstein M. The ins and outs of Mycobacterium tuberculosis protein export(Tuberculosis, 2012).