This is a revised application from Jacqueline Achkar, M.D., who is an Assistant Professor in Medicine at the Albert Einstein College of Medicine. Her long-term goal is to become an independent investigator in clinical translational research related to tuberculosis (TB), HIV, and their occurrence as co-infections. The proposed career development plan will provide her with in-depth training in clinical research methods, immunology, molecular techniques, epidemiology, decision-making analysis and biostatistics. TB is a global leading public health problem and the leading cause of death in people with AIDS. There is an urgent need for early and accurate diagnosis of pulmonary TB (PTB) to achieve the CDC goal of elimination of TB in the US, improve TB control worldwide, and identify and treat active TB before development of advanced disease. Currently, there are no rapid tests with high sensitivity and specificity available for the diagnosis of all classes of active TB. The candidate proposes to examine the accuracy and clinical value of antibody detection to two immunodominant proteins of M. tb for the rapid diagnosis of PTB. The central hypothesis of this proposal is that antibody responses to these two proteins contain sufficient information to provide an accurate serodiagnostic test for PTB relative to an accepted gold standard. This test can serve as an useful adjunct to enhance the sensitivity of conventional rapid tests for PBT.
The specific aims of this project are: (1) To assess the sensitivity, specificity and clinical value of the protein-based ELISA;(2) To determine total immunoglobulin (Ig) concentrations and titers of Ig isotypes and IgG subclasses to the two proteins, and compare them between HIV-infected and HIV-uninfected PTB patients;and (3) To test whether newly identified antigens of M. tb will enhance the sensitivity of the protein-based ELISA without compromising its specificity. This will be a prospective study. Consecutive adult patients (n=500) undergoing clinical evaluation for PTB will be enrolled from several hospital sites in New York City over a period of two years;125/500 (25%) are expected to have TB by gold standard, and 40% of the enrolled patients are expected to be HIV-infected. The results of serum antibody reactivity to the immunodominant proteins of M. tb will be compared to the gold standard of culture, histological or clinically proven PTB. Specificity will be assessed in 200 randomly selected culture-negative subjects who are diagnosed with a pulmonary disease other than PTB.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Mentored Patient-Oriented Research Career Development Award (K23)
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Microbiology and Infectious Diseases B Subcommittee (MID)
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Jacobs, Gail G
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Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Liu, Yanyan; Ndumnego, Okechukwu C; Chen, Tingting et al. (2018) Soluble CD14 as a Diagnostic Biomarker for Smear-Negative HIV-Associated Tuberculosis. Pathogens 7:
Goldman, David L; Nieves, Edward; Nakouzi, Antonio et al. (2018) Serum-Mediated Cleavage of Bacillus anthracis Protective Antigen Is a Two-Step Process That Involves a Serum Carboxypeptidase. mSphere 3:
Achkar, Jacqueline M; Cortes, Laetitia; Croteau, Pascal et al. (2015) Host Protein Biomarkers Identify Active Tuberculosis in HIV Uninfected and Co-infected Individuals. EBioMedicine 2:1160-8
Chan, John; Mehta, Simren; Bharrhan, Sushma et al. (2014) The role of B cells and humoral immunity in Mycobacterium tuberculosis infection. Semin Immunol 26:588-600
Siev, Michael; Wilson, Douglas; Kainth, Supreet et al. (2014) Antibodies against Mycobacterial proteins as biomarkers for HIV-associated smear-negative tuberculosis. Clin Vaccine Immunol 21:791-8
Achkar, Jacqueline M; Chan, John; Casadevall, Arturo (2014) Role of B cells and antibodies in acquired immunity against Mycobacterium tuberculosis. Cold Spring Harb Perspect Med 5:a018432
Helbig, S; Achkar, J M; Jain, N et al. (2013) Diagnosis and inflammatory response of patients with candiduria. Mycoses 56:61-9
Ziegenbalg, Anke; Prados-Rosales, Rafael; Jenny-Avital, Elisabeth R et al. (2013) Immunogenicity of mycobacterial vesicles in humans: identification of a new tuberculosis antibody biomarker. Tuberculosis (Edinb) 93:448-55
Achkar, Jacqueline M; Casadevall, Arturo (2013) Antibody-mediated immunity against tuberculosis: implications for vaccine development. Cell Host Microbe 13:250-62
Achkar, Jacqueline M; Ziegenbalg, Anke (2012) Antibody responses to mycobacterial antigens in children with tuberculosis: challenges and potential diagnostic value. Clin Vaccine Immunol 19:1898-906

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