Mycobacterium tuberculosis (Mtb) infects one-third of the world?s population and causes almost 1.3 million deaths per year, including 100, 000 children. Approximately 90% of infected persons have latent tuberculosis infection (LTBI), have protective immunity and remain well, but 10% develop primary tuberculosis (TB) soon after infection or reactivation TB many years later. Children are more susceptible to TB infection, due to an immature immune system. HIV infection in children markedly increases susceptibility to TB, and HIV-infected persons with LTBI have an 800-fold greater risk of developing active TB (www.cdc.gov/tb/). TB is the leading cause of death in HIV-infected persons and more than half a million coinfected people die annually. To develop adequate prophylaxis or therapy, it is important to understand immune responses to Mtb. Identification of HIV+ children with LTBI who are at greatly increased risk for development of TB would allow treating only high-risk children, facilitating completion of therapy for LTBI and preventing future development of TB. To identify these children, it is important to pinpoint the nature of the defective immune responses that permit development of active TB in HIV+LTBI+ pediatric patients. Over the past 18 years, we have published a series of articles demonstrating that human NK cells have the potential to contribute to both innate and adaptive immune responses to Mtb. Our recently published studies demonstrate that memory-like NK cells contribute to vaccine-induced protective immunity against Mtb and IL-21 is required for expansion of memory-like NK cells in both humans and mice. Based on our published studies, we hypothesize that HIV-LTBI+ children household contacts have defective memory-like NK cell expansion compared to HIV-LTBI+ adult household contacts and these defects are more severe in HIV+ LTBI+ children. The proposed studies in the current application will be performed in India as a part of RePORT-India consortium. This study will leverage the large Indo-US investment and TB/HIV research consortium of RePORT-India which has developed cohorts of TB cases and household contacts in India and has paired Indian investigators with US investigators at 6 sites. Already collected samples will be used for the proposed studies in aim 1.
Our specific aims are: 1. Determine Mtb specific memory-like NK cell responses of children in a large group of household contacts of TB patients. 2.Compare the memory-like NK cell responses of HIV+ and HIV- children with LTBI. 3. Determine whether KIR haplotypes and HLA polymorphism is associated with expansion of memory-like NK cells in children.
Mycobacterium tuberculosis (Mtb) infects one-third of the world?s population and causes almost 1.3 million deaths per year, including 100, 000 children. Approximately 90% of infected persons have latent tuberculosis infection (LTBI), have protective immunity and remain well, but 10% develop primary tuberculosis (TB) soon after infection or reactivation TB many years later. TB is the leading cause of death in HIV-infected persons and more than half a million coinfected people die annually. Children are more susceptible to TB infection, due to an immature immune system. HIV infection in children markedly increases susceptibility to TB. To develop adequate prophylaxis or therapy, it is important to understand immune responses to Mtb. Identification of HIV+ children with LTBI who are at greatly increased risk for development of TB would allow treating only high-risk children, facilitating completion of therapy for LTBI and preventing future development of TB. To identify these children, it is important to pinpoint the nature of the defective immune responses that permit development of active TB in HIV+LTBI+ pediatric patients. This proposal will identify a novel memory-like NK cell subpopulation mediated mechanisms that regulate immune responses and pinpoint the nature of the defective responses that permit development of active TB in HIV-LTBI+ and HIV+LTBI+ children. These studies will lay the groundwork for strategies to develop novel anti-tuberculosis vaccines that stimulate strong NK cell mediated immunity in HIV+ and HIV- children with LTBI, and reduce development of TB.
