Abstract
The level of bacterial activity is only poorly defined during asymptomatic Mycobacterium tuberculosis (MTB) infection. The objective was to study the capacity of a new biomarker, the expression of the T cell maturation marker CD27 on MTB-specific CD4 T cells, to identify active tuberculosis (TB) disease in subjects from a MTB and HIV endemic region. The frequency and CD27 expression of circulating MTB-specific CD4 T cells was determined in 96 study participants after stimulation with purified protein derivative (PPD) using intracellular cytokine staining for IFNgamma (IFNγ). Subjects were then stratified by their TB and HIV status. Within PPD responders, a CD27− phenotype was associated with active TB in HIV− (p = 0.0003) and HIV+ (p = 0.057) subjects, respectively. In addition, loss of CD27 expression preceded development of active TB in one HIV seroconverter. Interestingly, in contrast to HIV− subjects, MTB-specific CD4 T cell populations from HIV+ TB-asymptomatic subjects were often dominated by CD27− cells. These data indicate that down-regulation of CD27 on MTB-specific CD4 T cell could be used as a biomarker of active TB, potentially preceding clinical TB disease. Furthermore, these data are consistent with the hypothesis that late, chronic HIV infection is frequently associated with increased mycobacterial activity in vivo. The analysis of T cell maturation and activation markers might thus be a useful tool to monitor TB disease progression.
Highlights
Tuberculosis (TB) is amongst the most frequent causes of death from infection in humans, accounting for an estimated 1.8 million deaths annually (WHO TB Factsheet, 2009) and frequently affects immunocompromised patients co-infected with the human immunodeficiency virus-1 (HIV)
Our results indicated that monitoring CD27 expression on Mycobacterium tuberculosis (MTB)-specific CD4 T cells could be used as a biomarker of active TB in HIV2 and HIV+ subjects, potentially proceeding active TB
Active TB was associated with detectable PPDspecific CD4 T cell responses; 80% of active TB/HIV2 subjects (8/10) and 89% of active TB/HIV+ subjects (16/18) had detectable purified protein derivative (PPD)-specific CD4 T cell responses
Summary
Tuberculosis (TB) is amongst the most frequent causes of death from infection in humans, accounting for an estimated 1.8 million deaths annually (WHO TB Factsheet, 2009) and frequently affects immunocompromised patients co-infected with the human immunodeficiency virus-1 (HIV). In MTB endemic regions, up to 50% of HIV-infected individuals will eventually develop active TB in the absence of antiretroviral therapy [1]. In HIV-infected subjects, TB progresses rapidly and is characterized by a high mortality if left untreated [2]. Diagnosis of active TB is usually based on characteristic X-ray findings, clinical symptoms, tuberculin skin test (TST) and positive sputum-smear microscopy or culture results. In HIV-infected patients TB diagnosis is hampered by lower bacillary load in sputum [3] during pulmonary TB and reduced delayed type hypersensitive reactions during the TST [4]. There is no reliable test to rapidly diagnose and monitor MTB activity in patients at high risk of developing clinical disease such as HIV-infected patients or children
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