Immune Responses to the Mycobacterium tuberculosis -Specific Antigen ESAT-6 Signal Subclinical Infection among Contacts of Tuberculosis Patients

Abstract

Diagnosis of latentMycobacterium tuberculosis infection is considered essential for tuberculosis control but is hampered by the lack of specific reagents. We report that strong recognition of tuberculosis complex-specific antigen ESAT-6 by healthy household contacts of tuberculosis patients correlates with the subsequent development of active tuberculosis during a 2-year follow-up period.In the next year tuberculosis (TB) is expected to be responsible for more than 2 million deaths and up to 8 million new infections (11). Latently or subclinically infected individuals continually arise as new foci of infection, but the identification of infected individuals for treatment is extremely difficult, as it is based on intradermal injection of purified protein derivative (PPD). Unfortunately, PPD contains many antigens widely shared among mycobacteria, and the specificity of this reagent is therefore low. Several studies have demonstrated that PPD cannot reliably distinguish between previous Mycobacterium bovis BCG vaccination, exposure to environmental mycobacteria, or infection with M. tuberculosis (4,6,7). That the PPD skin test remains in use despite these limitations reveals the urgent need for better diagnostic tests for TB.Recently, genes which are deleted from BCG have been identified (2), and some of these also appear to be absent from most environmental mycobacteria. One such antigen, ESAT-6, has shown promising results for use as an immunodiagnostic reagent (1). Recent studies with humans have found that a test based on the detection of ESAT-6-specific T cells via their production of gamma interferon (IFN-␥) ex vivo specifically discriminates between M. tuberculosis infection and exposure to other mycobacteria (8,9,12).In the present study, healthy household contacts of sputumpositive TB patients were recruited from Hossana Regional Hospital, Hossanna, Ethiopia. The presence of active TB in all contacts at the time of entry into the study was excluded by radiological and clinical examinations and by sputum microscopy and culture, as described previously (5). Blood samples were obtained from all contacts at the time of entry into the study and were analyzed for in vitro responses to PPD and ESAT-6. The contacts were assessed again approximately 2 years after the first visit. On the second visit, the contacts received the same clinical and laboratory examinations for TB as they had previously.At follow-up, 12 of the 24 contacts (50%) were classified as "remaining healthy." They had no symptoms of TB and no lesions or other suspicious findings visible on X ray. Five of these contacts were sputum negative by microscopy and culture, while the remaining seven were unable to produce sputum.Of the remaining 12 contacts, 7 (29%) were found to have developed active TB on the basis of the presence of characteristic symptoms and findings on X rays (extensive infiltration of the lungs, calcification or lesions). For two of the contacts, the diagnosis of TB was confirmed by culture and/or microscopy, for one contact the r...

Humoral response to low molecular weight antigens of Mycobacterium tuberculosis by tuberculosis patients and contacts

“…The antigen possesses various specific T-cell epitopes that induce a cellular response and lead to increased interferon γ production in patients with subclinical or active tuberculosis but not in unexposed healthy individuals (13). This cell-mediated response has also been associated with increased risk of disease (30). A recent study showed that the humoral response to ESAT-6 may be associated with inactive tuberculosis but not with active tuberculosis (31).…”

Alteration of epitope recognition pattern in Ag85B and ESAT‐6 has a profound influence on vaccine‐induced protection against Mycobacterium tuberculosis

“…These data provide the first clear indication of why this may occur. It has an important implication for human TB as well: deviation of the immune response into an unproductive pathway may explain why infected individuals can progress to clinical TB even though they make a strong IFN-c response against M. tuberculosis antigens [38]. …”

LTBI: latent tuberculosis infection or lasting immune responses toM. tuberculosis? A TBNET consensus statement

“…Others recommend that IGRAs completely replace the tuberculin skin test for identifying latent infection [85]. Today, some data from prospective studies are now emerging that look at the risk of tuberculosis in those with a positive IGRA [86,88,121,122].…”