Lack of Immune Responses to Mycobacterium tuberculosis DosR Regulon Proteins following Mycobacterium bovis BCG Vaccination

Abstract

Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis (TB),Tuberculosis (TB) remains a major global health threat. Each year, about eight million new TB cases occur and two million people die from TB. It is estimated that one-third of the world population is latently infected with Mycobacterium tuberculosis. From this vast latent reservoir, about 10% of infected people are expected to develop overt TB disease during their lifetimes. However, with the expanding human immunodeficiency virus type 1-AIDS pandemic, this number is expected to soar in the next few decades (11, http://www.who.int /mediacentre/factsheets/fs104/en/).The current TB vaccine is the live attenuated bacterium Mycobacterium bovis Bacillus Calmette-Guérin (BCG). BCG is known to protect against severe forms of TB in young children and against leprosy. However, it does not efficiently and consistently protect against pulmonary TB in adults, the most prevalent and contagious form of TB; BCG also does not offer protection from reactivation of latent TB infection. This partly explains why BCG has little impact on the global TB epidemic despite its widespread use as a prophylactic TB vaccine (http: //www.who.int/wer/2004/en/wer7904.pdf). Over the years, many hypotheses have been put forward to explain the apparent variability in the protective efficacy of BCG, which varies from 0 to 80% (16). Explanations for this inconsistency include differences in trial methodology, host population genetics, use of different BCG vaccine strains (2), and heterogeneous immunity to a variety of environmental mycobacteria that may interfere with or mask the protection provided by BCG (7,26).Immune response profiles following BCG vaccination comprise myriad effector mechanisms, multiple T-cell subsets, and many targeted antigens. BCG is capable of inducing Th1 responses (38), which are critical in mycobacterial infections (17). In addition, BCG is also capable of inducing both CD4 ϩ and CD8ϩ T-cell responses to antigens shared with M. tuberculosis, such as secreted antigens of the mycolyl transferase family (Ag85) (19,20,33) and nondeleted members of the ESAT-6 family (e.g., TB10.4) (32), but also heat shock proteins like Hsp65 and Hsp70 (15). However, it is still not completely known how these and other antigen-specific immune responses contribute to protection against TB.Recently we studied human T-cell responses to DosR (Rv3133c) regulon-encoded antigens (referred to as TB latency antigens) of M. tuberculosis (24). We observed preferential recognition of latency antigens by Mantoux skin test-positive individuals with latent TB compared to patients with TB disease, suggesting that these immune responses are associated with latent TB disease (13,24). The DosR regulon is expressed by tubercle bacilli under in vitro conditions of hypoxia and

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

“…In this context, it is noteworthy that other studies also have reported reactivity to MTB-encoded antigens in HCs and NTM-infected/exposed individuals that is hypothesized to be as a result of exposure to NTMs (7,8,31). Furthermore, NTM exposure may explain the higher baseline reactivity to PPD that was found in MTB-naive young adults as compared with children (32).…”

“…For example, a population in Malawi with no history or scar evidence of prior bCG vaccination or MTB infection showed responsiveness to a variety of mycobacterial antigens and purified protein derivative (PPD) from different NTMs (5,6). In addition, non-MTB-infected and non-bCG-vaccinated individuals respond to MTB-encoded antigens, MTB lysate, and PPD (7,8).…”

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

“…Consequently, novel concepts have been investigated that include the use of different epitopes of RD antigens [11,12,36,37,58], readout different from IFN-c such as chemokines or cytokines [56,58], new antigens different from the RD genomic region, such as those defined as Rv1733c, Rv2029c, Rv2032, Rv2626c, Rv2627c, Rv2628 and HspX [29,[59][60][61], additional cytokines [56] or characteristic phenotypic markers [11,12,36,62]. Diagnostic sensitivity of IGRA can also be enhanced by incorporation of a novel RD1-encoded antigen, Rv3879c, without compromising diagnostic specificity [63].…”

An Unbiased Genome-Wide Mycobacterium tuberculosis Gene Expression Approach To Discover Antigens Targeted by Human T Cells Expressed during Pulmonary Infection

“…Endotoxin contents were ,50 IU/ mg as tested using a Limulus amebocyte lysate assay (Cambrex, East Rutherford, NJ). All recombinant proteins were tested in lymphocyte stimulation assays to exclude Ag nonspecific T cell stimulation and cellular toxicity using PBMC of in vitro-purified protein derivative of M. tuberculosis-negative healthy Dutch donors (Sanquin Blood Bank, Leiden, The Netherlands) (12,(40)(41)(42). Purified protein derivative of M. tuberculosis was purchased from Statens Serum Institute.…”