Immunogenicity of Novel DosR Regulon-Encoded Candidate Antigens of Mycobacterium tuberculosis in Three High-Burden Populations in Africa

Abstract

Increasing knowledge about DosR regulon-encoded proteins has led us to produce novel Mycobacterium tuberculosis antigens for immunogenicity testing in human populations in three countries in Africa to which tuberculosis (TB) is endemic. A total of 131 tuberculin skin test-positive and/or ESAT-6/CFP10-positive, human immunodeficiency virus-negative adult household contacts of active pulmonary TB cases from South Africa (n ‫؍‬ 56), The Gambia (n ‫؍‬ 26), and Uganda (n ‫؍‬ 49) were tested for gamma interferon responses to 7 classical and 51 DosR regulon-encoded M. tuberculosis recombinant protein antigens. ESAT-6/CFP10 fusion protein evoked responses in >75% of study participants in all three countries. Of the DosR regulon-encoded antigens tested, Rv1733c was the most commonly recognized by participants from both South Africa and Uganda and the third most commonly recognized antigen in The Gambia. The four most frequently recognized DosR regulon-encoded antigens in Uganda (Rv1733c, Rv0081, Rv1735c, and Rv1737c) included the three most immunogenic antigens in South Africa. In contrast, Rv3131 induced the highest percentage of responders in Gambian contacts (38%), compared to only 3.4% of Ugandan contacts and no South African contacts. Appreciable percentages of TB contacts with a high likelihood of latent M. tuberculosis infection responded to several novel DosR regulon-encoded M. tuberculosis proteins. In addition to significant similarities in antigen recognition profiles between the three African population groups, there were also disparities, which may stem from genetic differences between both pathogen and host populations. Our findings have implications for the selection of potential TB vaccine candidates and for determining biosignatures of latent M. tuberculosis infection, active TB disease, and protective immunity.

Response to Rv2628 latency antigen associates with cured tuberculosis and remote infection

“…The present results confirm that a cellular immune response to these latency antigens can be found in vitro, and show that this response can also be efficiently detected by means of a wholeblood 1-day assay. It was also found that the response to Rv2628 antigen was more clearly associated with a latent infection, as previously shown using other experimental approaches by LEYTEN et al [14] and BLACK et al [16] and confirmed by ROUPIE et al [26] in mice. However, from all of the studies reported, it is presently unclear why the response to Rv2628 may provide better discrimination between the different stages of TB infection.…”

“…However, from all of the studies reported, it is presently unclear why the response to Rv2628 may provide better discrimination between the different stages of TB infection. Among the studies performed on human samples [14][15][16][17], SCHUCK et al [15] did not show any immunogenic activity of Rv2628. This may probably be due to the selection of LTBI subjects that have not been clearly defined as recently or remotely infected.…”

“…The results provided the first support for the immunogenicity of DosR regulon proteins in human PBMC stimulation assays of TST-positive individuals. Subsequently, the latency antigens Rv1733c, Rv2029c, Rv2627c and Rv2628 were identified as the most frequently recognised antigens in latently infected individuals [14,16]. Similarly, the IFN-c response to Rv3407 has recently been shown to be a response specific to LTBI [15].…”

“…The functions of most DosR-regulonencoded proteins, hereafter referred to as latency antigens, are unknown [12,13]. However, it has recently been shown that certain latency antigens are recognised more frequently in TST-positive individuals without active TB than in diseased patients, whereas the opposite profile was found for CFP-10 and ESAT-6 [13][14][15][16][17]. In particular, it has been shown that Rv2627c, Rv2628 and Rv3407 induce strong long-term IFN-c responses in TST-positive individuals.…”

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

“…T-cell can response to three DosR antigens, namely Rv1733c, Rv2029c, Rv2031c, the top 10 most frequently recognized Mtb DosR proteins in Mtb-exposed individuals [Black et al, 2009;Commandeur et al, 2011;Leyten et al, 2006;Schuck et al, 2009]. Strong DosR antigen-specific single and double functional CD4 þ and CD8 þ T-cell responses are detected in LTBI.…”