TABLE 2.
Summary of the most important LTBI-RD related antigens for LTBI differential diagnosis.
| Antigensa |
Typesa
|
Product b | Functionb | Functional categoryb | LTBI differential diagnosis | References | |
| LTBI | RD | ||||||
| Rv1736c | DosR | Others | Probable nitrate reductase NarX | Involved in nitrate reduction, and in the persistence in the host | Intermediary metabolism and respiration | Induced by M. tuberculosis rather than 13 BCG strains or M. bovis | Honaker et al., 2008 |
| Rv1737c | DosR | Others | Possible nitrate/nitrite transporter NarK2 | Involved in excretion of nitrite, produced by the dissimilatory reduction of nitrate, across the membrane. Responsible for the translocation of the substrate across the membrane. | Cell wall and cell processes | (1) Higher TNF-α+ CD4+ T cells and IFN-γ+ TNF-α+ CD4+ T cells in LTBI vs. PTB. (2) Higher IFN-γ+ TNF-α+ CD8+ T cells in LTBI vs. HC | Chegou et al., 2012; Arroyo et al., 2016 |
| Rv2031c | DosR | Others | Heat shock protein HspX | Has a proposed role in maintenance of long-term viability during latent, asymptomatic infections, and a proposed role in replication during initial infection. | Virulence, detoxification, adaptation | (1) Higher IFN-γ+ TNF-α+ CD8+ T cells in LTBI vs. HCs (2) Higher concentrations of IFN-γ in LTBI vs. aTB vs. HC (3) Lower IFN-γ, IL-10, TNF-α in LTBI vs. aTB and HCs | Commandeur et al., 2011; Araujo et al., 2015; Belay et al., 2015 |
| Rv2626c | DosR | Others | Hypoxic response protein 1 Hrp1 | Unknown | Conserved hypotheticals | (1) 91% of CC QFT– subjects secreted low levels of IFN-γ, but 43% of HCWs QFT– people produced elevated IFN-γ, 69% of CC QFT+ subjects didn’t produce IFN-γ to Rv2626c (2) Higher IFN-γ producing T cells in CC vs. aTB and HC (3) IFN-γ response to Rv2626c has shown positivity of 88.57% in CC and 7.5% in PTB (4) Sensitivity and specificity of Rv2626c in aTB was of 77.1% and 85.1% | Ashraf et al., 2014; Prabhavathi et al., 2015; Amiano et al., 2020 |
| Rv2653c | NS | RD-13 | Possible PhiRv2 prophage protein | Unknown | Insertion seqs and phages | Less reactive DTH skin responses in M. tuberculosis-sensitized guinea pigs vs. PPD, but elicited no response in BCG-vaccinated guinea pigs. | Kasempimolporn et al., 2019 |
| Rv2654c | NS | RD-13 | Possible PhiRv2 prophage protein | Unknown | Insertion seqs and phages | (1) Higher IFN-γ levels TB vs. HC, had a high overall agreement (98.0%) with T-SPOT.TB, the combination of Rv2645 and CFP10-ESAT6 increased sensitivity and specificity of 96.0% and 98.2%, respectively. (2) Peptide Rv2654c51–65 boosted the quantitative performance of the QFT-GIT assay from 1.83 IU/ml to 2.83 IU/ml | Luo et al., 2015; Horvati et al., 2016 |
| Rv2656c | NS | RD-13 | Possible PhiRv2 prophage protein | Unknown | Insertion seqs and phages | Unknown | - |
| Rv2657c | NS | RD-13 | Probable PhiRv2 prophage integrase | Unknown | Insertion seqs and phages | Rv2657c react with the sera from LTBI Guinea pigs but not healthy Guinea pigs, SFCs of HCWs was significantly higher in HCWs vs. aTB | Yang, 2018 |
| Rv2658c | NS | RD-13 | Possible prophage protein | Unknown | Insertion seqs and phages | Unknown | - |
| Rv2659c | NS | RD-13 | Probable PhiRv2 prophage integrase | Sequence integration. Integrase is necessary for integration of a phage into the host genome by site-specific recombination | Insertion seqs and phages | Higher IFN-γ producing T cells in LTBI vs. aTB and HC | Bai, 2015 |
| Rv2660c | NS | RD-13 | Hypothetical protein | Unknown | Conserved hypotheticals | (1) Higher number of IFN-γ producing cells and the levels of cytokines (IFN-γ, IL-2, IL-10, and MIP-1621299821α 621299821) in LTBI vs. TB, and higher ratio of IFN-γ+ CD4+ T cells in LTBI vs. TB or HCs (2) A component of vaccine H56:IC31 and will affect the diagnosis of Rv2660c once the vaccine is available | He et al., 2015; Luabeya et al., 2015 |
| Rv1511 | Others | RD-6 | GDP-D-mannose dehydratase GmdA | Unknown, probably involved in nucleotide-sugar metabolism | Intermediary metabolism and respiration | Unknown | - |
| Rv1978 | Others | RD-2 | Conserved protein | Unknown | Conserved hypotheticals | ELISPOT of Rv1978 achieved sensitivities of 59% in aTB and specificities of 94% in BCG-vaccinated HC. | Chen et al., 2009 |
| Rv1980c | Others | RD-2 | Immunogenic protein Mpt64 | Unknown | Cell wall and cell processes | Sensitivity and specificity were 0.92 and 0.95, respectively, sensitivity of the MPT64 test was significantly higher in TB infected children than in adults. | Cao et al., 2021 |
| Rv1981c | Others | RD-2 | Ribonucleoside-diphosphate reductase (beta chain) NrdF1 | Involved in the DNA replication pathway. | Information pathways | ELISPOT of Rv1981c achieved sensitivities of 60% in aTB and specificities of 90% in BCG-vaccinated HC. | Chen et al., 2009 |
| Rv3872 | Others | RD-1 | PE family-related protein PE35 | Unknown | Pe/ppe | (1) Sensitivity and specificity of PE35 for detecting LTBI in children were 76% and 80%. (2) Elicited stronger immunoreactivity and could discriminate TB from HC vaccinated with BCG (better than Rv3878). | Mukherjee et al., 2007; Mahmoudi et al., 2017 |
| Rv3873 | Others | RD-1 | PPE family protein PPE68 | Unknown | Pe/ppe | Sensitivity and specificity of PE68 for detecting LTBI in children were 73% and 75%. | Mahmoudi et al., 2017 |
| Rv3878 | Others | RD-1 | ESX-1 secretion-associated protein EspJ | Unknown | Cell wall and cell processes | Elicited stronger immunoreactivity and could discriminate TB from HC vaccinated with BCG. | Mukherjee et al., 2007 |
| Rv3879c | Others | RD-1 | ESX-1 secretion-associated protein EspK | Unknown | Cell wall and cell processes | The immunodominance of Rv3879c is higher than that of Rv3878 and Rv3873 in aTB and LTBI subjects. | Hinks et al., 2009 |
| Rv3425 | Others | RD-11 | PPE family protein PPE57 | Unknown | Pe/ppe | (1) Rv0310c-E coupled with Rv3425 (sensitivity: 87.30%, specificity: 73.68%) had the strongest performance for diagnostics of aTB. (2) Rv3425 has the promising potential to distinguish aTB from HC vaccinated with BCG. | Zhang et al., 2007; Wang et al., 2013; Luo et al., 2017 |
| Rv3429 | Others | RD-11 | PPE family protein PPE59 | Unknown | Pe/ppe | ELISPOT of Rv3429 achieved sensitivities of 47% in aTB and specificities of 93% in BCG-vaccinated HC. | Chen et al., 2009 |
aThese antigens were included in both LTBI and RD.
bThe information of Product, Function, and Functional category of each antigen was obtained from mycobrowser database (https://mycobrowser.epfl.ch/) on April 26, 2021.
aTB, active TB; CC, TB close contacts (subjects exposed to M. tuberculosis for less than three months); DTH, delayed-type hypersensitivity; DosR, Dormancy survival regulon antigens; HCs, health controls; HCWs, healthcare workers (individuals exposed to M. tuberculosis at least 2 years); NS, nutrition starvation-associated antigens; PPD, purified protein derivative; PTB, pulmonary TB; QFT, QuantiFERON; RD, Region of Difference; TB, tuberculosis.