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Diagnosis of Latent TB Infection
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Ajit Lalvani, Clementine Fraser, Manish Pareek
ESAT-6 and CFP-10 are proteins encoded in the genomic region of MTB known as region of difference-1 (RD-1). During repeated passages of a virulent strain of M. bovis in vitro through ox bile, Calmette and Guérin developed the non-virulent vaccine strain. Exploration of the M.tb genome during the late twentieth century revealed that this process had resulted in the loss of several virulence-encoding genomic regions including RD-1, rendering BCG unable to produce these proteins. ESAT-6 and CFP-10 are the best understood and form a secreted heterodimer that is part of a type VII secretion system.8,9 Subsequent studies identified them to be highly immunodominant and therefore attractive candidates for a TB blood test.10,11 Only four species of environmental mycobacteria, Mycobacterium kansasii, M. szulgai, M. marinum, and M. riyadhense have RD-1-like regions minimizing false positives. The use of ESAT-6 and CFP-10 has led to the first generation of IGRAs. Over the years, further antigens that are targets of IFN-γ-secreting T-cells in M.tb-infected persons and that are also highly specific for M.tb, either by virtue of being RD1-encoded or RD1-dependent for virulence and secretion have been identified.12,13
Immunodiagnosis of Tuberculosis Infection
Published in Peter D O Davies, Stephen B Gordon, Geraint Davies, Clinical Tuberculosis, 2014
Ajit Lalvani, Manish Pareek, Katrina Pollock
ESAT-6 and CFP-10 are proteins encoded in the genomic region of MTB known as region of difference-1 (RD-1). Loss of RD-1 was the primary attenuating genetic deletion in the evolution of avirulent M. bovis BCG from virulent M. bovis. This key deletion occurred before M. bovis BCG was tested and used as a vaccine; therefore, RD-1 is absent from all clinical strains of BCG in use worldwide. ESAT-6 and CFP-10 are integral components as well as substrates of a mycobacterial type VII secretion system and are secreted as a heterodimer (Hsu, Hingley-Wilson et al. 2003; Champion, Stanley et al. 2006). Immunological studies early in the last decade identified them as highly immunodominant targets of CMI in MTB-infected humans; combined with their high specificity for MTB (by virtue of being RD-1-encoded), this made them attractive candidates for a TB blood test (Lalvani, Pathan et al. 2001b). Only four species of environmental mycobacteria, M. kansasii, M. szulgai, M. marinum and M. riyadhense, have RD-1-like regions (van Ingen, de Zwaan et al. 2009). Although the use of ESAT-6 and CFP-10 has led to the first generation of IGRAs, recent work has identified further antigens that are targets of IFN-γ-secreting T-cells in MTB-infected persons and that are also highly specific for MTB, either by virtue of being RD1-encoded (Dosanjh, Hinks et al. 2008) or RD1-dependent (Millington, Fortune et al. 2011).
Mycobacterial biofilms as players in human infections: a review
Published in Biofouling, 2021
Esmeralda Ivonne Niño-Padilla, Carlos Velazquez, Adriana Garibay-Escobar
Despite findings implicating the possible occurrence of in vivo mycobacterial biofilms, there are limited molecular and biochemical markers to confirm its presence in living tissues. Nine proteins expressed in in vitro M. tuberculosis biofilms, but not in planktonic cultures, have been identified in infected guinea pig sera, one of which, 3-ketoacyl-acyl carrier protein reductase (FabG4), is highly conserved among MTBC members, M. avium and M. smegmatis (Kerns et al. 2014). In particular, FabG4 mediates the conversion of β-oxoacyl-CoA to β-hydroxyacyl-CoA in the early steps of the fatty acid synthesis II (FAS-II) pathway, which is responsible for fatty acid chain elongation (Dutta et al. 2013). It is also possible that 6-kDa early secretory antigenic target (ESAT-6) and 10-kDa culture filtrate protein (CFP-10) from M. tuberculosis, the most investigated immunogens involved in the host–pathogen interaction and considered as both virulence factors and protective immunity promoters (Brodin et al. 2006; Simeone et al. 2009; Etna et al. 2015), play a role in biofilm formation. This is because members of the ESX-1 excretion system (espE, espF, espG, and espH) from M. marinum are fundamental for sliding motility and biofilm formation, and exhibit 79% homology with elements from the ESX type VII secretion system dedicated to the excretion of ESAT-6 and CFP-10 (Lai et al. 2018).