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Order Articulavirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The early secretory antigenic target 6 protein (ESAT-6) epitope from Mycobacterium tuberculosis, a potent T-cell epitope of 20 aa residues in length, was engineered into the antigenic region B of the HA from strain A/New Caledonia/20/99 H1N1 (Krammer et al. 2010). The VLPs consisting of M1 and ESAT6-HA or HA were produced in insect cells and subjected to immunization studies in mice. The high serum antibody titers detected against the ESAT-6 clearly demonstrated the feasibility of influenza A VLPs serving as an efficient platform for the presentation of valuable foreign immune epitopes. As mentioned earlier, the influenza VLPs could incorporate the VSV protein G (Latham and Galarza 2001).
BCG and Other Vaccines
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Three fusion protein/adjuvant vaccine candidates: Hybrid 1/IC31, Hybrid 4/IC31, and Hybrid 56/IC31 were designed by the Statens Serum Institut (SSI) in Copenhagen. H1/IC31 contains the fusion protein of Ag85B and ESAT-6 adjuvanted to a system combining the antibacterial peptide KLK with a synthetic Toll-like receptor (TLR)-9 agonist (ODN1a). This vaccine was safe in healthy, prior, or latently TB-infected and HIV-infected adults, and induced a robust and durable CD4+ T-cell response.165–167 However, the inclusion of ESAT-6 potentially confounds the IGRA diagnostic assay which uses a T-cell response to ESAT-6 and CFP-10 as evidence of M.tb infection. Indeed, a recent study found that 17% of participants receiving high-dose H1/IC31 developed a positive response to the QuantiFERON TB Gold in-tube assay.165 H4/IC31 (AERAS-404) circumvents this issue by replacing ESAT-6 with TB10.4, while still demonstrating moderate protective efficacy in preclinical models.168,169 In a recent phase II trial conducted in South African adolescents, H4/IC31 showed no protection against initial infection, and a non-statistically significant trend toward reduced sustained M.tb infections.57
Tuberculosis
Published in Keith Struthers, Clinical Microbiology, 2017
Interferon gamma tests (IGT) measure the presence of Mycobacterium tuberculosis-specific macrophage stimulating effector memory T cells in the patient's blood, and identify past exposure to the organism. The two antigens used, ESAT-6 and CFP-10, are proteins secreted by Mycobacterium tuberculosis that interfere with the primary response of T and B cells, and are critical for survival of the organism. The result obtained by the IGT is better correlated with latent infection and the presence of dormant organisms, and importantly, the result is not affected by prior bacillus Calmette–Guérin (BCG) vaccination, unlike the Mantoux or Heaf test.
Synergy between Th1 and Th2 responses during Mycobacterium tuberculosis infection: A review of current understanding
Published in International Reviews of Immunology, 2019
On the other hand, out of an estimated 2 billion people believed to have Mtb infection, only 10–12% develops clinical disease. The fact that the vast majority (over 90%) of Mtb infected individuals contain infection without apparent development of disease implies that natural immunity plays a central role. Therefore, it is possible to identify those host immune factors involved in response to infection and use them as biomarkers to guide development of vaccines [6]. In this regard, a strong association between decreased IFN-γ expression and development of clinical disease and increased expression of IFN-γ following successful chemotherapy of TB patients is a common experience [7–10]. Based on the above understanding, there were studies to determine protective molecular markers in cohorts of house hold contacts (HHCs) in TB high endemic setting. Using ESAT-6 the VASCEL group identified that those TB contacts with increased expression of ESAT-6-specific IFN-γ were at most risk of developing progressive disease [6]. In a study involving pulmonary TB patients (PTBP), their household contacts (HHCs), and community control (CCs), our group has found that IFN-γ against ESAT-6/CFP-10 was the highest in PTBP compared to HHCs and CCs, implying that elevated levels of IFN-γ may indicate risk of disease, but not necessarily immune protection [10,11].
Current updates in diagnosis of male urogenital tuberculosis
Published in Expert Review of Anti-infective Therapy, 2021
Owing to limitation of batch-to-batch variation and challenge of scalability for antibody generation, in vitro designing of high affinity DNA aptamers against specific biomarkers via SELEX could be alternative diagnostic reagents. The ease of synthesis, reproducibility and amenability of aptamers to functionalize with several ligands has stimulated unprecedented interest for designing aptamer-based TB diagnostic tests. Moreover, ALISA based on HspX, MPT64, and CFP10.ESAT-6 detection within bodily fluids of PTB/EPTB patients revealed superiority over antibody-based ELISA, Xpert, and real-time PCR [99,106]. Indeed, the utility of aptamer-based ALISA for detecting male UGTB cases may influence the suppression of UGTB.
Recent insights into Mycobacterium tuberculosis through proteomics and implications for the clinic
Published in Expert Review of Proteomics, 2019
Deepa Bisht, Devesh Sharma, Divakar Sharma, Rananjay Singh, Vivek Kumar Gupta
Aebersold and coworkers made the most significant contribution to the development of mycobacterial proteomics [29,30]. The proteome of the laboratory strain M.tb H37Rv has also been thoroughly focused. About 97% of the total annotated proteins have been confirmed by genomic sequences using comprehensive proteomic approaches. Protein expression profiles of M.tb under various growth conditions, genetic backgrounds and geographic distribution have been investigated [31–34]. Proteins overexpressed during latency or unique in intraphagosomal phase have also been identified. Analysis of the proteins of DosR regulon (associated with anaerobic survival of M.tb) exhibited changes in their representation under hypoxic conditions [35]. HspX protein increased 340 fold during hypoxia compared to normal conditions. DosR regulon was earlier studied only at transcripts level [36,37]. Comparative proteomic analysis of the proteins of latent H37Rv strain at exponential, logarithmic, and stationary phases using ICAT technique identified 193 and 241 proteins typical of the exponential and stationary phases respectively [29,35]. Although H37Rv and M.bovis BCG share more than 99.9% homology at the genomic level, 294 proteins have been identified to be different in two strains [23]. Much attention was given to ESAT-6 system, the proteins of which had been previously suggested as candidates for designing a new vaccine [38]. Besides, 22 differentially expressed proteins were proposed for designing diagnostic and vaccine agents [39]. Large sequence polymorphisms classified M.tb into 7 main lineages, which are lineage 1 (Indo-Oceanic), lineage 2 (East Asian including ‘Beijing’), lineage 3 (CAS/Delhi), lineage 4 (Euro-American including Latin American Mediterranean (LAM), Haarlem, X type and T families), lineage 5 and lineage 6 (West African 1 and 2, respectively), and lineage 7 [40]. Comparative proteomic analysis of M.tb Lineage 7 and Lineage 4 (H37Rv strains) revealed differentially abundant proteins [41], which provided an insight into the lineage seven-specific protein profile which may provide clues to understand the differential properties of lineage 7 strains in terms of slow growth, survival fitness and pathogenesis. Proteomic analysis of different purified protein derivative (PPD) preparations by Prasad et al. [42] might be crucial in development of better skin test antigen with higher specificity and sensitivity. Cell wall, membrane [43–45], cytosolic [19,46,47], and secreted proteins [48,49] have been described and are desirable for subunit vaccine generation or diagnostic marker. The membrane protein expression of dendritic cells upon M.tb exposure was quantitatively analyzed [50]. A lot of research has been done to improve the extraction of membrane proteins as they are hydrophobic and low in abundance. Proteomic studies were used to examine the pathways of cellular metabolism and mode of action of drugs in mycobacteria.