Abstract
Recent advancements in vaccinology have led to the development of the M72/AS01E subunit vaccine, of which the major component is the Mycobacterium tuberculosis (MTB) PPE18 protein. Previous studies have demonstrated the genetic variability of the gene encoding PPE18 protein and the resulting peptide changes in diverse clinical strains of MTB; however, none have modeled the structural changes resulting from these peptide changes and their immunological implications. In this study, we investigated the structural predictions of 29 variant PPE18 proteins previously reported. We found evidence that PPE18 is at least a two-domain protein, with a highly conserved first domain and a largely variable second domain that has different coevolutionary clusters. Further, we investigated putative epitope sites in the clinical variants of PPE18 using prediction software. We found a negative relationship between T-cell epitope number and residue variability, while B-cell epitope likelihood was positively correlated with residue variability. Moreover, we found far more residues in the second domain predicted to be B-cell epitopes compared with the first domain. These results suggest an important functional role of the first domain and a role in immune evasion for the second, which extends our knowledge base of the basic biology of the PPE18 protein and indicates the need for further study into non-traditional immunological responses to TB.
Highlights
Mycobacterium tuberculosis (MTB) is an ancient pathogen that is still responsible for a significant portion of global mortality and morbidity
To expand upon previous research done on this protein, we investigated computationally predicted protein structures of the 29 PPE18 amino acid variants originally described by Hebert et al Using the RaptorX web server, a template-based tertiary structure prediction software, and following the protocol previously described (Källberg et al, 2012), we predicted protein structures for each of the 29 PPE18 variants mentioned above as well as the MTB laboratory reference strain, H37RV
Using the predicted structures of the study variants of PPE18 protein, we found that the number of predicted B-cell epitopes for an individual variant structure ranged between 0 and 43 residues (Figure 3C)
Summary
Mycobacterium tuberculosis (MTB) is an ancient pathogen that is still responsible for a significant portion of global mortality and morbidity. The World Health Organization and its global stop tuberculosis (TB) partners have set an ambitious goal to reduce the global incidence of TB to less than 100 per million population by 2035 (World Health Organization [WHO], 2015). To meet this goal, it is necessary to develop better tools for TB diagnosis, treatment, and vaccination (Raviglione and Sulis, 2016). To improve and develop new tools to combat TB, there is a need for a better understanding of its causative pathogen.
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