Essay: Vaccine candidates for Atherosclerosis

The given work, directed towards the identification of vaccine candidates for Atherosclerosis caused by the factors of Periodontitis and this has resulted in the prediction of some acceptable epitopes that can be used to elicit immune response against both Atherosclerosis and Periodontitis. WDAPNGTPNPNPNPNPNPNPGTTTLSESFENGIPASWKTIDADGDGHGWKPGNAPGIAGYNSNGCV, LDDPFILRDVRGQVVNFAPLQYNPVTKTLRIYTEITVAVSET and SNLYSANFEYLIPANADPVVITQNIIVTGQGEVVIPGGVYDYCITN are recognised as B-cell epitopes. These epitope stretches contain MHC class-I binding peptides as NAPGIAGY, LQYNPVT and SNLYS respectively. Also MHC class-II binding peptides are obtained as IPASWTI, VTKTLRIYT and FEYLIPANA respectively. These peptide stretches bind to most of the MHC class I and II alleles with high affinity and these are antigenic. After finding the TAP binding regions, proteosomal cleavage sites and peptide stretches predicted on the basis of geographical locations three peptides are predicted, but one of the proteosomal cleavage site is lying in IPASWKTIDADGDGHGWKPGNAPGIAGY, therefore it is rejected and hence, two probable vaccine candidates are predicted as APLQYNPVTKTLRIYT and SNLYSANFEYLIPANA. So, these are T-cell epitopes derived from B-cell epitopes that may act as vaccine against Periodontitis leading to Atherosclerosis. These insilico results need to be confirmed by experimental validation to develop a good vaccine candidate that can be beneficial for therapeutic purpose.
7. DISCUSSION AND FUTURE PERSPECTIVE
Atherosclerosis is the one of the biggest killer of the twenty-first century among CAD. Atherosclerosis is a multifactorial and a multistep disease which is involved in chronic inflammation at each step, from initiation to the progression, and all the risk factors together contribute to pathogenesis.
The work will help in the future to treat the disease like atherosclerosis which is highly connected with the oral hygiene of the person i.e, the poor oral hygiene lead to periodontitis and further causes the disease-atherosclerosis. The role of inflammation in atherosclerosis provides a mechanistic framework to understand the clinical benefits of newer therapeutic strategies, and also the better understanding of pathogenesis may help in formulating preventive and therapeutic strategies which can reduce the mortality resulting from CAD.
More deep knowledge of the various pathogenic mechanisms that are involved in atherosclerosis can help in substantiating the current existing knowledge about the CAD epidemic. This knowledge will help clinicians to control and manage the disease in a better way, which affects Indians in its most severe form.
P. gingivalis is found in close contact with the subgingival epithelium of the periodontal pocket. The adherence of P. gingivalis to epithelial cells is the first step in colonization and which is important for the development of a disease. The non-covalent interactions of ligands from infecting organism with receptor targets on the surface of host cells through attachment of it to the host cell membrane is mediated. Some of the eukaryotic cell surface receptors which are identified in P. gingivalis’host interactions have extracellular matrix proteins and integrins. Transglutaminase2, the adhesion molecule which is present in host cells form the close association with the arginine gingipains-fibronectin complex and showed binding regions. B cell epitope predictions for Arginine gingipains A and Arginine gingipains B has shown many acceptable peptide stretches.
The advancement in the techniques and the tools available for analysing the sequence data have enabled prediction of probable vaccine candidates from the large number of proteins synthesized by an organism. Attempts are underway to create a vaccine that could prevent Atherosclerosis caused by periodontitis in humans.
The experimental data shows that some factors of Periodontitis are responsible for causing Atherosclerosis. Among all the microorganisms studied Porphyromonas gingivalis and its strains are highly responsible for inflammatory action and causing the disease. The phylogenetic analysis among their strains has shown the similarity among themselves. Porphyromonas gingivalis is an important and main causative agent of atherosclerosis specifically ATCC33277 strain of P.gingivalis. All the four strains that are ATCC33277, W83, W50, and TDC60 of P.gingivalis are more than ninety eight percent identical and covering ninety five percent of query length. Arginine gingipains present in Porphyromonas gingivalis form a complex with fibronectin and interacts with the Transglutaminase2 that is present in host cells. Here the two types of Arginine gingivalis (RgpA and RgpB) are the adhesion molecules and mediates the entry into the host cell and reach to the blood stream which in developmental process causing atherosclerosis.
The B cell epitope predictions of Arginine gingipains A and Arginine gingipains B has shown many acceptable stretches of peptide. Using bioinformatics tools like Bepipred, DiscoTope, ABCpred, IEDB Analysis epitope prediction for Antigenicity, Flexibility, Emini surface accessibility: many peptide stretches are obtained with the length size varying from 3mer to 50mer. Those peptide stretches are obtained which have shown high score for antigenicity, flexibility and surface accessibility. T-cell epitopes for HLA classI and classII are predicted using tools like: Multipred, NetMHC, CTLpred. Also TAP processing regions are predicted by TAPpred and Proteosomal cleavage sites are predicted by PAPROC. The T-cell epitopes which present in B-cell epitopes are obtained and 20 such peptide stretches are obtained. With the help of PrediVac tool for population coverage the peptide stretches which can act as possible candidate in different geographical locations: Asia, Eastern Europe, North Africa, Pacific, Sub-Saharan Africa, Australia, Middle East, North America, South and Central America, Western Europe are obtained. The total number of stretches sorted among B-cell epitopes for predicted T-cell epitopes are seven. Out of these seven which are showing their presence in different geographical locations are three. The B-cell epitopes are: WDAPNGTPNPNPNPNPNPNPGTTTLSESFENGIPASWKTIDADGDGHGWKPGNAPGIAGYNSNGCV LDDPFILRDVRGQVVNFAPLQYNPVTKTLRIYTEITVAVSET SNLYSANFEYLIPANADPVVITQNIIVTGQGEVVIPGGVYDYCITN. These have overlapping regions as shown:
IPASWKTIDADGDGHGWKPGNAPGIAGY- NAPGIAGY classI, IPASWTI class II, ASWKTIDAD TAP binding regions
APLQYNPVTKTLRIYT- LQYNPVT classI, VTKTLRIYT classII, LQYNPVT TAP binding regions
SNLYSANFEYLIPANA- SNLYS classI, FEYLIPANA classII, ANFEYLIPA TAP binding regions
IPASWKTIDADGDGHGWKPGNAPGIAGY is prevalent in North African, Pacific and Sub-Saharan regions where as SNLYSANFEYLIPANA is prevalent in Asian geographical locations. But the IPASWKTIDADGDGHGWKPGNAPGIAGY contains one of the proteosomal cleavage sites inside it so not considered. So the later two peptides are predicted as the probable vaccine candidates.
The resultant candidate can act against both atherosclerosis as well as against periodontal disease. Further for the future study other microorganisms causing atherosclerosis can be studied and conserved regions can be find out and a common candidate can be form out of them and which can act as a vaccine candidate for them also.
Additionally, this antigen is selected in a way that it has the potential to evoke both branches of adaptive immunity.
Such broad range vaccines, if able to clear clinical trials, will be a tool to prevent infectious diseases which have one than one causative agent. The development of such broad range vaccines needs a lot more to be done in the field of immunoinformatics, a field which is in its infantile stage. The successful development of accurate antigen prediction methods will surely cut down the laboratory resources needed to identify pathogenic proteins as candidate subunit vaccines.