Ebolavirus (EBOV) is responsible for one of the most fatal diseases encountered by mankind. Cellular T-cell responses have been implicated to be important in providing protection against the virus. Antigenic variation can result in viral escape from immune recognition. Mapping targets of immune responses among the sequence of viral proteins is, thus, an important first step towards understanding the immune responses to viral variants and can aid in the identification of vaccine targets. Herein, we performed a large-scale, proteome-wide mapping and diversity analyses of putative HLA supertype-restricted T-cell epitopes of Zaire ebolavirus (ZEBOV), the most pathogenic species among the EBOV family. All publicly available ZEBOV sequences (14,098) for each of the nine viral proteins were retrieved, removed of irrelevant and duplicate sequences, and aligned. The overall proteome diversity of the non-redundant sequences was studied by use of Shannon’s entropy. The sequences were predicted, by use of the NetCTLpan server, for HLA-A2, -A3, and -B7 supertype-restricted epitopes, which are relevant to African and other ethnicities and provide for large (~86%) population coverage. The predicted epitopes were mapped to the alignment of each protein for analyses of antigenic sequence diversity and relevance to structure and function. The putative epitopes were validated by comparison with experimentally confirmed epitopes. ZEBOV proteome was generally conserved, with an average entropy of 0.16. The 185 HLA supertype-restricted T-cell epitopes predicted (82 (A2), 37 (A3) and 66 (B7)) mapped to 125 alignment positions and covered ~24% of the proteome length. Many of the epitopes showed a propensity to co-localize at select positions of the alignment. Thirty (30) of the mapped positions were completely conserved and may be attractive for vaccine design. The remaining (95) positions had one or more epitopes, with or without non-epitope variants. A significant number (24) of the putative epitopes matched reported experimentally validated HLA ligands/T-cell epitopes of A2, A3 and/or B7 supertype representative allele restrictions. The epitopes generally corresponded to functional motifs/domains and there was no correlation to localization on the protein 3D structure. These data and the epitope map provide important insights into the interaction between EBOV and the host immune system.

/pdf/mapping-hla-a2-a3-and-b7-supertype-restricted-t-cell-stdl1pl3y0.pdf

Mapping HLA-A2, -A3 and -B7 supertype-restricted T-cell epitopes in the ebolavirus proteome

Mucins and mucin-like molecules are highly O-glycosylated proteins present on the cell surface of mammals and other organisms. These glycoproteins are highly diverse in the apoprotein and glycan cores and play a central role in many biological processes and diseases. Mucins are the most abundant macromolecules in mucus and are responsible for its biochemical and biophysical properties. Mucin-like molecules cover various protozoan parasites, fungi and viruses. In humans, modifications in mucin glycosylation are associated with tumors in epithelial tissue. These modifications allow the distinction between normal and abnormal cell conditions and represent important targets for vaccine development against some cancers. Mucins and mucin-like molecules derived from pathogens are potential diagnostic markers and targets for therapeutic agents. In this review, we summarize the distribution, structure, role as immunomodulators, and the correlation of human mucins with diseases and perform a comparative analysis of mucins with mucin-like molecules present in human pathogens. Furthermore, we review the methods to produce pathogenic and human mucins using chemical synthesis and expression systems. Finally, we present applications of mucin-like molecules in diagnosis and prevention of relevant human diseases.

/pdf/mucins-and-pathogenic-mucin-like-molecules-are-1qslbqnxm7.pdf

Mucins and pathogenic mucin-like molecules are immunomodulators during infection and targets for diagnostics and vaccines

The incidence of various ocular, CNS, and musculoskeletal complaints in the convalescent period following recovery from Ebola Virus Disease (PEVDS) has become an intense area of interest in the aftermath of the recent West Africa outbreak 2014-2015. A review of past outbreaks involving EBOV, SUDV, TAFV, and BDBV revealed similar, but poorly documented symptoms in the convalescent period. Additionally, viable virus has been identified in the recovery phase in sperm and ocular fluid up to 9 months after recovery with no evidence of viremia. A prior study by Yang in 2000 demonstrated the mucin-like domain was responsible for the vascular permeability and inflammation seen in EVD with Zaire ebolavirus infections but not in Reston ebolavirus infections. To study the mucin-like domain further, a comparative multi-sequence amino acid analysis of the poorly conserved MLD was performed and all 16 B-cell epitopes previously identified comparing all virulent species of Ebolavirus against RESTV was used to identify regions that could explain the differential virulence and vascular access to regions of immune privileged regions. Within the E1 epitope (301-316) of the MLD, the charged motif R (X1) EELSF demonstrated significant homology (86%) within the virulent species but poorly conserved in RESTV (25%). In E5-E8, charged tandem grouping of charged residues in the motif Glu-336, Asp-337, and His-338 of EBOV were conserved as to charge in the virulent group but these charged residues were replaced by the uncharged Pro-336, Thr-337, and Arg-338 in the RESTV sequence. The C-terminus GLINT motif in epitope E16 of the MLD at the GP2 junction was moderately conserved between all species including RESTV and therefore not felt to contribute to the overall differential virulence. Within the MHC class I predictions, there did not appear to be a statistically significant difference between the virulent species and RESTV. However, the MHC Class II predicted epitopes did identify a statistically significant difference between the virulent species and RESTV. Three epitopes of acceptable binding affinities in the virulent group were significantly different from RESTV (p>.05) This study suggests that the residues located within the B-cell E1 epitope (301-316) and three MHC Class II epitopes may be responsible for vascular access to these immune privileged site and persistent symptoms observed in the convalescent PEVDS. Further studies are required into the potential role of VP40 in viral persistence and reemergence within these immune privileged areas; therefore potentially provide a therapeutic strategy in PEVDS and viral persistence associated with reemergence.

https://www.webmedcentral.com/wmcpdf/Article_WMC005042.pdf

The Glycoprotein Mucin-Like Domain (MLD) In The Zaire Ebolavirus (EBOV) May Be Responsible For The Manifestations Of Post-Ebola Virus Disease Syndrome (PEVDS)

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The Glycoprotein Mucin-Like Domain (MLD) In The Zaire Ebolavirus (EBOV) May Be Responsible For The Manifestations Of Post-Ebola Virus Disease Syndrome (PEVDS)