A convenient synthetic method to improve immunogenicity of mycobacterium tuberculosis related T-cell epitope peptides

TY - JOUR

T1 - A convenient synthetic method to improve immunogenicity of mycobacterium tuberculosis related T-cell epitope peptides

AU - Horváti, Kata

AU - Pályi, Bernadett

AU - Henczkó, Judit

AU - Balka, Gyula

AU - Szabó, Eleonóra

AU - Farkas, Viktor

AU - Biri-Kovács, Beáta

AU - Szeder, Bálint

AU - Fodor, Kinga

N1 - Funding Information: Funding: This work was financed by the National Research Development and Innovation Office, Hungary (grants OTKA 115431, 124077), ELTE Institutional Excellence Program (1783-3/2018/FEKUTSTRAT) supported by the Hungarian Ministry of Human Capacities and grants from the European Union and the State of Hungary, co-financed by the European Regional Development Fund (VEKOP-2.3.3-15-2017-00020, VEKOP-2.3.2-16-2017-00014). Project no. 2018-1.2.1-NKP-2018-00005 was implemented with the support provided from the National Research Development and Innovation Fund of Hungary. K. Horváti, Gy. Balka and V. Farkas were supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/9

Y1 - 2019/9

N2 - Epitopes from different proteins expressed by Mycobacterium tuberculosis (Rv1886c, Rv0341, Rv3873) were selected based on previously reported antigenic properties. Relatively short linear T-cell epitope peptides generally have unordered structure, limited immunogenicity, and low in vivo stability. Therefore, they rely on proper formulation and on the addition of adjuvants. Here we report a convenient synthetic route to induce a more potent immune response by the formation of a trivalent conjugate in spatial arrangement. Chemical and structural characterization of the vaccine conjugates was followed by the study of cellular uptake and localization. Immune response was assayed by the measurement of splenocyte proliferation and cytokine production, while vaccine efficacy was studied in a murine model of tuberculosis. The conjugate showed higher tendency to fold and increased internalization rate into professional antigen presenting cells compared to free epitopes. Cellular uptake was further improved by the incorporation of a palmitoyl group to the conjugate and the resulted pal-A(P)I derivative possessed an internalization rate 10 times higher than the free epitope peptides. Vaccination of CB6F1 mice with free peptides resulted in low T-cell response. In contrast, significantly higher T-cell proliferation with prominent expression of IFN-γ, IL-2, and IL-10 cytokines was measured for the palmitoylated conjugate. Furthermore, the pal-A(P)I conjugate showed relevant vaccine efficacy against Mycobacterium tuberculosis infection.

AB - Epitopes from different proteins expressed by Mycobacterium tuberculosis (Rv1886c, Rv0341, Rv3873) were selected based on previously reported antigenic properties. Relatively short linear T-cell epitope peptides generally have unordered structure, limited immunogenicity, and low in vivo stability. Therefore, they rely on proper formulation and on the addition of adjuvants. Here we report a convenient synthetic route to induce a more potent immune response by the formation of a trivalent conjugate in spatial arrangement. Chemical and structural characterization of the vaccine conjugates was followed by the study of cellular uptake and localization. Immune response was assayed by the measurement of splenocyte proliferation and cytokine production, while vaccine efficacy was studied in a murine model of tuberculosis. The conjugate showed higher tendency to fold and increased internalization rate into professional antigen presenting cells compared to free epitopes. Cellular uptake was further improved by the incorporation of a palmitoyl group to the conjugate and the resulted pal-A(P)I derivative possessed an internalization rate 10 times higher than the free epitope peptides. Vaccination of CB6F1 mice with free peptides resulted in low T-cell response. In contrast, significantly higher T-cell proliferation with prominent expression of IFN-γ, IL-2, and IL-10 cytokines was measured for the palmitoylated conjugate. Furthermore, the pal-A(P)I conjugate showed relevant vaccine efficacy against Mycobacterium tuberculosis infection.

KW - Maleimide conjugation

KW - Mycobacterium tuberculosis

KW - Peptide-based vaccines

KW - T-cell epitope

KW - Tuftsin

UR - https://www.scopus.com/pages/publications/85073337335

U2 - 10.3390/vaccines7030101

DO - 10.3390/vaccines7030101

M3 - Article

AN - SCOPUS:85073337335

SN - 2076-393X

VL - 7

JO - Vaccines

JF - Vaccines

IS - 3

M1 - 101

ER -