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Virus-like Particle Display of the ?-Gal Carbohydrate for Vaccination against Leishmania Infection.

ABSTRACT: Secreted and surface-displayed carbohydrates are essential for virulence and viability of many parasites, including for immune system evasion. We have identified the ?-Gal trisaccharide epitope on the surface of the protozoan parasites Leishmania infantum and Leishmania amazonensis, the etiological agents of visceral and cutaneous leishmaniasis, respectively, with the latter bearing larger amounts of ?-Gal than the former. A polyvalent ?-Gal conjugate on the immunogenic Q? virus-like particle was tested as a vaccine against Leishmania infection in a C57BL/6 ?-galactosyltransferase knockout mouse model, which mimics human hosts in producing high titers of anti-?-Gal antibodies. As expected, ?-Gal-T knockout mice infected with promastigotes of both Leishmania species showed significantly lower parasite load in the liver and slightly decreased levels in the spleen, compared with wild-type mice. Vaccination with Q?-?-Gal nanoparticles protected the knockout mice against Leishmania challenge, eliminating the infection and proliferation of parasites in the liver and spleen as probed by qPCR. The ?-Gal epitope may therefore be considered as a vaccine candidate to block human cutaneous and visceral leishmaniasis.

SUBMITTER: Moura APV

PROVIDER: S-EPMC5620979 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Virus-like Particle Display of the α-Gal Carbohydrate for Vaccination against Leishmania Infection.

Moura Anna Paula V APV Santos Luiza C B LCB Brito Carlos Ramon Nascimento CRN Valencia Edward E Junqueira Caroline C Filho Adalberto A P AAP Sant'Anna Mauricio R V MRV Gontijo Nelder F NF Bartholomeu Daniella C DC Fujiwara Ricardo T RT Gazzinelli Ricardo T RT McKay Craig S CS Sanhueza Carlos A CA Finn M G MG Marques Alexandre Ferreira AF

ACS central science 20170913 9

Secreted and surface-displayed carbohydrates are essential for virulence and viability of many parasites, including for immune system evasion. We have identified the α-Gal trisaccharide epitope on the surface of the protozoan parasites Leishmania infantum and Leishmania amazonensis, the etiological agents of visceral and cutaneous leishmaniasis, respectively, with the latter bearing larger amounts of α-Gal than the former. A polyvalent α-Gal conjugate on the immunogenic Qβ virus-li ...[more]

PMID: 28979944

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Project description:The protozoan parasite Leishmania (Viannia) braziliensis is among Latin America's most widespread Leishmania species and is responsible for tegumentary leishmaniasis (TL). This disease has multiple clinical presentations, with cutaneous leishmaniasis (CL) being the most frequent. It manifests as one or a few localized skin ulcers, which can spread to other body areas. Hence, early diagnosis and treatment, typically with pentavalent antimonials, is critical. Traditional diagnostic methods, like parasite culture, microscopy, or the polymerase chain reaction (PCR) for detection of the parasite DNA, have limitations due to the uneven distribution of parasites in biopsy samples. Nonetheless, studies have revealed high levels of parasite-specific anti-α-Gal antibodies in L. (V.) braziliensis-infected patients. Previously, we demonstrated that the neoglycoprotein NGP28b, consisting of the L. (Leishmania) major type-2 glycoinositolphospholipid (GIPL)-3-derived trisaccharide Galpα1,6Galpα1,3Galfβ conjugated to bovine serum albumin (BSA) via a linker, acts as a reliable serological biomarker (BMK) for L. (V.) braziliensis infection in Brazil. This indicates the presence of GIPL-3 or a similar structure in this parasite, and its terminal trisaccharide either functions as or is part of an immunodominant glycotope. Here, we explored whether extending the trisaccharide with a mannose unit would enhance its efficacy as a biomarker for the serological detection of L. (V.) braziliensis. We synthesized the tetrasaccharide Galpα1,6Galpα1,3Galfβ1,3Manpα(CH2)3SH (G31SH) and conjugated it to maleimide-functionalized BSA to afford NGP31b. When we assessed the efficacy of NGP28b and NGP31b by chemiluminescent enzyme-linked immunosorbent assay on a cohort of CL patients with L. (V.) braziliensis infection from Bolivia and Argentina against a healthy control group, both NGPs exhibited similar or identical sensitivity, specificity, and accuracy. This finding implies that the mannose moiety at the reducing end is not part of the glycotope recognized by the parasite-specific anti-α-Gal antibodies in patients' sera, nor does it exert a relevant influence on the terminal trisaccharide's conformation. Moreover, the mannose does not seem to inhibit glycan-antibody interactions. Therefore, NGP31b is a viable and dependable BMK for the serodiagnosis of CL caused by L. (V.) braziliensis.

Project description:This review describes the significance of the α-gal epitope (Galα-3Galβ1-4GlcNAc-R) as the core of human blood-group A and B antigens (A and B antigens), determines in mouse models the principles underlying the immune response to these antigens, and suggests future strategies for the induction of immune tolerance to incompatible A and B antigens in human allografts. Carbohydrate antigens, such as ABO antigens and the α-gal epitope, differ from protein antigens in that they do not interact with T cells, but B cells interacting with them require T-cell help for their activation. The α-gal epitope is the core of both A and B antigens and is the ligand of the natural anti-Gal antibody, which is abundant in all humans. In A and O individuals, anti-Gal clones (called anti-Gal/B) comprise >85% of the so-called anti-B activity and bind to the B antigen in facets that do not include fucose-linked α1-2 to the core α-gal. As many as 1% of B cells are anti-Gal B cells. Activation of quiescent anti-Gal B cells upon exposure to α-gal epitopes on xenografts and some protozoa can increase the titer of anti-Gal by 100-fold. α1,3-Galactosyltransferase knockout (GT-KO) mice lack α-gal epitopes and can produce anti-Gal. These mice simulate human recipients of ABO-incompatible human allografts. Exposure for 2-4 weeks of naïve and memory mouse anti-Gal B cells to α-gal epitopes in the heterotopically grafted wild-type (WT) mouse heart results in the elimination of these cells and immune tolerance to this epitope. Shorter exposures of 7 days of anti-Gal B cells to α-gal epitopes in the WT heart result in the production of accommodating anti-Gal antibodies that bind to α-gal epitopes but do not lyse cells or reject the graft. Tolerance to α-gal epitopes due to the elimination of naïve and memory anti-Gal B cells can be further induced by 2 weeks in vivo exposure to WT lymphocytes or autologous lymphocytes engineered to present α-gal epitopes by transduction of the α1,3-galactosyltransferase gene. These mouse studies suggest that autologous human lymphocytes similarly engineered to present the A or B antigen may induce corresponding tolerance in recipients of ABO-incompatible allografts. The review further summarizes experimental works demonstrating the efficacy of α-gal therapies in amplifying anti-viral and anti-tumor immune-protection and regeneration of injured tissues.

Dataset Information

Virus-like Particle Display of the ?-Gal Carbohydrate for Vaccination against Leishmania Infection.

Publications

Virus-like Particle Display of the α-Gal Carbohydrate for Vaccination against <i>Leishmania</i> Infection.

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