Virus-like Particle Display of the α-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 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-like particle was tested as a vaccine against Leishmania infection in a C57BL/6 α-galactosyltransferase knockout mouse model, which mimics human hosts in producing high titers of anti-α-Gal antibodies. As expected, α-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 Qβ–α-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 α-Gal epitope may therefore be considered as a vaccine candidate to block human cutaneous and visceral leishmaniasis.

Vaccination with Alpha-Gal Protects Against Mycobacterial Infection in the Zebrafish Model of Tuberculosis

“…The possibility of using the antibody-mediated immune response against α-Gal for the control of infectious diseases caused by pathogens with this modification on their surface in hosts such as humans, birds, and fishes that do not have the capacity to synthesize α-Gal was initially suggested by results in the malaria mouse model [15]. Then, results in leishmaniasis and Chagas disease further supported this possibility [18][19][20], leading to proposing the possibility of development of a single-antigen pan-vaccine for the control of major infectious diseases worldwide [11,16,17,30]. Pathogens causing infectious diseases with high incidence worldwide and with α-Gal modifications include Plasmodium, Mycobacterium, Leishmania, Trypanosoma, Anaplasma, Borrelia, and Aspergillus species and viruses such as human immunodeficiency virus (HIV), measles virus, vaccinia virus, paramyxovirus, vesicular stomatitis virus, Sindbis virus, and retroviruses [6,9,14,15,[17][18][19][20][21].…”

“…Within the conflict and cooperation that drove the evolution of tick-host-pathogen interactions [13], humans evolved by losing the capacity to synthesize α-Gal to increase the protective immune response against pathogens with this modification on their surface while increasing the risk to develop the AGS [6]. This evolutionary adaptation suggested the possibility of developing vaccines and other interventions to induce the anti-α-Gal IgM/IgG protective response against pathogen infection to prevent or control major infectious diseases worldwide [14][15][16][17][18][19][20].…”

“…Recently, the C57BL/6 α1,3-Galactosyltransferase-knockout (α1,3-GalT-KO) mouse animal model was used to study the antibody response to the carbohydrate α-Gal and its potential for the control of infectious diseases such as malaria, leishmaniasis, Chagas disease, granulocytic anaplasmosis, and influenza caused by pathogens with this modification on their surface and/or by enhancing the protective immune response against these pathogens [15][16][17][18][19][20][21][22]. The results showed protection against pathogen infection in response to α-Gal-containing vaccine formulations [15,[18][19][20][21][22]. However, the protective effect of the anti-α-Gal immune response for the control of tuberculosis caused by Mycobacterium spp.…”

Allergic Reactions and Immunity in Response to Tick Salivary Biogenic Substances and Red Meat Consumption in the Zebrafish Model

“…Recently, C57BL/6 α1,3-galactosyltransferase-knockout (α1,3-GalT-KO) mice that like humans do not synthesize α-Gal have been used as a model to characterize the percutaneous sensitization to α-Gal and Amblyomma sculptum tick saliva (Araujo et al, 2016) and the IgE-mediated immune response to cutaneous exposure to Amblyomma americanum tick proteins (Chandrasekhar et al, 2019). Additionally, this animal model has been used to study the antibody response to the carbohydrate α-Gal and its potential for the control of infectious diseases caused by pathogens with this modification on their surface (Yilmaz et al, 2014;Cabezas-Cruz et al, 2016;Iniguez et al, 2017;Moura et al, 2017;Portillo et al, 2019). In this context, various fish species constitute models for investigating human diseases (Schartl, 2014), and zebrafish (Danio rerio Hamilton 1822) is a relevant animal model for research in genetics, developmental biology, toxicology, oncology, immunology, and allergy (Huang et al, 2018).…”

Virus-like particle vaccines: immunology and formulation for clinical translation

“…The diversity of VLP can also be characterized based on the variety of diseases these vaccines have been developed to prevent or treat. These include VLP vaccines developed for both human and veterinary pathologies, with some examples including an HBV HBcAg core particle-based vaccine for HER2 + cancer [37], an adenovirus VLP-based vaccine for placental malaria [38], and a Qβ VLP-based vaccine for Leishmania infection [39]. A selection of recently developed and investigated novel VLP vaccines are provided in Table 2.…”