A prophylactic α-Gal-based glycovaccine effectively protects against murine acute Chagas disease

Abstract

Chagas disease (ChD), caused by the hemoflagellate parasite Trypanosoma cruzi, affects six to seven million people in Latin America. Lately, it has become an emerging public health concern in nonendemic regions such as North America and Europe. There is no prophylactic or therapeutic vaccine as yet, and current chemotherapy is rather toxic and has limited efficacy in the chronic phase of the disease. The parasite surface is heavily coated by glycoproteins such as glycosylphosphatidylinositol (GPI)-anchored mucins (tGPI-mucins), which display highly immunogenic terminal nonreducing α-galactopyranosyl (α-Gal)-containing glycotopes that are entirely absent in humans. The immunodominant tGPI-mucin α-Gal glycotope, the trisaccharide Galα1,3Galβ1,4GlcNAc (Galα3LN), elicits high levels of protective T. cruzi-specific anti-α-Gal antibodies in ChD patients in both the acute and chronic phases. Although glycoconjugates are the major parasite glycocalyx antigens, they remain completely unexplored as potential ChD vaccine candidates. Here we investigate the efficacy of the T. cruzi immunodominant glycotope Galα3LN, covalently linked to a carrier protein (human serum albumin (HSA)), as a prophylactic vaccine candidate in the acute model of ChD, using the α1,3-galactosyltransferase-knockout (α1,3GalT-KO) mouse, which mimics the human immunoresponse to α-Gal glycotopes. Animals vaccinated with Galα3LN-HSA were fully protected against lethal T. cruzi challenge by inducing a strong anti-α-Gal antibody-mediated humoral response. Furthermore, Galα3LN-HSA-vaccinated α1,3GalT-KO mice exhibited significant reduction (91.7–99.9%) in parasite load in all tissues analyzed, cardiac inflammation, myocyte necrosis, and T cell infiltration. This is a proof-of-concept study to demonstrate the efficacy of a prophylactic α-Gal-based glycovaccine for experimental acute Chagas disease.

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).…”

Infection with Toxocara canis Inhibits the Production of IgE Antibodies to α-Gal in Humans: Towards a Conceptual Framework of the Hygiene Hypothesis?

“…Anti-α-Gal Abs, principally immunoglobulin (Ig)G, IgM, and IgA isotypes, are typically produced by healthy human individuals as an immunological response to continuous antigenic stimulation by gastrointestinal bacteria producing α-Gal on their outer surface [7]. Interestingly, the resulting IgG and IgM Abs were found to be protective against important microbial and parasitic infections [8][9][10][11]. However, hyperproduction of specific IgE Abs to α-Gal triggered by bites of ixodid ticks (Acari: Ixodidae) may lead to a delayed and potentially fatal anaphylactic reaction to mammalian meats (e.g., beef, pork, lamb) and other α-Gal-containing products [12,13].…”