Attenuated Salmonella sp. as a DNA Delivery System for Trypanosoma cruzi Antigens
Chagas disease is an important neglected disease affecting thousands of people in the Americas. Novel strategies for prophylactic and therapeutic vaccines against the etiological agent, the intracellular protozoan Trypanosoma cruzi, are urgently needed. V
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ion Trypanosoma cruzi is an intracellular protozoan parasite and the etiological agent of Chagas disease, the major cause of death from cardiomyopathy in endemic Latin America. The parasite is mainly transmitted to humans by infected feces of triatomine insects that feed on mammals’ blood. According to the World Health Organization estimates, the number of infected people globally amounts to eight million, and more than 10,000 deaths are thought to occur annually (World Health Organization. WHO Fact Sheet No 340. http://www.who.int/mediacentre/ factsheets/fs340/en/). To date there is no safe and effective vaccine against T. cruzi infection. In this chapter we describe the use of attenuated Salmonella as a live Trojan horse T. cruzi antigen. The widespread use of Salmonella as a vaccine vector relies on the easiness with these bacteria for genetic modification, the existence of the serovar Typhimurium mouse model for preclinical work and a positive previous human experience with a FDA-approved live attenuated vaccine S. typhi Ty21a for typhoid fever (http://www.cdc.gov/ vaccines/hcp/vis/visstatements/typhoid.html). Salmonella elicits a strong innate immune response due to many pathogen-associated molecular patterns (PAMPs) present in the bacteria, such as LPS [1], bacterial CpG [2, 3], flagellin or bacterial lipoproteins [4, 5] that stimulate antigen presenting cells to mature and migrate to secondary lymph node, to initiate an adaptive response. In this manner, Salmonella-derived PAMPs Augusto E. Bivona and Natacha Cerny contributed equally. Sunil Thomas (ed.), Vaccine Design: Methods and Protocols, Volume 2: Vaccines for Veterinary Diseases, Methods in Molecular Biology, vol. 1404, DOI 10.1007/978-1-4939-3389-1_44, © Springer Science+Business Media New York 2016
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amplify the immune response against the transported T. cruzi antigens acting as adjuvants. Salmonella-based vaccine effectiveness and versatility lie on the plasticity of the immune response modulated by Salmonella. Different arms of the immune system, both humoral [6, 7] and cell-mediated responses, including CD4+ T cells [8, 9], cytotoxic CD8+ T cell (CTL) [10, 11], secretion of inflammatory cytokines and chemokines, upregulation of co-stimulatory molecules and regulatory T cells (Tregs) [12–14], are known to be induced at mucosal and systemic level with Salmonella infection and mediate protection against different diseases. Immunity to Salmonella is mainly Th1-cell dependent and consequently, Th1-biased immune responses are usually elicited against the antigens delivered by Salmonella, which includes elevated IFN-γ production and IgG2a antibody production in mice as well as cytotoxic CD8+ T cells toward the antigens. The major advantage of live vectors is that they produce the antigen in its native conformation, which is important for generating neutralizing antibodies and can facilitate antigen entry into the MHC class I processing pathway for the induction of CD8+ CTL. Considering T. cruzi is an intracellular proto
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