Chlamydia trachomatis infections are widespread throughout the World. This bacterial pathogen affects multiple organ systems producing acute symptomatology and persistent infections that can result in long-term sequelae. If implemented in a timely manner, antibiotic therapy is effective in controlling C. trachomatis infections. Unfortunately, many cases are asymptomatic, others are treated late, and/or are unsuccessfully managed. Efforts to produce a vaccine against trachoma were initiated decades ago. More recently, with the uncovering of the role of C. trachomatis in sexually transmitted infections, several laboratories have focused their efforts on producing a vaccine against genital infections. Our long-term goal is to engineer a vaccine that can protect against C. trachomatis infections. The hypothesis we want to test is that a vaccine formulated with the native major outer membrane protein (MOMP) of Chlamydia associated with amphipols (APols) can protect female mice against an intravaginal challenge. Generally, membrane proteins (MPs) are kept soluble in aqueous solutions using detergents. However, detergents tend to destabilize MPs, which can lead to the loss of protective conformational epitopes. APols are a novel type of polymeric surfactants that can substitute to detergents. They have been shown to be particularly favorable towards maintaining MP structure, function and stability. Our preliminary experiments indicate that candidate vaccines formulated with APol-trapped MOMP are more effective than their detergent-based equivalents. We propose to build on this observation by i) studying the stability and structure of MOMP/APol complexes in various types of vaccine formulations and ii) testing the protective effect of adjuvant-carrying APols. Indeed, as they associate permanently with MPs, APols can be used to deliver adjuvants to target cells concomitantly with antigenic MPs, which is expected to favor a strong systemic and mucosal immune response. Female mice will be challenged intravaginally and the course of the infection will be followed with vaginal cultures. Protection will be determined based on the number of animals with positive vaginal cultures and the severity and length of the infection. Subsequently, the mice will be mated to determine the fertility rates. In order to optimize the candidate vaccines, we will compare the immune response elicited by different vaccination protocols using various adjuvants linked in various ways to various APols, so as to modulate the release of the adjuvant in different cellular compartments. In conclusion, C. trachomatis infections are a major health problem in both developed and underdeveloped countries. The goal of this proposal is to formulate a vaccine with MOMP trapped by adjuvant-carrying APols. Decreasing the incidence and prevalence of these infections with a vaccine would have a major health impact worldwide. Furthermore, the development of vaccine formulations based on amphipol solubilized membrane proteins has the potential to impact a broad spectrum of pathogens.
The goal of this proposal is to formulate a vaccine with MOMP trapped by adjuvant-carrying APols. Decreasing the incidence and prevalence of these infections with a vaccine would have a major health impact worldwide. Furthermore, the development of vaccine formulations based on amphipol solubilized membrane proteins has the potential to impact a broad spectrum of pathogens.
|Pal, Sukumar; Tifrea, Delia F; Zhong, Guangming et al. (2018) Transcervical Inoculation with Chlamydia trachomatis Induces Infertility in HLA-DR4 Transgenic and Wild-Type Mice. Infect Immun 86:|
|Pal, Sukumar; Favaroni, Alison; Tifrea, Delia F et al. (2017) Comparison of the nine polymorphic membrane proteins of Chlamydia trachomatis for their ability to induce protective immune responses in mice against a C. muridarum challenge. Vaccine 35:2543-2549|
|Tifrea, Delia F; Barta, Michael L; Pal, Sukumar et al. (2016) Computational modeling of TC0583 as a putative component of the Chlamydia muridarum V-type ATP synthase complex and assessment of its protective capabilities as a vaccine antigen. Microbes Infect 18:245-53|
|Pal, Sukumar; Tatarenkova, Olga V; de la Maza, Luis M (2015) A vaccine formulated with the major outer membrane protein can protect C3H/HeN, a highly susceptible strain of mice, from a Chlamydia muridarum genital challenge. Immunology 146:432-43|
|Zoonens, Manuela; Popot, Jean-Luc (2014) Amphipols for each season. J Membr Biol 247:759-96|
|Le Bon, Christel; Popot, Jean-Luc; Giusti, Fabrice (2014) Labeling and functionalizing amphipols for biological applications. J Membr Biol 247:797-814|
|Provine, Nicholas M; Larocca, Rafael A; Penaloza-MacMaster, Pablo et al. (2014) Longitudinal requirement for CD4+ T cell help for adenovirus vector-elicited CD8+ T cell responses. J Immunol 192:5214-25|
|Le Bon, Christel; Della Pia, Eduardo Antonio; Giusti, Fabrice et al. (2014) Synthesis of an oligonucleotide-derivatized amphipol and its use to trap and immobilize membrane proteins. Nucleic Acids Res 42:e83|
|Tifrea, Delia F; Pal, Sukumar; Popot, Jean-Luc et al. (2014) Increased immunoaccessibility of MOMP epitopes in a vaccine formulated with amphipols may account for the very robust protection elicited against a vaginal challenge with Chlamydia muridarum. J Immunol 192:5201-13|
|Della Pia, Eduardo Antonio; Holm, Jeppe V; Lloret, Noemie et al. (2014) A step closer to membrane protein multiplexed nanoarrays using biotin-doped polypyrrole. ACS Nano 8:1844-53|
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