Meritxell Genescà Ferrer
The group is led by Dr Meritxell Genescà who, who joined the IGT on a Ramón y Cajal award contract in 2011. The group is part of the Clinical and Basic AIDS Research Group (2014 SGR 211) led by Dr. B. Clotet at the IrsiCaixa on the Can Ruti Campus.
This laboratory focuses on female genital tract immunity and mucosal vaccine development against sexually transmitted infections (STI). The group is interested in defining the nature of protective immune responses against pathogens that use the cervicovaginal mucosa as their portal of entry, such as Chlamydia or HIV. One of the ultimate goals of their research is to determine how to induce and evaluate an effective vaccine-induced immune response at the level of the genital mucosa. The group collaborates with several basic and clinical research groups in order to conduct translational comparative medicine.
STI seriously compromise the health of women and children and the problem is particularly acute in low-income countries. The long-term consequences of STIs including pelvic inflammatory disease, cancer, sterility, miscarriages, newborn malformation, etc. not only are highly relevant at the social and health level but also have a major economical impact. Although the growing concern about the impact of STI in public health, several of these diseases still represent major epidemics. For example, in the specific case of Chlamydia trachomatis, even though the antimicrobial therapy is successful, about 80% of acute chlamydial infections are asymptomatic. The untreated infection can ascend to upper genital tract, affecting the reproductive organs and reducing significantly fertility. Thus, the development of a vaccine against Chlamydia is the best solution to this serious public health issue, as also occurs with HIV infection.
Efforts to develop vaccines against herpesvirus-2, HIV and bacterial STI have been hampered by an inability to accurately measure immune responses in the female genital tract. An effective vaccine against an STI should generate localized immune responses at sites of potential exposure. Current assays used to understand the magnitude and quality of immune responses in the female genital tract rely primarily on blood samples and thus only provide an incomplete picture of immune control. Basic knowledge of the genital mucosa immune system and new methods to measure and manipulate immune responses are required to develop effective STI vaccines.
Biomarkers of genital mucosa immunity (immune correlates of protection)
Limiting the analyses of vaccine-induced immunity to general systemic responses might be misleading. Thus, although technically challenging, we must increase our efforts to assess mucosal responses in our search for correlates of protection during both preclinical and clinical evaluation of vaccine candidates. These studies are based on translational research where we systematically compare human and animal samples.
Specifically, we are interested in providing new biomarkers of vaccine immunogenicity against sexually transmitted infections in women. To this aim we are working on defining the homing profile of lymphocytes migrating to the female genital. Adhesion molecules expressed on effector T cells during genital tract infection could become excellent surrogate markers of genital tract immunity because of their accessibility and feasibility.
In this sense, we have observed an important increment on the expression of a well-known marker of dendritic cells, which is usually not considered as a T cell immunity biomarker. However, in the context of genital tract infection and related disorders, we have determined a clear expansion of T cells expressing this molecule. Thus, measuring cells expressing this molecule in blood could be an indicator of T cell immunity directed to tissue of difficult access, such as the female genital tract. Additionally, if cells expressing this molecule are indeed protective, it would be desirable to induce this type of cells in the context of sexually transmitted disease vaccine development. Defining the role and clinical value of this biomarker in the context of female genital tract infections is a promising new tool that will certainly aid in the search of an effective vaccine.
Novel molecules as adjuvants for mucosal vaccine development
Protection against STI relies on the induction of a mucosal immune response at sites of potential exposure. Certain vaccines types, such as subunit vaccines, need potent adjuvants to initiate and maintain strong immunological memory. Similarly, vaccines directed to the epithelium also require a potent adjuvant to overcome the induction of tolerance that occurs upon mucosal exposure to an antigen. The main goal of artificial adjuvants is to induce immunity that closely resembles a natural immune response to the intended pathogen. Thus, identification of adjuvants that elicit a protective immune response is one of the main challenges for the development of an effective vaccine against most STI and it is an area of interest in our group.
Invariant natural killer T (iNKT) cells are major immune regulators, bridging innate and adaptive immunity, and responding within hours after activation. They have become an attractive target for vaccine development since, when activated, these cells trigger downstream activation of antigen presenting dendritic cells, antibody producing B cells, NK cells and T cells. Further, among others pathogens like HIV, Chlamydia has evolved strategies to evade iNKT cell responses supporting their relevance in antimicrobial mucosal immunity. With the generation of new agonists and iNKT modulators, the interest of using these compounds as adjuvants for both, preventive and therapeutic vaccines is rising.
This line of research is based on the human cervicovaginal explant model, which has been established in our laboratory thanks to the collaboration with the Gynecology and the Anatomical Pathology departments from the HUGTP. Using this model, we are testing novel glycolipids as potential adjuvants for mucosal vaccine development. Dr. A. Llebaria, a chemist collaborator from the IQAC-CSIC who has generated a library of glycolipid compounds, provides these molecules that specifically activate iNKT cells. Selected iNKT modulators will be further studied in vivo in a well-established murine model of vaginal Chlamydia infection. The study of novel iNKT modulators in the context of Chlamydia infection will not only inform on the protective role of activating these cells during mucosal vaccination, but also shed light on the immune stimulatory capacity of these molecules for other therapeutic interventions.
Bacterial infection immunopathology and its implications for HIV coinfection
Pre-existing female genital tract infections affect the development and pathogenesis of other STI, as occurs with the pro-inflammatory environment generated by bacterial vaginosis and the enhancement of HIV replication. A better understanding of the effect of bacterial infection and co-infection on female genital tract immunity, may allow the development of more specific vaccine candidates.
Besides the inflammatory component generated by concomitant bacterial infections which may directly favor HIV infection susceptibility, the type of cells infiltrated in the genital tissue during certain STI may also impact on HIV-1 acquisition. Here our interest centers on the modulation of HIV receptors on dendritic cells and CD4+ T cells from the cervicovaginal mucosa caused by Chlamydia and other bacterial infections. Additionally, we are interested in studying how modifications in vaginal microbiota affect the frequency and phenotype of the immune populations present at the mucosa.
Meritxell Genescà Ferrer
(+34) 93 497 86 79