Immunoregulatory and pathogenic mechanisms underlying inflammatory diseases of the male genital tract

Project 1: Chlamydia trachomatis infection of the male genital tract. Assessment of the molecular epidemiology, the induced inflammatory response and their consequences on sperm quality

Director: PhD. Rubén Darío Motrich

Chlamydia trachomatis (CT) is the most prevalent cause of sexually transmitted bacterial infections worldwide. Despite the similar incidence of CT urogenital infections in men and women, most diagnostic approaches, prevention and control strategies, and research have been focused on women. In that regard, the local epidemiology of male genital tract infections (MGT) caused by CT is currently unknown. Moreover, much less is known about the possible relationship between certain genotypic variants of CT, the inflammatory response induced in MGT and its consequences on sperm quality. The aim of this project is to analyze the local molecular epidemiology of CT-caused MGT infections by studying a large number of young and middle-aged adult male patients. In addition, we will analyze the immune response induced in the MGT by different identified and isolated CT genotypic variants and their effects on sperm quality. Results obtained will allow identifying possible sexual transmission networks and to develop better infection control and eradication strategies. On the other hand, it will make it possible to establish possible associations between the circulating CT genotypic variants, the inflammation induced in the MGT and its possible deleterious effects on sperm and male fertility potential. 

Project 2: Chronic inflammation of the male genital tract as a risk factor for male infertility. Analysis of its impact on the immunomodulation ability of the female genital tract and offspring fitness

Director: PhD. Rubén Darío Motrich

Infertility currently affects 15-20% of couples worldwide, being female or male causative factors implicated in similar proportions. The causes of male infertility are multiple and include infections and inflammation of the male genital tract (MGT). The aim of this project is to study the role of chronic inflammation of the MGT as a possible cause of male infertility focusing on the analysis of the consequences on the physiologic ability of semen to modulate the immune response of the female genital tract (FGT) to favor optimal uterine remodeling, embryo implantation, pregnancy outcome and offspring health. The presence of pro-inflammatory mediators in semen could generate detrimental consequences in the different molecular and cellular immunomodulatory events that are triggered in TGF early after copulation/insemination, which would lead to impaired fertility rates, embryo development and offspring health. The results of this project will allow a better understanding of the current knowledge of infertility causes and pathogenic mechanisms besides showing the biological contribution of the male to pregnancy and progeny fitness beyond the simple provision of male gametes. Moreover, generated evidence will provide new and important data crucial for the future design of diagnostic and therapeutic approaches for infertility.

Project 3: Urea cycle defects in Argentinean patients. Assessment of the genotype-fenotype correlation and physiopathologic implications on the immune system

Director: PhD. Rubén Darío Motrich

Urea cycle defects (UCD) are inherited metabolic diseases that have serious effects on the central nervous and cardiopulmonary systems, causing serious physical and intellectual disabilities. Despite strict adherence to treatment, patients experience periodic episodes of metabolic decompensation with high morbimortality. In that regard, intercurrent infections are the main events commonly associated with metabolic decompensation crises. During these infections, the associated inflammatory response often aggravates the hyperammonemia and the general condition of the patient. Despite the great advances in the knowledge of the pathophysiology of these diseases, very little is still known about the pathophysiology of UCD and whether the intercurrent infections typically presented by these patients are the cause or consequence of hyperammonemia/metabolic decompensation crises. The aim of this project is to study UCD in Argentine patients, including diagnosis, genotypic-phenotypic analysis, characterization of different effector components of the immune system and their relationship with hyperammonemia crises. In addition, in vitro and in vivo experimental models of hyperammonemia will be analyzed. Generated evidence will allow a significant advance in current knowledge of UCD pathophysiology that will allow a better understanding of these poorly studied diseases, which will pave the way for a better clinical-therapeutic management and quality of life for patients.

Project 4: Human papillomavirus (HPV) infection of the male genital tract. Assessment of the molecular epidemiology, the induced inflammatory response and alterations on male fertility

Director: PhD. Virginia Elena Rivero

HPV infection is the most prevalent sexually transmitted infection in the world. Most of the studies on HPV focus on the potential capacity of the virus to cause malignancy, leaving little explored other aspects of the infection such as the local and systemic immune response that the virus induces, its strong asymptomatic nature, the possibility of producing reproductive function alterations, and others. Regarding men, reported studies are scarce and with very few data referring to the effects of the infection on male fertility and the immune response induced in the genital tract. On the other hand, there are few epidemiological data reported about the the molecular epidemiology of this virus in our region. The general objective of this project is to describe the local epidemiology of HPV infection of the male genital tract in adult patients of reproductive age who attend the urological clinic. In addition, the immune response induced by the infection will be characterized, and its effects on sperm quality, in order to analyze whether the infection has deleterious consequences on male fertility.

Project 5: Regulatory T cells in mice with differential susceptibility to develop autoimmune disorders

Director: PhD. Virginia Elena Rivero

Abstract: Foxp3+ regulatory T cells (Treg) are crucial for maintenance of tolerance and immune homeostasis. Low numbers or decreased functionality in this population are associated with autoimmunity in animal models and human autoimmune diseases, thus highlighting the possible therapeutic potential of Treg adoptive transfer in autoimmunity. It is currently known that the expression of Foxp3 is a process regulated at transcriptional and post-translational level. Defects in the amounts and/or functionality of Treg have been described in patients with Systemic Lupus Erythematosus and in strains of mice that spontaneously develop lupus, although there is no information regarding the stability of Foxp3 and/or the greater or lesser expression of mediators involved in the aforementioned processes. In this project we investigate whether patients diagnosed with systemic lupus erythematosus (SLE) and NZM mice, who develop lupus spontaneously, have alterations in the quantity, quality, and stability of their Tregs, focusing especially on stability and molecules that participate in the same. The results of this project will allow a significant advance in aspects not yet studied of this cell population in autoimmune individuals and will be therapeutically relevant for the use of expanded Treg therapy in autoimmunity.