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Chronic Chlamydia Infections in Males: Impacts on Testicular Function and Spermatogenesis

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Chronic Chlamydia Infections in Males: Impacts on Testicular Function and Spermatogenesis CHRONIC CHLAMYDIA INFECTIONS IN MALES: IMPACTS ON TESTICULAR FUNCTION AND SPERMATOGENESIS Emily Rose Bryan Bachelor of Biomedical Science (Honours) Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Biomedical Sciences Faculty of Health Queensland University of Technology 2018 Keywords Chronic Chlamydia infection, male infertility, testicular infection, Sertoli cells, germ cells, Leydig cells, macrophages, spermatogenesis, sperm, DNA damage, transcriptome, offspring. Chronic Chlamydia infections in males: Impacts on testicular function and spermatogenesis i Abstract Chlamydia trachomatis is the most common cause of bacterial sexually transmitted disease worldwide. Recent estimates indicate that 131 million people have genital C. trachomatis infections. This estimate does not account for unreported and asymptomatic infections. A large proportion of infections are asymptomatic; approximately 50% of male and 75% of female infections. Screening programs have largely been targeted at women, leaving men as a potential reservoir of undetected infections. Chronic infections, which are largely uncharacterized, may develop as a result of untreated, asymptomatic colonization. C. trachomatis causes reproductive tract inflammation and damaging pathology in a large proportion of infections, potentially causing infertility in men and women. Female models of infection are more frequent than male models of infection. This has led to knowledge gaps in understanding of (i) the male immune response to chlamydial infection, (ii) cell and tissue types that are susceptible to infection and subsequent pathology in the male reproductive tract (MRT), (iii) duration of MRT infection, and (iv) effective prevention and treatment strategies for males. Currently, C. trachomatis infection has been associated with poor sperm quality, but not necessarily with pathology. Rodent models of infection revealed that Chlamydia can be found in almost the entire length of the MRT including the urethra, bladder, seminal vesicles, prostate, epididymis, and testes. An acute model of infection showed that sperm immobility and malformation compromised fertility. This was likely the result of specialized Sertoli cell and spermatogonial stem cell (SSC) death within testicular tissue. Despite ii Chronic Chlamydia infections in males: Impacts on testicular function and spermatogenesis the indications that chronic infection may be possible, the pathological effect on the MRT and on male fertility after this point remained uncharacterized. In this study, several in vitro and in vivo models were established to produce key pieces of MRT infection information, with a focus on chronic testicular infections. The hypothesis was that testicular cells are functionally compromised by chlamydial infection. This impairs spermatogenesis, and therefore fertility. Each of the testicular cell lineages have critical roles in spermatogenesis. For example, Sertoli cells form the blood-testis-barrier, SSCs are the lineage from which all sperm are produced, Leydig cells secrete androgens, and Tmφ are required for maintenance of testicular immune privilege. In the study presented here, TM3 Leydig, TM4 Sertoli, and GC-1 germ cell lines were productively infected with Chlamydia muridarum. RAW264.7 macrophages, simulating Tmφ, were also susceptible and capable of transmitting infection to the testicular cells. Infection caused DNA fragmentation and hypomethylation within TM3, TM4, and GC-1 cells. Differential gene expression analysis also revealed up- regulation of interferon-beta mediated pro-inflammatory and WBC chemokine transcripts in TM3 and GC-1 cells, and altered regulation of structural elements during a stress-like response in TM4 cells. Following intra-penile infection of C57BL/6 mice, rapid dissemination of Chlamydia to the testes occurred via macrophages. Actively replicating Chlamydia was detected at six-months post infection in the testes, indicating a chronic infection had been established. Mice had testicular histological changes including (i) significant loss of Sertoli cells, tight junctions, and Myoid cells and (ii) significantly increased testicular WBCs. Systemic anti-sperm antibodies were also detected. The testicular Chronic Chlamydia infections in males: Impacts on testicular function and spermatogenesis iii abnormalities likely contributed to the significant decreases in sperm motility, normal morphology, oocyte binding capacity, and DNA integrity. When the chronically infected mice were bred with healthy, C57BL/6 females, the offspring had decreased viability and developmental abnormalities, including having reduced body size and stunted reproductive tract growth. The sperm isolated from the male pups was also abnormal, having reduced sperm count, motility and oocyte binding capacity similar to their infected sires. The in vivo mouse studies were followed up with a human component. Chlamydia was detected in 43.75% of open testicular biopsies with Sertoli cell only, germ cell arrest, and hypospermatogenesis diagnoses. Chlamydia was also detected in three out of five fresh fine-needle testicular biopsies from current male infertility patients. The biopsies from these patients were aspermic, so IVF was unsuccessful. None of these patients had a history of STI. This study demonstrates the destructive nature of testicular chlamydial infections in fertility, and the potential for multigenerational effects on male infertility. Although only emerging as an important MRT pathogen, this study highlights the inadequacy of current chlamydial detection methods and the need for alternative treatment options other than the currently available antibiotics. This likely includes the development of a male targeted vaccine. Further investigation into the pathogenic capacity of Chlamydia within the MRT is required, particularly whether treatment can recover fertility. However, this study has provided information that fills major knowledge gaps in the literature and the foundations for further investigation to commence. iv Chronic Chlamydia infections in males: Impacts on testicular function and spermatogenesis Table of Contents Keywords .................................................................................................................................. i Abstract .................................................................................................................................... ii List of Figures ....................................................................................................................... viii List of Tables ............................................................................................................................x List of Abbreviations .............................................................................................................. xi Statement of Original Authorship ......................................................................................... xiv Acknowledgements .................................................................................................................xv Chapter 1: Introduction ............................................................................................ 1 1.1 Background .........................................................................................................................2 1.2 Hypothesis and Specific Aims of the Study ........................................................................3 1.3 Significance of the Study ....................................................................................................4 Chapter 2: Literature Review ................................................................................... 7 2.1 Chlamydial impact on the community ................................................................................8 2.2 Chlamydial Infections .......................................................................................................11 2.2.1 Chlamydial lifecycle and transmission ................................................................11 2.2.2 Chlamydial Pathogenesis .....................................................................................13 2.2.3 Chronic and Persistent Infections ........................................................................17 2.3 The Male Reproductive Tract ...........................................................................................18 2.3.1 Testicular cells and structure ...............................................................................20 2.3.2 Leydig cells ..........................................................................................................20 2.3.3 Sertoli cells ..........................................................................................................21 2.3.4 Spermatogenic cells and Spermatogenesis ..........................................................23 2.3.5 Semen and Spermatogenesis Dysregulation ........................................................25 2.3.6 Testicular macrophages .......................................................................................28 2.3.7 Chlamydia and macrophages ...............................................................................30 2.4 Male infertility and Chlamydia .........................................................................................33 2.4.1 C. trachomatis and male factor infertility ............................................................33 2.4.2 C. muridarum
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