The Role of the Immune Response in Chlamydia trachomatis Infection of the Male Genital Tract: A Double-Edged Sword

Abstract

Chlamydia trachomatis (CT) is the most prevalent bacterial sexually transmitted infection in the world, with more than 100 million cases reported annually. While there have been extensive studies into the adverse effects that CT infection has on the female genital tract, and on the subsequent ability of these women to conceive, studies into the consequences on male fertility have been limited and controversial. This is in part due to the asymptomatic nature of the infection, where it is estimated that 50% of men with Chlamydia fail to show any symptoms. It is accepted, however, that acute and/or persistent CT infection is the causative agent for conditions such as urethritis, epididymitis, epididymo-orchitis, and potentially prostatitis. As with most infections, the immune system plays a fundamental role in the body's attempts to eradicate the infection. The first and most important immune response to Chlamydia infection is a local one, whereby immune cells such as leukocytes are recruited to the site of infections, and subsequently secrete pro-inflammatory cytokines and chemokines such as interferon gamma. Immune cells also work to initiate and potentiate chronic inflammation through the production of reactive oxygen species (ROS), and the release of molecules with degradative properties including defensins, elastase, collagenase, cathespins, and lysozyme. This long-term inflammation can lead to cell proliferation (a possible precursor to cancer), tissue remodeling, and scarring, as well as being linked to the onset of autoimmune responses in genetically disposed individuals. This review will focus on the ability of the immune system to recognize and clear acute and persistent chlamydial infections in the male genital tract, and on the paradoxical damage that chronic inflammation resulting from the infection can cause on the reproductive health of the individual.

Keywords: Chlamydia; infection; inflammation; male fertility; persistence.

Figure 1

Chlamydia undergo a unique biphasic developmental cycle. The infectious form of Chlamydia, the elementary body (EB) enters into the host cell via endocytosis. Upon entry, the EB convert into the metabolically active, non-infectious reticulate body (RB), which replicates within a vaculolar compartment, termed the inclusion. Once the developmental cycle is almost complete, the RBs revert back into EBs, stimulating host cell lysis and release of the infectious EBs into the extracellular space. These EBs then move onto to infect new host cells. Adapted from Roan and Starnbach (346).

Figure 2

Mammalian spermatogenesis occurs within the seminiferous tubules of the testis, with development of the mature sperm cells occurring in a radial fashion from the basement membrane into the lumen. Spermatogonia reside on the basement membrane and undergo mitotic division to produce pre-leptotene spermatocytes. These primary spermatocytes undergo meiosis to give two pachytene spermatocytes, which in turn undergo meiosis to give round spermatids. These cells elongate and develop into mature spermatozoa. Sertoli cells support the germ cells as they develop, providing essential nutrients. Adapted from ‘Spermatogenesis Online’. Reproduction Data Systems 2011–2012. mcg.ustc.edu.cb/sdap1/spermgenes

Figure 3

The presence of the blood–testis barrier creates a region of immune privilege within the testis. At the onset of puberty, developing sperm cells express novel antigens that the immune system would normally identify as “foreign.” However, segregation of antigens in the seminiferous tubules from the immune cells that are able to enter into the interstitial space of the testis prevents the body from eliciting an immune response against these vulnerable cells. Adapted from ‘Blood-Testis Barrier’. Immunopaedia.org 2010. www.immunopaedia.org.za/index.php?id+668

Figure 4

Innate and adaptive immune responses to Chlamydia infection. Upon infection, antigen presenting cells (APC) such as macrophages and dendritic cells are sequestered to the site of infection where they begin to release pro-inflammatory cytokines such as IFNγ and IL-12. The chemokines in turn activate natural killer (NK) cells and induce the maturation of T cells into either CD8⁺ or CD4⁺ T cells. CD4⁺ T cells go on to form either T-helper 1 (Th1) or T-helper 2 type (Th2) T cells. Th1 cell interact with B cells via the T cell receptor (TCR) and the major histocompatibility complex (MHC) to produce antibodies against the chlamydial infection.