Dottorato in MALATTIE INFETTIVE, MICROBIOLOGIA E SANITA' PUBBLICA

Titolo della tesi: CHLAMYDIA TRACHOMATIS IN THE ETIOPATHOGENESIS OF MALE INFERTILITY: ALTERATIONS OF THE STRUCTURAL AND FUNCTIONAL INTEGRITY OF HUMAN SERTOLI CELLS

Chlamydia trachomatis has recently acquired clinical importance in male infertility for it is known to disseminate to the upper genital tract, causing epididymitis or epididymo-orchitis, well established risk factors for infertility, although, to date, the correlation between C. trachomatis and male infertility is still largely unexplored. In recent years, it has been hypothesized that C. tra-chomatis might contribute to male infertility by altering the testicular epitheli-um via the infection of Sertoli cells. Sertoli cells are key elements for the sper-matogenesis, guiding germ cell development and protecting them against in-fectious agents through the activation of innate immune pathways like toll-like receptors. In our research, we investigated, for the first time, the cellular and mo-lecular mechanisms underlying C. trachomatis infection of primary human Ser-toli cells in the etiopathogenesis of male infertility. To do so, we set up an in vitro infection model of primary human Sertoli cells with C. trachomatis serovar D to study the integrity of F-actin, Vimentin and Tubulin fibres by confocal microscopy, and the host cell response to C. trachomatis via the de-termination of TLRs as well as the respective signaling pathways and inflam-matory cytokines (e.g. IL-1α, IL-6 and IFNs). Our results demonstrated C. trachomatis ability to infect Sertoli cells as well as to remain within them for a long time, inducing a generalized alteration of the cell cytoskeleton. In particular, this was characterized by the lack of F-actin ring surrounding chlamydial inclusions, that might explain the absence of cell lysis observed in Chlamydia-infected Sertoli cells up to 96 hours post in-fection. Lastly, the prevalent activation of TLR3 followed by the inhibition of NF-κB and IRF-3 and the absent production of inflammatory cytokines, as demonstrated in our study, hinted to the hypothesis that C. trachomatis might evade the host-cell response, and, hence, generate a chronic infection. Overall, our data suggest possible mechanisms underlying the disorders of the male re-productive system caused by C. trachomatis infection (Filardo S et al., Sci. Rep. 2019; Di Pietro M et al., J. Biol. Regul. Homeost. Agents 2020).