During syphilis infection, T. pallidum replication within primary and secondary lesions triggers a strong inflammatory response that attracts macrophages, lymphocytes and plasma cells to the site of infection. Following the appearance of an adaptive host immune response, the majority of T. pallidum cells are cleared by opsonophagocytosis, and lesions spontaneously resolve, leading to the asymptomatic stage of the disease known as latency. Despite the host’s efficient eradication, a few T. pallidum cells avoid immune clearance and persist in the host. In absence of treatment, this smoldering persistence can cause recrudescence of early symptoms or, after prolonged latency, trigger disease reactivation and progression to its tertiary stage, characterized by manifestations such as gummatous disease, cardiovascular syphilis, general paresis, or tabes dorsalis.
Dr. Giacani's work at the University of Washington focuses on the role of T. pallidum sigma (σ) factors in inducing transcriptional modifications that help the pathogen counteract the host defenses and persist in the face of an active immune response. Bacterial σ factors are proteins required for initiation of RNA synthesis that transiently bind the core RNA polymerase (cRNAP) to transcribe specific groups of genes (called regulons), each controlling a subset of cellular functions. In the rabbit model of primary syphilis, transcription of T. pallidum σ factors associated with stress response and motility (σ24 and σ28, respectively) is significantly up-regulated at the time of immune clearance with respect to all other T. pallidum σ factors, predicted to control housekeeping functions (σ70 and σ43) and nitrogen metabolism (σ54). This evidence suggests a possible causal link between σ24 and σ28 up-regulation and the appearance of phagocytosis-resistant T. pallidum cells. The implications of σ24 and σ28 up-regulation for the pathogenesis of syphilis are currently being investigated in collaboration with Drs. Sheila Lukehart and Arturo Centurion-Lara. In addition, Dr. Giacani is currently investigating T. pallidum natural competence for uptake of exogenous DNA to be used as substrate for homologous recombination.
Centurion-Lara A, Giacani L, Godornes C, Molini BJ, Brinck Reid T, Lukehart SA. Fine analysis of genetic diversity of the tpr gene family among treponemal species, subspecies and strains. PLoS NTD. 2013; 7(5): e2222.
• PLoS NTDS Abstract
Giacani L, Tompa M, Denisenko O, Lukehart SA, Centurion-Lara A. Identification of the Treponema pallidum subsp. pallidum TP0092 (RpoE) regulon and its
implications for pathogen persistence in the host and syphilis pathogenesis. J Bacteriol. 2013; 195(4): 896-907.
• PubMed Abstract
Giacani L, Brandt SL, Puray-Chavez M, et al. Comparative investigation of the genomic regions involved in antigenic variation of the TprK antigen among treponemal species, subspecies, and strains. J Bacteriol. 2012; 194(16), 4208-25.
• PubMed Abstract
Giacani L, Chattopadhyay S, Centurion-Lara A, et al. Footprint of positive selection in Treponema pallidum subsp. pallidum genome sequences suggests adaptive microevolution of the syphilis pathogen. PLoS NTD. 2012; 6(6): e1698.
• PLoS NTD Abstract
Giacani L, Jeffrey BM, Molini BJ, et al. Complete genome sequence and annotation of the Treponema pallidum subsp. pallidum Chicago strain. J Bacteriol. 2010; 192(10): 2645-6.
• NCBI Abstract
Giacani L, Molini BJ, Kim EY, et al. Antigenic variation in Treponema pallidum: TprK sequence diversity accumulates in response to immune pressure during experimental syphilis. J Immunol. 2010; 184(7): 3822-9.
• NCBI Abstract