Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 78-98).

Clinical and epidemiological studies have provided a large body of evidence supporting a link between HIV and other sexually transmitted co-infections. Co-infections have been associated with promoting HIV transmission and acquisition. One of the closest studied interactions is the co-infection with N. gonorrhoeae, the etiological agent of gonorrhea, yet a clear understanding of this relationship is still elusive. Studies aimed at deciphering how N. gonorrhoeae mediates these effects have provided mixed results with some suggesting co-infection promotes HIV replication, and others suggesting the opposite. The aim of this thesis is to uncover molecular mechanisms that explain these results through in vitro co-infection studies using a combination of mixed peripheral mononuclear blood cells (PBMCs) and isolated human cell types. The results presented here demonstrate that gonococcal co-infection profoundly inhibits HIV replication in co-infected PBMCs. This inhibition is due to both the release of anti-HIV IFN via TLR9-mediated activation of plasmacytoid dendritic cells (pDCs), and the activation of  T cells. In addition, I show that responses between CD4+ T cell lines, such as the Jurkat cell line, and primary CD4+ T cells can differ, which may explain some of the contrasting results seen in published literature. The results in this thesis have implications for understanding the relationship between gonococci and HIV, providing new insight into molecular and immunological interactions that influence viral transmission, and reveal new opportunities to combat HIV.

Highly infectious pathogenic strains of bacteria are becoming increasingly resistant to the current clinical antibiotics which have created a dire need for the development of novel antibiotics. O-Acetylpeptidoglycan esterase 1 (Ape1) is a periplasmic esterase present in several peptidoglycan (PG) O-acetylating pathogenic species of Gram-positive and all Gram-negative bacteria that perform this modification to this essential cell wall polymer. Inhibition of this growth-limiting enzyme may prove the principle that Ape1 has the potential to be the target for the development of a novel class of antibiotics. Ape1 plays a crucial role in bacterial growth by regulating PG turnover through catalytic removal of the C-6 acetyl group from O-acetylPG. This activity is required for the continued metabolism of PG because the major autolytic enzymes involved, the lytic transglycosylases, require a free C-6 hydroxyl group to produce their reaction product, 1,6-anhydromuramic acid. Several of the compounds that have been identified to effectively inhibit Ape1, were re-evaluated by determining their kinetic parameters. Work presented in this thesis explored the inhibitory potential of these compounds, belonging to the anthraquinone (alizarin, quinizarin, quinalizarin, emodin, sennoside A) or tannin (ellagic acid) families of compounds, both in vitro and in vivo, among species of bacteria that are known to O-acetylate their PG. Of the inhibitory compounds tested, ellagic acid was found to be most effective in vitro, with an IC50 value of 0.91 µM ± 0.06, Ki 1.18 ± 0.04 and in vivo it was shown to reduce bacterial growth.

Clinical and epidemiological studies have provided a large body of evidence supporting a link between HIV and other sexually transmitted co-infections. Co-infections have been associated with promoting HIV transmission and acquisition. One of the closest studied interactions is the co-infection with N. gonorrhoeae, the etiological agent of gonorrhea, yet a clear understanding of this relationship is still elusive. Studies aimed at deciphering how N. gonorrhoeae mediates these effects have provided mixed results with some suggesting co-infection promotes HIV replication, and others suggesting the opposite. The aim of this thesis is to uncover molecular mechanisms that explain these results through in vitro co-infection studies using a combination of mixed peripheral mononuclear blood cells (PBMCs) and isolated human cell types. The results presented here demonstrate that gonococcal co-infection profoundly inhibits HIV replication in co-infected PBMCs. This inhibition is due to both the release of anti-HIV IFN via TLR9-mediated activation of plasmacytoid dendritic cells (pDCs), and the activation of  T cells. In addition, I show that responses between CD4+ T cell lines, such as the Jurkat cell line, and primary CD4+ T cells can differ, which may explain some of the contrasting results seen in published literature. The results in this thesis have implications for understanding the relationship between gonococci and HIV, providing new insight into molecular and immunological interactions that influence viral transmission, and reveal new opportunities to combat HIV.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 3 uppsatser.

Thesis (M.Sc. (Microbiology))--University of Medical Sciences, 1967.

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references (leaves [141]-172).

Techn. Univ., Diss., 2010--München.

Thèse (M.Sc.)--Université Laval, 2004. / Bibliogr.: f. 62-76. Publié aussi en version électronique.