Pathogenic Neisseria infections of human neutrophils and epithelial cells: focusing on host responses and immune evasion

By: Niklas Söderholm
Opponent: Prof. Thomas Rudel, University of Würzburg, Germany
Host: Helena Aro

N. meningitidis and N. gonorrhoeae are obligate human pathogens that colonize mucosal surfaces and are often carried asymptomatically. These bacteria have developed adhesive structures that promote adherence to host cells and efficient colonization of new hosts. N. gonorrhoeae causes the sexually transmitted disease gonorrhea, which remains one of the most common sexually transmitted diseases, despite the availability of effective antibiotic treatments. N. meningitidis is frequently found in the nasopharynx of healthy individuals as a part of the normal microbiota. However, this bacterial species is a major cause of mortality when it causes septicemia and epidemic meningitidis. The design of vaccines conferring protection against multiple serogroups is difficult; this fact, combined with increased global resistance to antibiotics, emphasizes the need for a better understanding of the pathogenesis of these species. The aim of this thesis was to study the effects of bacterial adherence to human neutrophils (PMNs) and epithelial cells. The adherence of N. meningitidis and N. gonorrhoeae to primary PMNs was investigated in Paper I. Specific adherence of the bacteria to the PMN uropod was observed. By adhering to the uropod, the bacteria could avoid phagocytosis and use the migrating PMNs for transportation. The type IV pilus, which is a known bacterial adhesin, was found to promote uropod adherence. In Paper II, adherence of N. gonorrhoeae to non-polarized cervical and vaginal epithelial cells was found to cause DNA damage and delay cell cycle progression. Upregulation and nuclear localization of the cyclin-dependent kinase inhibitors p21 and p27 were observed, which could contribute to reduced cell proliferation. Interestingly, the levels of tumor suppressing protein 53 (TP53) were affected by bacterial colonization in a non-tumor cell line. In Paper III, colonization by Lactobacillus spp. was found to induce the accumulation of host cells in G1 phase and the upregulation of p21. The adherence of N. gonorrhoeae to polarized epithelial cells and the impact of PMN presence were investigated in Paper IV. N. gonorrhoeae adherence to polarized epithelial cells was significantly higher than adherence to non polarized cells. Cell culture medium containing degranulated products from stimulated PMNs was found to promote bacterial adherence. Finally, PMNs with bacteria adhered to the uropod were able to transport the bacteria through a polarized cell layer. In summary, this thesis investigates the impact of adhesion of pathogenic Neisseria spp. to host epithelial cells and PMNs.