Studies initiated to identify factors involved in the pathogenesis of infections caused by the pathogenic Neisseria species (N. Gonorrhoeae, N. Meningitidis) showed that apart from variable expressed outer membrane surface antigens such as pili, opacity (Opa) proteins, and lipopolysaccharide (LPS), host environmental factors are key determinants of infection. Using a mammalian epithelial cell line defective in gonococcal uptake, bacterial entry was restored by a glycoprotein present in normal human serum. Other serum factors inhibited the binding of the Opa adhesin to the previously identified heparan sulfate proteoglycan receptor present on human mucosal cells. One of the inhibitory serum components was identified as a polyanionic polysacchardie. Another inhibitory compound in serum is CMP-NANA which is a natural substrate for the neisserial LPS sialyltransferase that mediates the transfer of sialic acid onto LPS. In vitro infection experiments and bactericidal assys with an available gonococcal LPS sialyltransferase mutant showed that the incorporation of host-derived CMP-NANA into certain LPS phenotypes is essential for the previously reported LPS variation-related modulation of bacterial entry into mucosal cells and bacterial resistance to complement-mediated killing. In collaboration with several other investigators, surface variation of the closely-related pathogen N. Meningitidis was found to be a critical determinant of infection as well. In a developed in vitro infection model of primary cultures of human nasopharyngeal cells, bacterial colonization and penetration of the mucosal barrier were associated with alterations in capsule expression, lipopolysaccharide, piliation as well as opacity protein (Opa/Opc) expression. Two genetic mechanisms of capsule variation in N. Meningitidis were identified. One is based on the presence of a transposable genetic element that reversibly inactivates an essential sialic acid capsule biosynthesis gene. The other involves spontaneous reversible changes in a homopolymeric stretch of cytidine residues in a different essential capsule biosynthesis gene, resulting in a frame shift and variation in capsule expression. The latter mechanism was found to occur in clinical meningococcal isolates and was associated with outbreak of meningococcal disease.
| Matheu, Melanie P; Teijaro, John R; Walsh, Kevin B et al. (2013) Three phases of CD8 T cell response in the lung following H1N1 influenza infection and sphingosine 1 phosphate agonist therapy. PLoS One 8:e58033 |
