Tailoring host immune responses to Listeria by manipulation of virulence genes -- the interface between innate and acquired immunity.
Although attenuated strains of microbial pathogens have triggered vaccine development from its origin, the role of virulence factors in determining host immunity has remained largely unexplored. Using the murine listeriosis model, we investigated whether the induction and expansion of protective and inflammatory T cell responses may be modified by selective manipulation of virulence genes. We intentionally deleted specific genes of Listeria monocytogenes, including those encoding the positive regulatory factor (prfA), hemolysin (hly), the actin nucleator (actA), and phospholipase B (plcB). The resulting strains showed decisive differences in their immunogenic properties. In particular, we identified a double-deletion mutant that retained Listeria's profound ability to induce protective CD8(+) T cells, but that is strongly attenuated and exhibits a significantly reduced ability to induce CD4(+) T cell-mediated inflammation. We conclude that this mutant, L. monocytogenes DeltaactADeltaplcB, is at present the most promising mutant for a bacterial vaccine vector and is able to safely induce potent CD8(+) T cell-mediated immunity.
Peters
Christian
C
Aventis Behring, Clinical Research and Development, 1020 First Avenue, King of Prussia, PA 19406, USA. christian.peters@aventis.com
Domann
Eugen
E
Darbouche
Abdelhak
A
Chakraborty
Trinad
T
Mielke
Martin E A
ME
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001427:Bacterial Toxins; D001428:Bacterial Vaccines; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D017353:Gene Deletion; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics; D006460:Hemolysin Proteins; D006968:Hypersensitivity, Delayed / Q000209:etiology / Q000276:immunology; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000097:blood; D008087:Listeria / Q000235:genetics / Q000472:pathogenicity; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008212:Lymphocyte Depletion; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010454:Peptide Termination Factors; D012333:RNA, Messenger / Q000096:biosynthesis; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics; D014169:Transformation, Bacterial; D010738:Type C Phospholipases / Q000172:deficiency / Q000235:genetics; D014613:Vaccines, Attenuated; D014774:Virulence / Q000235:genetics
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D001428:Bacterial Vaccines; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D008222:Lymphokines; D010454:Peptide Termination Factors; D012333:RNA, Messenger; D015534:Trans-Activators; D014613:Vaccines, Attenuated; D007371:Interferon-gamma; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; C038705:hlyA protein, Listeria monocytogenes