title: Selected prfA* mutations in recombinant attenuated Listeria monocytogenes strains augment expression of foreign immunogens and enhance vaccine-elicited humoral and cellular immune responses.
abstract: While recombinant Listeria monocytogenes strains can be explored as vaccine candidates, it is important to develop attenuated but highly immunogenic L. monocytogenes vaccine vectors. Here, prfA* mutations selected on the basis of upregulated expression of L. monocytogenes PrfA-dependent genes and proteins were assessed to determine their abilities to augment expression of foreign immunogens in recombinant L. monocytogenes vectors and therefore enhance vaccine-elicited immune responses (a prfA* mutation is a mutation that results in constitutive overexpression of PrfA and PrfA-dependent virulence genes; the asterisk distinguishes the mutation from inactivation or stop mutations). A total of 63 recombinant L. monocytogenes vaccine vectors expressing seven individual viral or bacterial immunogens each in nine different L. monocytogenes strains carrying wild-type prfA or having prfA* mutations were constructed and investigated. Mutations selected on the basis of increased PrfA activation in recombinant L. monocytogenes prfA* vaccine vectors augmented expression of seven individual protein immunogens remarkably. Consistently, prime and boost vaccination studies with mice indicated that the prfA(G155S) mutation in recombinant L. monocytogenes DeltaactA prfA* strains enhanced vaccine-elicited cellular immune responses. Surprisingly, the prfA(G155S) mutation was found to enhance vaccine-elicited humoral immune responses as well. The highly immunogenic recombinant L. monocytogenes DeltaactA prfA* vaccine strains were as attenuated as the recombinant parent L. monocytogenes DeltaactA vaccine vector. Thus, recombinant attenuated L. monocytogenes DeltaactA prfA* vaccine vectors potentially are better antimicrobial and anticancer vaccines.
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Jin
authors.initials: J
authors.lastname: Qiu
authors.forename: Jianbo
authors.initials: J
authors.lastname: Chen
authors.forename: Bridgett
authors.initials: B
authors.lastname: Ryan-Payseur
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Wang
authors.forename: Lijun
authors.initials: L
authors.lastname: Rong
authors.forename: Jody A
authors.initials: JA
authors.lastname: Melton-Witt
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Freitag
authors.forename: Zheng W
authors.initials: ZW
authors.lastname: Chen
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D001428:Bacterial Vaccines / Q000235:genetics / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000096:biosynthesis; D008089:Listeria monocytogenes / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010454:Peptide Termination Factors / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000914:Antibodies, Viral; D001428:Bacterial Vaccines; D010454:Peptide Termination Factors; D011994:Recombinant Proteins; D014613:Vaccines, Attenuated; D007371:Interferon-gamma