4.4 Article

Selected prfA* mutations in recombinant attenuated Listeria monocytogenes strains augment expression of foreign immunogens and enhance vaccine-elicited humoral and cellular immune responses

Journal

INFECTION AND IMMUNITY
Volume 76, Issue 8, Pages 3439-3450

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00245-08

Keywords

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Funding

  1. National Institutes of Health [HL64560, RR13601, A141816]
  2. U01 grant [A1070426]

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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 Delta actA 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 Delta actA prfA* vaccine strains were as attenuated as the recombinant parent L. monocytogenes Delta actA vaccine vector. Thus, recombinant attenuated L. monocytogenes Delta actA prfA* vaccine vectors potentially are better antimicrobial and anticancer vaccines.

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