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Infection and Immunity, August 2008, p. 3439-3450, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00245-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Selected prfA* Mutations in Recombinant Attenuated Listeria monocytogenes Strains Augment Expression of Foreign Immunogens and Enhance Vaccine-Elicited Humoral and Cellular Immune Responses{triangledown}

Lin Yan,1,2,{dagger} Jin Qiu,1,2,{dagger} Jianbo Chen,1,2,3,{dagger} Bridgett Ryan-Payseur,1,2 Dan Huang,1,2 Yunqi Wang,1,2 Lijun Rong,1 Jody A. Melton-Witt,4 Nancy E. Freitag,1 and Zheng W. Chen1,2*

Department of Microbiology and Immunology,1 Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, Illinois 60612,2 Department of Microbiology, Sun Yat-sen University, Guangzhou, China 510080,3 Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-32024

Received 20 February 2008/ Returned for modification 5 April 2008/ Accepted 22 April 2008

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.

* Corresponding author. Mailing address: MC790, 909 S. Wolcott Ave., Chicago, IL 60612. Phone: (312) 355-0531. Fax: (312) 996-6415. E-mail: zchen{at}uic.edu

{triangledown} Published ahead of print on 12 May 2008.

Editor: A. J. Bäumler

{dagger} L.Y., J.Q., and J.C. contributed equally to this work.

Infection and Immunity, August 2008, p. 3439-3450, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00245-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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