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Infection and Immunity, July 2002, p. 3948-3952, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3948-3952.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Sigma B Contributes to PrfA-Mediated Virulence in Listeria monocytogenes

Celine A. Nadon, Barbara M. Bowen, Martin Wiedmann, and Kathryn J. Boor*

Department of Food Science, Cornell University, Ithaca, New York

Received 20 February 2002/ Returned for modification 18 March 2002/ Accepted 4 April 2002


   ABSTRACT
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Transcription of the Listeria monocytogenes positive regulatory factor A protein (PrfA) is initiated from either of two promoters immediately upstream of prfA (prfAp1 and prfAp2) or from the upstream plcA promoter. We demonstrate that prfAp2 is a functional {sigma}B-dependent promoter and that a sigB deletion mutation affects the virulence phenotype of L. monocytogenes. Thus, the alternative sigma factor {sigma}B contributes to virulence in L. monocytogenes.


   TEXT
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Bacterial survival within a host and establishment of infection depend in part on the ability of pathogenic bacteria to modulate gene expression in response to environmental conditions encountered during infection. Associations between alternative sigma factors and core RNA polymerase provide one mechanism for timely alterations in gene expression by directing transcription of different regulons in response to cellular signals (17). Alternative sigma factors have been demonstrated to contribute to cellular survival under adverse conditions. For example, the stress-responsive alternative sigma factor {sigma}B contributes to the ability of stationary-phase Listeria monocytogenes cells to adapt to and resume growth at reduced temperatures (3). {sigma}B also has been shown to contribute to L. monocytogenes survival under in vitro conditions of oxidative stress, starvation, and reduced pH (9). In addition to its presence in L. monocytogenes, {sigma}B has been identified in diverse gram-positive organisms, including Listeria innocua, Staphylococcus aureus, Bacillus subtilis, Bacillus anthracis, Bacillus licheniformis, and Staphylococcus epidermidis (2, 5, 10, 13, 14, 15, 18, 23, 24). Preliminary evidence suggests that {sigma}B may contribute to virulence in gram-positive pathogens (8, 10, 15, 16, 23). We hypothesize that bacterial virulence capabilities are linked with environmental stress responses mediated by alternative sigma factors and thus propose that stress-responsive alternative sigma factors (and specifically {sigma}B) contribute to the ability of L. monocytogenes to cause disease. In this report, we demonstrate that {sigma}B contributes to regulation of L. monocytogenes virulence gene expression and that loss of {sigma}B function impairs L. monocytogenes virulence in a murine model.

Loss of {sigma}B impairs L. monocytogenes virulence in a murine model. In previous work, we found modest effects of a {Delta}sigB mutation on L. monocytogenes virulence in the murine model. Specifically, when the wild-type and {Delta}sigB strains were inoculated separately into individual animals, the {Delta}sigB strain was found to be impaired in its ability to spread to murine liver and spleen (23). In this report, we describe the application of a competitive-index method (1), which is designed to control for multiple experimental variables, including interanimal variability (23), to sensitively assess virulence differences between bacterial strains. For competitive-index studies, equal numbers of two different strains, one of which must bear a selectable marker, are inoculated into the same animal, and then both strains are enumerated at multiple postinfection time points (1). To ensure that the presence of the selectable marker does not confer a competitive advantage or disadvantage, a control mixture, which is comprised of the strain bearing the marker and an otherwise isogenic strain lacking the marker, is tested in parallel.

The relative virulence of a {Delta}sigB null mutant was determined using a competitive-index strategy in a murine model of listeriosis as described by Auerbuch et al. (1). Cultures of 10403S, DP-L3903 (erythromycin-resistant [Ermr] 10403S), and FSL A1-254 ({Delta}sigB; erythromycin sensitive [Erms]) (Table 1) were grown in brain heart infusion broth (BHI; Becton Dickinson, Sparks, Md.) at 37°C with shaking (250 rpm). Inocula for competitive-index experiments were prepared by mixing L. monocytogenes strains in a 1:1 ratio according to spectrophotometrically determined cell density (optical density at 600 nm), which had been verified by plating to yield equal numbers of viable cells. The test mixture consisted of equal numbers of the Erms {Delta}sigB mutant and the Ermr DP-L3903; the control mixture consisted of the Erms 10403S parent strain and the Ermr DP-L3903. The cells were washed, resuspended in phosphate-buffered saline, and diluted to 104 or 109 CFU per 100 µl. Ten mice (female BALB/c; 5 weeks old) were each administered either the test or control inoculum either intragastrically (109 CFU) or intraperitoneally (i.p.) (104 CFU). Four mice were inoculated with sterile phosphate-buffered saline. Food was withheld from the mice for 5 h prior to infection. The mice were sacrificed at 2 and 4 days postinfection. The mice were housed in an Association for Assessment and Accreditation of Laboratory Animal Care-International-accredited facility, and animal experiments were reviewed and approved by Cornell University's Institutional Animal Care and Use Committee.


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  		TABLE 1. L. monocytogenes strainsa

 
To quantify L. monocytogenes cells in mouse livers and spleens, the organs were homogenized in a nonionic detergent (0.2% Igepal CA-630; Sigma Chemical Co., St. Louis, Mo.), and serial 10-fold dilutions were plated on BHI agar and incubated at 37°C for 24 h. Plates with 30 to 150 colonies were replica plated onto BHI agar containing 1 µg of erythromycin/ml. Differential enumeration was conducted as follows: Erms L. monocytogenes = total colonies on BHI - total colonies on BHI-erythromycin (Ermr L. monocytogenes). The competitive index was calculated as the ratio of Ermr L. monocytogenes to Erms L. monocytogenes. As log-transformed competitive indices were normally distributed within each treatment group, parametric procedures were used for statistical analyses. Statistix version 7.0 was used for statistical hypothesis testing and multiple regression.

Our multivariate experimental design defined virulence (competitive index) as an additive function of the bacterial strain (test mixture [Erms {Delta}sigB strain + Ermr wild type] versus control mixture [Erms parent strain + Ermr wild type]), route of infection (i.p. or intragastric), time postinfection (2 or 4 days), and organ tested (liver or spleen), which enabled us to control for the coordinate effects of these variables. Log10 CFU/g recovered from mouse livers and spleens at 2 or 4 days postinfection is shown in Table 2. Higher numbers of the wild-type Ermr DP-L3903 than of the {Delta}sigB strain were recovered from the livers (P = 0.109) and spleens (P = 0.013) of i.p.-infected animals after 4 days. When the data were analyzed using the competitive-index strategy, the index generated for bacteria recovered after 4 days from the spleens of mice that had been infected i.p. with the test mixture (Erms {Delta}sigB mutant and Ermr DP-L3903) was higher than the index for the corresponding mice infected with the control mixture; this difference was statistically significant (Table 3). There was a similar trend in the indices from the livers of i.p.-infected mice, although it was not statistically significant. In summary, the results from the index analyses demonstrate that the {Delta}sigB strain is slightly impaired in its ability to spread to the murine spleen following i.p. infection, further supporting the hypothesis that {sigma}B-regulated gene expression contributes to infection and virulence at specific temporal and spatial points during host-agent interactions.


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  		TABLE 2. Recovery of L. monocytogenes wild-type 10403S and {Delta}sigB from tissues of infected mice after intragastric or i.p. infection

 

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  		TABLE 3. Ratios of log-transformed Ermr to Erms bacterial isolates expressed as competitive indices and 95% confidence intervalsa

 
{sigma}B contributes to PrfA-directed virulence in vitro. Expression of the majority of recognized virulence genes in L. monocytogenes is regulated by the positive regulatory factor A protein (PrfA) (7, 11). PrfA is a DNA binding protein that recognizes a 14-bp palindrome in the promoter region of the virulence genes under its control (11). Previous studies have revealed that prfA transcription can be directed by three promoters: prfAp1 and prfAp2, which are located immediately upstream of prfA, as well as the upstream plcA promoter, which directs expression of a plcA-prfA read-through transcript (Fig. 1) (12). We hypothesized that {sigma}B contributes to virulence gene expression through direction of transcription at the prfAp2 promoter, which we proposed to be {sigma}B dependent, based on prfAp2's sequence similarity to known {sigma}B-dependent promoters. Compared with known {sigma}B-dependent promoters, the prfAp2 sequence, 5' TTGTTACT-N14-GGGTAT 3' (GenBank accession no. AJ002742), was found to strongly resemble the consensus sequences for the -35 and -10 regions of {sigma}B-dependent promoters identified in B. subtilis (19), B. anthracis (10), S. aureus (13), and L. monocytogenes (2, 23).



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  		FIG. 1. Map of the L. monocytogenes plcA-prfA region.

 
Previous studies had shown that deletion of either prfAp1 or prfAp2 affected in vitro expression of PrfA-regulated genes (12). Unexpectedly, in spite of these in vitro observations, strains with deletions in either promoter were fully virulent in vivo. Deletion of both P1 and P2, however, resulted in significant virulence attenuation (12). Based on these observations, we predicted that the phenotype of a {Delta}sigB {Delta}prfAp1 double mutant should be identical to that of a {Delta}prfAp1 {Delta}prfAp2 double mutant if prfAp2 is indeed activated in a {sigma}B-dependent fashion. Therefore, we constructed a {Delta}sigB {Delta}prfAp1 double mutant (FSL B2-002 [Table 1]) to evaluate the functional importance of {sigma}B-dependent transcription from the prfAp2 promoter. The {Delta}sigB {Delta}prfAp1 double mutant strain was created by allelic-exchange mutagenesis following introduction of the Escherichia coli-L. monocytogenes shuttle vector pTJA57 (pKSV7 bearing sigB with an internal deletion [23]) into DP-L1956 ({Delta}prfAp1). Electroporation and allelic exchange were done as previously described (6).

To examine specific {sigma}B contributions to PrfA-mediated virulence, the relative characteristics of L. monocytogenes strains 10403S, FSL A1-254 ({Delta}sigB), DP-L1956 ({Delta}prfAp1), DP-L1957 ({Delta}prfAp2), DP-L1964 ({Delta}prfAp1 {Delta}prfAp2), and FSL B2-002 ({Delta}sigB {Delta}prfAp1) (Table 1) were assessed by (i) plaque assays in mouse L cells, (ii) an intracellular-growth assay in mouse macrophage-like J774 cells, and (iii) an in vitro hemolysis assay. The mouse L-cell plaque assay was performed as previously described (22) to evaluate the intracellular-spreading capabilities of the different strains. Briefly, L. monocytogenes 10403S, DP-L1956 ({Delta}prfAp1), DP-L1957 ({Delta}prfAp2), DP-L1964 ({Delta}prfAp1 {Delta}prfAp2), and FSL B2-002 ({Delta}sigB {Delta}prfAp1) were grown overnight at 30°C (without shaking) and inoculated at approximately 3 x 104 CFU per well onto a monolayer of mouse L cells grown in six-well plates. The inocula were enumerated by plating serial dilutions on BHI agar. Plaque sizes were measured and expressed relative to the plaque size of the wild-type 10403S strain, which was assigned a plaque size of 100%. As had been reported previously for the {Delta}prfAp1 {Delta}prfAp2 double mutant (12), in our experiments, both double mutants ({Delta}prfAp1 {Delta}prfAp2 and {Delta}sigB {Delta}prfAp1) produced some plaques that were similar in size to those observed for the wild-type 10403S strain, while others were substantially smaller (data not shown). In contrast, all control strains (wild-type 10403S, {Delta}sigB, {Delta}prfAp1, and {Delta}prfAp2) showed uniform plaques of similar size. The average plaque sizes for the {Delta}prfAp1 {Delta}prfAp2 double mutant and the {Delta}sigB {Delta}prfAp1 double mutant were substantially smaller (67 and 76%, respectively; average of four independent experiments) than the plaques formed by the wild-type parent strain, 10403S (100%). The plaque size was approximately 91% of the wild type for either single mutant (average of four independent experiments).

The intracellular-growth assay was conducted as described previously (20). Both double mutants ({Delta}sigB {Delta}prfAp1 and {Delta}prfAp1 {Delta}prfAp2) showed delayed intracellular growth compared to the wild-type parent strain, 10403S, and the {Delta}prfAp1 and {Delta}prfAp2 strains (Fig. 2). Specifically, although equal numbers of each strain had been introduced at the initiation of infection, the intracellular numbers of both double mutants were lower than those observed for the wild type and both single mutant strains at 4 h postinfection and throughout the remaining 24 h. The {Delta}prfAp2 mutant demonstrated the same intracellular growth and spread as wild-type 10403S, while the L. monocytogenes {Delta}prfAp1 mutant showed slight attenuation (Fig. 2). The results from both the intracellular-growth assay (Fig. 2) and the mouse L-cell plaque assay showed that loss of {sigma}B function ({Delta}sigB) combined with a deletion in the -10 region of prfAp1 resulted in a striking temporally associated reduction in virulence, identical to the phenotype found when both prfAp1 and prfAp2 were deleted.



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  		FIG. 2. Intracellular growth of L. monocytogenes {Delta}sigB and prfA promoter mutant strains in mouse macrophage-like J774 cells. The data are shown as the mean CFU per coverslip and standard errors (bars) of six independent experiments. Equal numbers of viable cells were added to each well at infection initiation. At each time point, the numbers of recovered {Delta}sigB {Delta}prfAp1 and {Delta}prfAp1 {Delta}prfAp2 strains were lower than those of wild-type 10403S, {Delta}prfAp1, or {Delta}prfAp2. {blacksquare}, 10403S; {circ}, {Delta}prfAp2; •, {Delta}prfAp1; {triangleup}, {Delta}sigB {Delta}prfAp1; {blacktriangleup}, {Delta}prfAp1 {Delta}prfAp2.

 
Hemolytic activity was assayed as previously described (20) using overnight cultures of L. monocytogenes 10403S, DP-L1956 ({Delta}prfAp1), DP-L1957 ({Delta}prfAp2), DP-L1964 ({Delta}prfAp1 {Delta}prfAp2), and FSL B2-002 ({Delta}sigB {Delta}prfAp1). The results were reported as percent hemolysis relative to the wild type. Specifically, data were normalized to the hemolytic activity of strain 10403S, which was assigned a value of 100%. Hemolytic activities for the {Delta}sigB and {Delta}prfAp2 mutants were very similar to those of the wild-type strain, whereas the {Delta}prfAp1 mutant showed a nearly threefold reduction in hemolytic activity compared to the wild type (Table 4), which is also consistent with the intracellular growth attenuation phenotype displayed by the {Delta}prfAp1 strain (Fig. 2). As with the {Delta}prfAp1 {Delta}prfAp2 double mutant, the {Delta}sigB {Delta}prfAp1 double mutant showed no hemolytic activity (Table 4). Our hypothesis that loss of {sigma}B activity has the same effect as deletion of prfAp2 is supported by the fact that the phenotype of our {Delta}sigB {Delta}prfAp1 double mutant resembles that of the previously described {Delta}prfAp1 {Delta}prfAp2 double mutant (12).


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  		TABLE 4. Hemolytic activities of L. monocytogenes {Delta}sigB and prfA promoter mutant strainsa

 
We conclude that the P2 promoter of prfA is indeed {sigma}B dependent and that {sigma}B directly contributes to virulence via regulation of prfA expression. This conclusion is consistent with the previous observation that expression of some PrfA-dependent proteins, including ActA, is induced under stress conditions, such as heat shock or entry into stationary phase (21). In parallel, L. monocytogenes {sigma}B activity also increases following exposure of cells to heat and upon entry into stationary phase (2). Our discovery that prfAp2 is a bona fide {sigma}B-dependent promoter extends the work of Freitag and Portnoy, who showed that although elimination of either prfAp1 or prfAp2 affected in vitro expression of PrfA-regulated genes, strains with either of these mutations remained fully virulent in vivo (12). Expression of a global virulence gene regulator under the direction of multiple sigma factors (e.g., {sigma}A and {sigma}B) may help to ensure that virulence factors are efficiently transcribed as needed under a wide variety of in vivo environmental conditions. Thus, loss of either the {sigma}A-dependent prfAp1 or the {sigma}B-dependent prfAp2 promoter may result in only subtle virulence defects that may be undetectable in commonly used animal models.


   ACKNOWLEDGMENTS
 
We thank our colleagues for their assistance: J. Scarlett for statistical analyses, E. Fortes for animal experiments and plaque assays, C. Brown and J. Lewis for mouse inoculations, M. Roma for cell culture, B. Miller for construction of double mutants, and A. Roberts for reviewing the manuscript. Strains DP-L3903, DP-L1956, DP-L1957, and DP-L1964 were gifts from D. Portnoy. We thank V. Auerbuch for her consultation on the competitive-index model.

This research was supported in part by the Cornell University Agricultural Experiment Station federal formula funds, Project no. NYC-143422, received from Cooperative State Research, Education, and Extension Service, U.S. Department of Agriculture (to M.W.).

Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture.


   FOOTNOTES
 
* Corresponding author. Mailing address: Department of Food Science, 413 Stocking Hall, Cornell University, Ithaca, NY 14853. Phone: (607) 255-3111. Fax: (607) 254-4868. E-mail: kjb4{at}cornell.edu. Back

Editor: J. T. Barbieri


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Infection and Immunity, July 2002, p. 3948-3952, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3948-3952.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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