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Infection and Immunity, July 1999, p. 3667-3669, Vol. 67, No. 7
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Isolation and Characterization of a sigB Deletion Mutant of Staphylococcus aureus

R. O. Nicholas,* Tong Li, D. McDevitt, Andrea Marra,dagger S. Sucoloski, P. L. Demarsh, and D. R. Gentry

SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania

Received 13 January 1999/Returned for modification 15 February 1999/Accepted 13 April 1999


    ABSTRACT
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The sigB gene of Staphylococcus aureus, coding for the alternate sigma factor B, has been deleted by allelic replacement mutagenesis. The mutant grew as well as the parent in vitro, although it was deficient in clumping factor, coagulase, and pigment. In two murine and one rat infection model the mutant showed no reduction in virulence.


    TEXT
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Bacteria often modulate gene expression in response to environmental or physiological change by employing alternative sigma factors (12). These sigma  subunits direct the core RNA polymerase to specific promoters and initiate transcription. Recently, Wu et al. (21) reported the presence of a gene for a second sigma factor in the gram-positive pathogen Staphylococcus aureus. This sigma  factor is distinct from the general housekeeping sigma  (PlaC/SigA) and shows homology to sigma B of Bacillus subtilis; it has been designated SigB. sigma B is the stress or stationary-phase sigma factor of B. subtilis and controls a very large regulon of an estimated 50 genes (3). It is induced in response to energy stress, by entry into the stationary phase, and by environmental stress, such as salt stress, heat shock, or ethanol addition (11). Transcription of the S. aureus sigB operon has been shown to change on entry into stationary phase and under ethanol or heat stress (14). Since the pathogen is thought to be subject to environmental stress in host tissue it is reasonable to propose that sigma B may play a role in the adaptation and survival of S. aureus during infection. One of the promoters of the global regulator sar (which is involved in the pleiotropic expression of extra cellular proteins, including potential virulence factors) bears a strong resemblance to sigma B-dependent promoters in B. subtilis (2). Deora et al. have demonstrated that in vitro transcription from this promoter by S. aureus RNA polymerase is sigma B dependent (7).

Recently, several S. aureus sigB mutants have been constructed (4, 6, 15) to elucidate the role of this sigma factor. Phenotypic changes have been noted in vitro, but in the single animal model studied (murine subcutaneous abscess) a sigB mutant did not differ in its pathogenicity from the parent strain (4). We have constructed, by allelic replacement, a deletion mutation of the S. aureus sigB gene in the clinical isolate WCUH29 and examined the phenotypic effects of the mutation on the strain and its ability to cause infection in three distinct animal infection models.

Construction of the Delta sigB::Tc mutant. A pBluescript derivative, pBlueErm(Delta H), containing the S. aureus ermC gene, was used. Regions (500 to 600 bp) flanking the sigB gene in S. aureus WCUH29 were amplified by PCR with outer BamHI or EcoRI sites and inner HindIII sites. The two fragments were then ligated with BamHI- and EcoRI-cut pBlueErm(Delta H). The resulting plasmid was linearized by digestion with HindIII and ligated with a 2.3-kb HindIII fragment containing the S. aureus tetK gene. Plasmid DNA was transformed into S. aureus RN4220 by electroporation. Four transformants resistant to both erythromycin and tetracycline were obtained, a phage 11 lysate of one of these constructs was transduced into S. aureus 8325-4, and transductants were selected on tetracycline. Six of 120 transductants showed loss of resistance to erythromycin. A phage 85 lysate of one of the mutants was transduced into S. aureus clinical strain WCUH29. The tetracycline-resistant sigB mutant Delta sigB::Tc was obtained, and its construction was verified by PCR analysis (data not shown) and Southern hybridization (Fig. 1). Chromosomal DNA from the parent and Delta sigB::Tc mutant strains was isolated, digested with EcoRV, and probed in Southern hybridization experiments with an EcoRV fragment including part of the 5' end of the sigB gene. A single band of 1.4 kb hybridized from the parental strain, while a single 2.6-kb band hybridized from the mutant Delta sigB::Tc, as expected (Fig. 1). When a tetK gene probe was used, no hybridizing fragments were detected from chromosomal DNA of the parent, while two fragments of 2.6 and 1.1 kb hybridized from the Delta sigB mutant, as expected.


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  		FIG. 1.   Inactivation of the S. aureus sigB gene. (A) Southern hybridization blot of EcoRV-digested chromosomal DNA from parent strain WCUH29 (WT) and its Delta sigB::Tc mutant, using two probes based on sigB and tetK sequences. Marker sizes in kilobase pairs are shown on the left. (B) Diagram of the construction used to delete the sigB gene. RV denotes restriction sites for EcoRV.

The successful construction of a sigB deletion mutant indicated that in S. aureus this gene is not essential for growth in vitro. sigma B mutants of B. subtilis are also viable and show no effect on growth or sporulation (13), although reduced survival is seen under extreme growth conditions (8).

The WCUH29 Delta sigB::Tc mutant grew as well as the parent in tryptic soy broth at 37°C. On solid medium the mutant showed no differences in growth on high salt concentration (2 M NaCl), bile, or low pH or in carbohydrate utilization apart from its ability, unlike the parent, to utilize ribose. Colonies of the mutant were slightly larger than the parent but lacked the orange-yellow pigmentation. Interestingly, the mutant was deficient in production of both clumping factor (fibrinogen receptor) and coagulase activity (Table 1). The mutant showed no evidence of self-aggregation. On rabbit-blood agar plates the mutant showed enhanced production of alpha-hemolysin, as indicated by zones around individual colonies twice the diameter of those around the parent. Neither WCUH29 nor the mutant produced significant amounts of beta-hemolysin on sheep-blood agar plates. Enhanced production of alpha-hemolysin was observed in a sigB mutant by Cheung et al. (6) but not by Chan et al. (4).

                              
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  		TABLE 1.   Titration of clumping factor and coagulase of WCUH29 and its Delta sigB::Tc mutant

The deficiency of clumping factor expression is consistent with the presence of a putative sigma B-dependent promoter upstream of its gene (clfA). Alternatively gene expression could be modulated through one or more of the loci of global regulators identified in S. aureus, e.g., sae, agr, and sar (5, 9, 16). Kullik et al. noted that a sigB mutant of strain Newman had a greater tendency to cellular aggregation in the absence of fibrinogen, but this was not observed for the sigB mutants of two other strains (15).

On prolonged incubation the mutant did show a slight decrease in survival compared with the parent (Fig. 2), but there were no microscopic differences in the morphologies of the parent and mutant.


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  		FIG. 2.   Survival of S. aureus WCUH29 (open circle ) and its Delta sigB::Tc mutant () in stationary phase.

The sigB operon of S. aureus COL was identified as the position of two Tn551 insertion mutations which caused a drastic reduction in resistance to methicillin, suggesting that a functioning stress regulon was important to maintenance of high resistance to methicillin (21). WCUH29 is not intrinsically resistant to methicillin, and there was no evidence of an increase over the wild type in the sensitivity of the Delta sigB::Tc mutant to methicillin or a variety of common antibiotics.

Virulence testing. The mutant was compared with the parent in three different infection models. For a murine wound infection model, sutures were soaked in phosphate-buffered saline-washed cells from overnight cultures of S. aureus WCUH29 and the Delta sigB::Tc mutant. Six-week-old male CD-1 mice were anesthetized, a 2-cm incision was made in the shaved back, an infected suture was secured under the skin, and the skin was closed with a surgical staple. After 5 days the animals were sacrificed, the skin surrounding the wound was removed aseptically, cut into pieces, and homogenized in 1 ml of phosphate-buffered saline in a stomacher, and bacterial viable counts were determined.

In a hematogenous pyelonephritis model, 200 µl of a bacterial suspension adjusted to an A600 of 0.3 was used to infect 6- to 8-week-old male CD-1 mice via the tail vein. After 5 days, surviving animals were sacrificed, pairs of kidneys were homogenized as above, and viable counts were determined.

In a rat osteomyelitis model, bacteria (4 × 106 to 5 × 106) were injected into a small hole drilled into the bone cortex of the tibia. The opening was sealed with bone wax to prevent leakage, and the skin was closed with surgical staples. On days 14, 28, 42, and 56 animals were sacrificed, tibias were removed and homogenized, and viable counts were determined.

The organism loads (log10 CFU per milliliter ± standard deviation) after 5 days for the parent (WCUH29) and the Delta sigB::Tc mutant were 7.4 ± 0.1 and 7.2 ± 0.5, respectively, in the wound model, and 5.34 ± 0.7 and 6.08 ± 0.4, respectively, in the pyelonephritis model. In the rat osteomyelitis model the corresponding figures for the parent and mutant were 5.5 ± 0.1 and 5.4 ± 0.2 on day 14, 5.7 ± 0.2 and 5.4 ± 0.2 on day 28, 6.5 ± 0.3 and 6.6 ± 0.1 on day 42, and 6.8 ± 0.1 and 6.3 ± 0.1 on day 56. These results clearly demonstrate that the Delta sigB::Tc mutant was as virulent as the WCUH29 parent in all infection models tested.

If clumping factor and coagulase are also not produced in vivo by the mutant then these results imply little role for these proteins in the infection models examined. Previous results with site-specific allelic replacement mutants have shown that lack of coagulase had no effect in a variety of infection models (1, 18, 19). On the other hand, a mutant with clumping factor deleted had reduced infectivity of about 50% in an endocarditis model (18). It is generally regarded that the pathogenicity of S. aureus is the result of a delicate balance in the expression of several virulence genes (10). It is clear from this and other recent studies (4, 6, 15) that the background of the strain influences the in vitro phenotype of the sigB mutation.

The three infection models described here add to the observation of Chan et al. that a sigB insertionally inactivated mutant of S. aureus was as pathogenic as its parent in a murine subcutaneous abscess model (4). Recently, Wiedemann and colleagues reported that deletion of the sigma B gene of Listeria monocytogenes did not affect spreading of the mutant to the liver after intragastric or intraperitoneal inoculation (20).

Summary. Allelic replacement of the gene for sigma B in S. aureus brought about some phenotypic changes, most noticeably deficiency in coagulase and clumping factor and enhanced alpha-hemolysin production. However, there was no effect on virulence in either of two different mouse models of acute infection or in a rat model of chronic infection. The physiological role of sigma B in this gram-positive pathogen is not yet defined, but these data demonstrate that it is not important in systemic and dermal infection.


    FOOTNOTES

* Corresponding author. Mailing address: Anti-infectives Research, SmithKline Beecham Pharmaceuticals, 1250 S. Collegeville Rd., P.O. Box 5089, Collegeville, PA 19426-0989. Phone: (610) 917-7378. Fax: (610) 917-7901. E-mail: richard_o_nicholas{at}sbphrd.com.

dagger Present address: Protein Design Labs, Inc., Fremont, CA 94555.

Editor:   E. I. Tuomanen


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Infection and Immunity, July 1999, p. 3667-3669, Vol. 67, No. 7
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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