Virulence Factors As Targets For Vaccine And Therapy Against Drug-Resistant Pathogens

10 February, 1999

Virulence Factors As Targets For Vaccine And Therapy Against Drug-Resistant Pathogens

The emergence of drug resistance has made many of the available antibiotics ineffective. The situation with an increase of antibiotic-resistant Staphylococcus aureus is particularly critical: About 1/3 of S. aureus isolated from hospitalized patients are resistant to all antibiotics but one, vancomycin, and the resistance to this last resort is increasing. Additional antibiotics have to be developed before the loss of the last line of defense, or alternative methods for prevention and treatment of drug-resistant infections are needed in the clinical arena.
S. aureus is a Gram-positive pathogen that causes from minor skin infections to pneumonia, endocarditis, meningitis, septicemia, post-operative wound infections, and toxic shock syndrome. Like other Gram-positive bacteria, it causes diseases chiefly by the production of virulence factors such as hemolysins, enterotoxins, and toxic shock syndrome toxin. The control of virulence determinant expression in S. aureus is a complex process involving global regulatory loci such as sar and agr. The sar locus consists of a 372 bp sarA open reading frame (ORF) preceded by a triple promoter region interspersed with two putative smaller ORFs (ORF3 and ORF4). The triple promoter system yields three overlapping sar transcripts (sarA, sarC and sarB of 0.56, 0.8 and 1.2 kb respectively). The SarA protein binds to the agr promoter region (P2 and P3 interpromoter region; Chien Y, Cheung AL , 1998: uid=9446568) to stimulate the transcription of RNAII and RNAIII (510-nucleotide), two major transcripts encoded within the agr locus.

The synthesis of above-mentioned virulence factors in S. aureus is stimulated by this RNA molecule RNAIII encoded by rnaiii gene in the arg locus, while the transcription of some other genes encoding cell surface proteins, like spa (protein A) and fnb (fibronectin binding proteins) is repressed. Besides being a regulator, RNAIII is also an mRNA coding for staphylococcal delta-lysin. The rnaiii gene is auto-induced at the mid-log phase of growth by another RNAIII-activating protein (RAP, 38K), that is continuously secreted from the bacterial cells (Balaban N and Novick RP, 1995: uid=95183517).

Balaban N et al (1998: uid=9545222) have now reported that once vaccinated with RAP, mice were protected from S. aureus pathology: Upon injection of pathogenic S. aureus under the skin, 72% of RAP-vaccinated mice remained free of disease, compared with 30% free in mice immunized with complete Freunds adjuvant and with none free in the untreated control. In addition, the size of the lesions was 76% smaller in the vaccinated animals than that of the untreated control. Only 3% of the vaccinated animals died as a result of challenge, compared with 22% of the control.

Another point of interest is RIP (RNAIII-inhibiting peptide, YSPXTNF) that is most likely derived from the RAP amino terminus and produced in non-pathogenic S. aureus mutants. RIP inhibits rnaiii gene transcription and competes with RAP activation of the virulence (Balaba N and Novick RP, 1995: uid=95183517). When 10 ug of purified RIP and synthetic analog Pep (YSPWTNF) were used, then 90% of protected mice showed no sign of disease, whereas all the control animals developed lesions.

The prevention and treatment inferred from the above-mentioned results may not produce all or none clear-cut results but should be beneficial in decreasing selective pressure for the emergence of drug-resistant pathogens. Since it takes longer than a week to mount immune response, possible vaccines described here would benefit those who are at risk of infection, such as diabetics, dialysis and surgery patients. Regulatory mechanisms for the virulence auto-inducer have also been described in Bacillus, Streptococcus, and Pseudomonas for a similar conceptual approach to diseases caused by these microbes.
Please send your comments and ideas through e-mail form at this website.
(go back to top)

Home | Site Map | Contact Us | About iHumans | Alliance and R&D Collaboration | Seach Executives and Scientists | Job Openings and Opportunities | Health Care | News and Commentaries | ニホン語のページ (Japanese Pages) |