C3 binding polypeptide of Streptococcus agalactiae group b...

Details C3 binding polypeptide of Streptococcus agalactiae group b... C3 binding polypeptide of Streptococcus agalactiae group b...

2000-07-01

2003-06-24

Navarro, Mark (Department: 1645)

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Bacteria or actinomycetales; media therefor

C435S320100, C435S325000, C536S023700

Reexamination Certificate

active

06582950

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to
Streptococcus agalactiae
, Group B Streptococcus, and in particular this invention relates to the identification of a
S. agalactiae
polypeptide and a gene encoding it that may be implicated in Group B streptococcal adhesion and/or virulence. The
S. agalactiae
polypeptide according to the invention demonstrates binding of human complement C3.
BACKGROUND OF THE INVENTION
Streptococcus agalactiae
, or group B Streptococcus (GBS), is a leading cause of infant mortality. GBS encompasses an estimated prevalence of several thousand cases per year resulting in an annual mortality rate in the United States between about 10% and 15% (Schuchat, Clin. Micro Rev., 11(3):497-513 (1998)). Although worldwide prevalence is known, insufficient specific epidemiological data is not readily available.
Several virulence factors have been reported in GBS,. In addition to the streptococcal capsule, which is an important virulence factor, lipotechoic acid, a glycerol-phosphate polymer extending throughout the cell wall, is a virulence factor that may mediate adhesion (Teti et al.,
Infection and Immunity,
55(12):3057-3064 (1987)). Proteins such as hyaluronate lyase, cAMP factor, proteases, nucleases, hippuricase, neuraminidase, hemolysin, and C5a peptidase are expressed from GBS and many have been shown to be virulence factors (Nizet et al.,
Streptococcal Infections,
Stevens D L and Kaplan E L, Eds. (2000); Bohnsack et al.,
Biochimica et Biophysica Acta,
1079:222-228 (1991)). In short, many studies are underway to define virulence factors molecularly by the mutation of genes encoding these proteins under question and the examination in assays for biological function.
The C proteins, or antigens, have been further characterized as alpha proteins (Madoff et al.,
Infection and Immunity,
59(1):204-210 (1991)), as beta proteins (Russell-Jones et al.,
J. Exp Med.
160:1467-1475 (1984); Jerlstrom et al.,
Mol. Microbiol.,
5:843-849 (1991)), and as gamma and delta proteins (Brady et al.,
Infect. Immun.,
57:1573-1581 (1989)). Not much is known about gamma and delta C proteins as there have not been further reports since their identification. The alpha C protein, which is resistant to the protease trypsin, varies in molecular weight from about 30 kDa to about 190 kDa in a ladder-like array (Madoff et al.,
Infection and Immunity,
59(1):204-210 (1991)). The beta C protein, which is sensitive to the protease trypsin and typically exhibits less variability in size (molecular weight of about 14 kDa to about 145 kDa), is typically expressed as a single 130 kDa protein that is capable of binding human IgA (Russell-Jones et al.,
J. Exp. Med.,
160:1467-1475 (1984)).
C proteins are suggested to contribute to GBS virulence in infant rat models (Ferrieri et al.,
Infection and Immunity,
27(3):1023-1032 (1980)) and some GBS strains without C protein are more easily killed in an opsonophagocytic bactericidal assay (Payne and Ferrieri,
J Infectious Diseases,
151(4):672-681 (1985)). Other alpha-like proteins have also been reported (Kvam et al,
Pathogenic Streptococci: Present and Future,
Lancer Publication (A. Totolian (Ed.), St. Petersburg, Russia (1994)), and are under further investigation.
R proteins, or antigens, first identified by Lancefield and Perlman, were further characterized (Wilkinson,
Infection and Immunity,
4(5):596-604 (1971); Bevanger et al.,
APMIS,
103:731-736 (1995)) and later determined to resemble the alpha C proteins in multiple molecular weight forms, resistance to trypsin, and imunogenicity (Wilkinson,
Infection and Immunity,
4(5):596-604 (1971); Madoff et al.,
Infection and Immunity,
59(8):2638-2644 (1991); Flores and Ferrieri,
Zbl.Bakt.,
285:44-51 (1996)). The R proteins were identified as separate proteins R1, R2, R3, R4, and R5 by various investigators (Flores and Ferrieri,
Zbl.Bakt.,
285:44-51 (1996); Wilkinson,
Applied Microbiology,
24(4):669-670 (1972)). Finally, a similar protein designated “Rib” (Stalhammar-Carlemalm et al.,
J. Experimental Medicine,
177:1593-1603 (1993)), while proposed as an individual entity, is suspected to be an R protein (Flores and Ferrieri,
Zbl.Bakt.,
285:44-51 (1996)). Whereas these proteins have been characterized and grouped phenotypically, further molecular characterization of these groups is underway as well as the identification of new surface proteins unique in structure and biological functions.
Human mothers colonized with GBS represent approximately 15-35% of the U.S. population, and are known to transmit GBS to their infants before birth. This results in an incidence of neonatal GBS disease at a rate of 1 to 2 infants per 1,000 live births, and a mortality after birth due to complications of bacteremia/sepsis, and/or meningitis, or GBS infection in utero possibly resulting in stillbirth (Schuchat,
Clin. Micro Rev.,
11(3):497-513 (1998)). Even infant survivors of GBS meningitis suffer from resulting chronic neurologic injury ranging from deafness, learning disabilities, as well as motor, sensory, and cognitive impairment (Baker et al.,
Infectious Diseases of the Fetus and Newborn Infant.,
(4th Ed.) W.B. Saunders Company (1995)). Currently, antibiotic prophylaxis in parturients is the recommended approach for prevention of neonatal disease; however, this approach may be ineffective. With the resurgence of antibiotic resistance in other streptococcal species, a similar plight in group B Streptococcus may occur, making the need for effective vaccines urgent. It is known that infants do not make sufficient protective antibodies to GBS capsular polysaccharides, and maternal antibodies to capsule may not be sufficient for placental transfer and protection. Even after vaccination with current polysaccharide vaccines, antibody titers are low in individuals at greatest risk for colonization and severe infection (Linden et al.,
Int. Archs. Allergy Appl. Immun.,
71:168-172 (1983)).
In addition to infants, other persons at high risk for GBS infection are the elderly and immuno-compromised persons (Farley et al.,
N. Engl. J. Med.,
328:1807-1811 (1993)). Although currently under investigation, sufficient data on antibody production in the elderly is lacking. Antibody titers, however, may also be deficient in this age group, and it remains possible that immunization may protect elderly against invasive GBS disease (Schuchat,
Clin. Micro Rev.,
11(3):497-513 (1998)).
In addition to the problems confronting humans, many GBS strains are known to cause bovine mastitis in cows resulting in a monetary loss to dairy farmers as well as GBS strains known to cause mastitis in goats and other lactating mammals. GBS in cows is currently controlled by prophylactic antibiotic treatment (Keefe,
Can. Vet. J.,
38(7):429-37 (1997)). Concerns, however, have been raised regarding residual antimicrobials in milk from this prophylactic treatment, as well as the growing antimicrobial resistance in GBS strains (Baynes et al.,
J Food Prot.,
62(2):177-80(1999)).
In response to the dilemmas described above, protein conjugate vaccines have been developed, and several are currently in clinical trials (Larsson et al.,
Infection and Immunity,
64(9):3518-3523 (1996)). Proteins that could be used as components of vaccines, as conjugates coupled to capsular polysaccharide (which act as adjuvants to boost antibody response), or as whole protein vaccine candidates themselves are under investigation. Problems existing with some protein conjugate vaccines include variability in protein structure resulting in a ladder-like array of proteins (Gravekamp et al.,
Infection and Immunity.,
65(12):5216-5221 (1997)).
Another significant issue is that current protein conjugate vaccines are restricted to the GBS serotypes prevalent only in the United States. This includes mainly types I, II, III, and V, in contrast to a range of nine different serotypes that are able to colonize and cause invasive disease (Harrison et al.,
J. of Infectious Disease,
177:998-1002 (1998)). Since 1990, four new capsular serotypes I

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