Immunization of dairy cattle with Mig protein

Details Immunization of dairy cattle with Mig protein Immunization of dairy cattle with Mig protein

2001-06-11

2004-05-25

Navarro, Mark (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Amino acid sequence disclosed in whole or in part; or...

C424S190100, C424S234100, C424S244100, C530S350000

Reexamination Certificate

active

06740322

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to bacterial antigens and genes encoding the same. More particularly, the present invention pertains to the cloning, expression and characterization of the Mig Fc-receptor protein from several Streptococcus bacteria species, and the use of the same in vaccine compositions.
BACKGROUND
Mastitis is an infection of the mammary gland usually caused by bacteria or fungus. The inflammatory response following infection results in decreased milk yield as well as quality, and causes major annual economic losses to the dairy industry.
Among the bacterial species most commonly associated with mastitis are various species of the genus Streptococcus, including
Streptococcus aureus, Streptococcus uberis
(untypeable),
Streptococcus agalactiae
(Lancefield group B),
Streptococcus dysgalactiae
(Lancefield group C),
Streptococcus zooepidemicus
, and the Lancefield groups D, G, L and N streptococci. Some of those species are contagions (e.g.
S. agalactiae
), while others are considered environmental pathogens (e.g.
S. dysgalactiae
and
S. uberis
).
The environmental pathogen
S. uberis
is responsible for about 20% of all clinical cases of mastitis (Bramley, A. J. and Dodd, F. H. (1984)
J. Dairy Res.
51:481-512; Bramley, A. J. (1987)
Animal Health Nutrition
42:12-16; Watts, J. L. (1988)
J. Dairy Sci.
71:1616-1624); it is the predominant organism isolated from mammary glands during the non-lactating period (Bramley, A. J. (1984)
Br. Vet. J.
140:328-335; Bramley and Dodd (1984)
J. Dairy Res.
51:481-512; Oliver, S. P. (1988)
Am. J. Vet. Res.
49:1789-1793).
Mastitis resulting from infection with
S. uberis
is commonly subclinical, characterized by apparently normal milk with an increase in somatic cell counts due to the influx of leukocytes. The chemical composition of milk is changed due to suppression of secretion with the transfer of sodium chloride and bicarbonate from blood to milk, causing a shift of pH to a more alkaline level.
S. uberis
mastitis may also take the form of an acute clinical condition, with obvious signs of disease such as clots or discoloration of the milk and swelling or hardness of the mammary gland. Some cases of the clinical disease can be severe and pyrexia may be present. For a review of the clinical manifestations of S. uberis mastitis, see, Bramley (1991) Mastitis: physiology or pathology. p. 3-9. In C. Burvenich, G. Vandeputte-van Messom, and A. W. Hill (ed.),
New insights into the pathogenesis of mastitis
. Rijksuniversiteit Gent, Belgium; and Schalm et al. (1971) The mastitis complex-A brief summary. p. 1-3. In
Bovine Mastitis
. Lea & Febiger, Philadelphia.
Conventional antibacterial control methods such as teat dipping and antibiotic therapy are effective in the control of many types of contagious mastitis, but the environmental organisms typically found in all dairy barns are often resistant to such measures. Vaccination is therefore an attractive strategy to prevent infections of the mammary glands, and has been shown to be beneficial in the case of some contagious mastitis pathogens.
However, the literature is limited regarding vaccination studies with environmental pathogens such as
S. dysgalactiae
and
S. uberis
, and variable results have been observed. In some cases, immunization has resulted in increased sensitivity to the specific organism and in other cases strain-specific protection has been obtained.
For example, previous studies have shown that primary infection with
S. uberis
can considerably reduce the rate of infection following a second challenge with the same strain (Hill, A. W. (1988)
Res. Vet. Sci.
44:386-387). Local vaccination with killed
S. uberis
protects the bovine mammary gland against intramammary challenge with the homologous strain (Finch et al. (1994)
Infect. Immun.
62:3599-3603). Similarly, subcutaneous vaccination with live
S. uberis
has been shown to cause a dramatic modification of the pathogenesis of mastitis with the same strain (Hill et al. (1994)
FEMS Immunol. Med. Microbiol.
8:109-118). Animals vaccinated in this way shed fewer bacteria in their milk and many quarters remain free of infection.
Nonetheless, vaccination with live or attenuated bacteria can pose risks to the recipient. Further, it is clear that conventional killed vaccines are in general largely ineffective against
S. uberis
and
S. agalactiae
, either due to lack of protective antigens on in vitro-grown cells or masking of these antigens by molecular mimicry.
The current lack of existing mastitis vaccines against
S. agalactiae
or the contagious streptococcus strains is due at least in part to a lack of knowledge regarding the virulence determinants and protective antigens produced by those organisms which are involved in invasion and protection of the mammary gland (Collins et al. (1988)
J. Dairy Res.
55: 25-32; Leigh et al. (1990)
Res. Vet. Sci.
49: 85-87; Marshall et al. (1986)
J. Dairy Res.
53: 507-514).
S. dysgalactiae
is known to bind several extracellular and plasma-derived proteins such as fibronectin, fibrinogen, collagen, alpha-II-macroglobulin, IgG, albumin and other compounds. The organism also produces hyaluronidase and fibrinolysin and is capable of adhering to and invading bovine mammary epithelial cells. However, the exact roles of the bacterial components responsible for these phenotypes in pathogenesis is not known.
Similarly, the pathogenesis of
S. uberis
infection is poorly understood. Furthermore, the influence of
S. uberis
virulence factors on host defense mechanisms and mammary gland physiology is not well defined. Known virulence factors associated with
S. uberis
include a hyaluronic acid capsule (Hill, A. W. (1988)
Res. Vet. Sci.
45:400-404), hyaluronidase (Schaufuss et al. (1989)
Zentralbl. Bakteriol. Ser. A
271:46-53), R-like protein (Groschup, M. H. and Timoney, J. F. (1993)
Res. Vet. Sci.
54:124-126), and a cohemolysin, the CAMP factor, also known as UBERIS factor (Skalka, B. and Smola, J. (1981)
Zentralbl. Bakteriol. Ser. A
249:190-194), R-like protein, plasminogen activator and CAMP factor. However, very little is known of their roles in pathogenicity.
The use of virulence determinants from Streptococcus as immunogenic agents has been proposed. For example, the CAMP factor of
S. uberis
has been shown to protect vertebrate subject from infection by that organism (Jiang, et al., U.S. Pat. No. 5,863,543).
The &ggr; antigen of the group B Streptococci strain A909 (ATCC No. 27591) is a component of the c protein marker complex, which additionally comprises an &agr; and &bgr; subunit (Boyle, U.S. Pat. No. 5,721,339). Subsets of serotype Ia, II, and virtually all serotype Ib cells of group B streptococci, have been reported to express components of the c protein. Use of the &ggr; subunit as an immunogenic agent against infections by Lancefield Group B Streptococcus infection has been proposed. However, its use to prevent or treat bacterial infections in animals, including mastitis in cattle, has not been studied.
The group A streptococcal M protein is considered to be one of the major virulence factors of this organism by virtue of its ability to impede attack by human phagocytes (Lancefield, R. C. (1962)
J. Immunol.
89:307-313). The bacteria persist in the infected tissue until antibodies are produced against the M molecule. Type-specific antibodies to the M protein are able to reverse the antiphagocytic effect of the molecule and allow efficient clearance of the invading organism.
M proteins are one of the key virulence factors of
Streptococcus pyogenes
, due to their involvement in mediating resistance to phagocytosis (Kehoe, M. A. (1991)
Vaccine
9:797-806) and their ability to induce potentially harmful host immune responses via their superantigenicity and their capacity to induce host-cross-reactive antibody responses (Bisno, A. L. (1991)
New Engl. J. Med.
325:783-793; Froude et al. (1989)
Curr. Top. Microbiol. Immunol.
145:5-26; Stollerman, G. H. (1991)
Clin. Immunol. Immunopathol.
61:131-142).
However

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