Anti-bacterial vaccine compositions

Details Anti-bacterial vaccine compositions Anti-bacterial vaccine compositions

2001-03-15

2004-09-14

Housel, James (Department: 1648)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023100, C435S006120, C435S069100, C435S243000, C435S252300, C435S320100

Reexamination Certificate

active

06790950

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the identification of genes responsible for virulence of Pasteurellaceae bacteria, thereby allowing for production of novel attenuated mutant strains useful in vaccines and identification of new anti-bacterial agents that target the virulence genes and their products.
BACKGROUND OF THE INVENTION
The family Pasteurellaceae encompasses several significant pathogens that infect a wide variety of animals. In addition to
P. multocida
, prominent members of the family include
Pasteurella
(
Mannheimia
)
haemolytica, Actinobacillus pleuropneumoniae
and
Haemophilus somnus. P. multocida
is a gram-negative, nonmotile coccobacillus which is found in the normal flora of many wild and domestic animals and is known to cause disease in numerous animal species worldwide [Biberstein, In M. Kilian, W. Frederickson, and E. L. Biberstein (ed.),
Haemophilus, Pasteurella
, and
Actinobacillus
. Academic Press, London, p.61-73 (1981)]. The disease manifestations following infection include septicemias, bronchopneumonias, rhinitis, and wound infections [Reviewed in Shewen, et al., In C. L. Gyles and C. O. Thoen (ed.),
Pathogenesis of Bacterial Infections in Animals
. Iowa State University Press, Ames, p. 216-225 (1993), incorporated herein by reference].
Infection by
P. multocida
generally results from invasion during periods of stress, but transmission may also occur by aerosol or contact exposure, or via flea and tick vectors. In fowl,
P. miltocida
infection gives rise to acute to peracute septicemia, particularly prevalent in domestic turkeys and wild waterfowl under stress conditions associated with overcrowding, laying, molting, or severe climatic change. In cattle, a similar hemorrhagic septicemia follows infection and manifests conditions including high fever and depression, generally followed by quick death. Transmission is most likely through aerosol contact, but infection can also arise during periods of significant climatic change. In rabbits, infection gives rise to recurring purulent rhinitis, generally followed by conjunctivitis, otitis media, sinusitis, subcutaneous abscesses, and chronic bronchopneumonia. In severe infections, rabbit mortality arises from acute fibrinous bronchopneumonia, septicemia, or endotoxemia. Disease states normally arise during periods of stress. In pigs, common
P. multocida
disease states include atrophic rhinitis and bacterial pneumonia. Similar pneumonia conditions are also detected in dogs, cats, goats, and sheep.
P. multocida
is commonly detected in oral flora of many animals and is therefore a common contaminant in bite and scratch wounds.
P. multocida
strains are normally designated by capsular serogroup and somatic serotype. Five capsular serogroups (A, B, D, E, and F) and 16 somatic serotypes are distinguished by expression of characteristic beat-stable antigens. Most strains are host specific and rarely infect more than one or two animals. The existence of different serotypes presents a problem for vaccination because traditional killed whole cell bacteria normally provide only serotype-specific protection. However, it has been demonstrated that natural infection with one serotype can lead to immunological protection against multiple serotypes [Shewen, et al., In C. L. Gyles and C. O. Thoen (Ed.),
Pathogenesis of Bacterial Infections in Animals
. Iowa State University Press, Ames, p. 216-225 (1993)] and cross protection can also be stimulated by using inactivated bacteria grown in vivo [Rimler, et al.,
Am J Vet Res
. 42:2117-2121 (1981)]. One live spontaneous mutant
P. multocida
strain has been utilized as a vaccine and has been shown to stimulate a strong immune response [Davis,
Poultry Digest
. 20:430-434 (1987), Schlink, et al.,
Avian Dis
. 31(1):13-21 (1987)]. This attenuated strain, however, has been shown to revert to a virulent state or cause mortality if the vaccine recipient is stressed [Davis,
Poultry Digest
. 20:430-434 (1987), Schlink, et al.,
Avian Dis
. 31(1):13-21 (1987)].
Another member of the Pasteurella family,
A. pleuropneumoniae
exhibits strict host specificity for swine and is the causative agent of highly contagious porcine pleuropneumonia. Infection normally arises in intensive breeding conditions, and is believed to occur by a direct mode of transmission. The disease is often fatal and, as a result, leads to severe economic loss in the swine producing industry.
A. pleuropneumoniae
infection may be chronic or acute, and infection is characterized by a hemorrhagic, necrotic bronchopneumonia with accompanying fibrinous pleuritis. To date, bacterial virulence has been attributed to structural proteins, including serotype-specific capsular polysaccharides, lipopolysaccharides, and surface proteins, as well as extracellular cytolytic toxins. Despite purification and, in some instances cloning, of these virulence factors, the exact role of these virulence factors in
A. pleuropneumoniae
infection is poorly understood.
Twelve serotypes of
A. pleuropneumoniae
have been identified based on antigenic differences in capsular polysaccharides and production of extracellular toxins. Serotypes 1, 5, and 7 are most relevant to
A. pleuropneumoniae
infection in the United States, while serotypes 1, 2, 5, 7, and 9 are predominant in Europe. There are at least three significant extracellular toxins of
A. pleuropneumoniae
that are members of the haemolysin family and are referred to as RTX toxins. RTX toxins are produced by many Gram negative bacteria, including
E. coli, Proteus vulgarisa
, and
Pasteurella haemolytica
, and the proteins generally share structural and functional characteristics. Toxins from the various serotypes differ, however, in host specificity, target cells, and biological activities.
The major
A. pleuropneumoniae
RTX toxins include ApxI, ApxII, and ApxIII. ApxI and ApxII have haemolytic activity, with ApxI being more potent. ApxIII shows no haemolytic activity, but is cytotoxic for alveolar macrophages and neutrophils. Most
A. pleuropneumoniae
serotypes produce two of these three toxins. For example, serotypes 1, 5, 9, and 11 express ApxI and ApxII, and serotypes 2, 3, 4, 6, and 8 express ApxII and ApxIII. Serotype 10, however, produces only ApxI, and serotypes 7 and 12 express only ApxII. Those
A. pleuropneumoniae
serotypes that produce both ApxI and ApxII are the most virulent strains of the bacteria.
The Apx toxins were demonstrated to be virulence factors in murine models and swine infection using randomly mutated wild type bacteria [Tascon, et al.,
Mol. Microbiol
. 14:207-216 (1994)]. Other
A. pleturopneumoniae
mutants have also been generated with targeted mutagenesis to inactivate the gene encoding the AopA outer membrane virulence protein [Mulks and Buysee, Genie 165:61-66 (1995)].
At least eleven serotypes (1, 2, 5-9, 12-14 and 16) have been demonstrated within
Mannhemia.[Pasteurella] haemolyticca
[Angen, et al.,
Vet Microbiol
65(4):283-90 (1999)], a Pasteurellaceae species which is responsible for serious outbreaks of acute pneumonia in neonatal, weaned, growing and adult lambs, calves, and goats [Ackermann, et al.,
Microbes Infect
2(9):1079-88 (2000)]. Transportation, viral infections, overcrowding, and other stressful conditions predispose animals to
M. haemolytica
infection [Ackermann , et al., supra.] The leukotoxin (Lkt) of
M. haemolytica
is believed to play a significant role in pathogenesis, causing cell lysis and apoptosis that lead to the lung pathology characteristic of bovine shipping fever [Highlander, et al.,
Infect Immun
68(7):3916-22 (2000)] as well as lung injury in bovine pneumonic pasteurellosis [Jeyaseelan, et al.,
Microb Pathog
30(2):59-69 (2001)]. Lkt is a pore-forming exotoxin that has the unique property of inducing cytolysis only in ruminant leukocytes and platelets [Jeyaseelan, et al., (2001), supra.]. Cytolysis of many

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