Pathogenesis of B. bronchiseptica infection in cats
Since the first publications about the role of B. bronchiseptica in feline URTD, a large number of cases have been reported, including cases leading to mortality as a result of B. bronchiseptica infection (Welsh 1996). The pathogenesis in cats is still unknown, but is expected to be comparable to other species. Furthermore, a lot can be learned from other bordetella species. B. pertussis (which infects people) and B. parapertussis (which infects sheep and people) are closely related to B. bronchiseptica and may represent human (and ovine) adapted lineages of B. bronchiseptica.

Bordetella infections of domestic species
B. bronchiseptica displays a broad host range which includes mice, rats, guinea pigs, rabbits, cats, dogs , pigs , sheep, horses, and bears (Goodnow 1980) causing a variety of respiratory diseases such as kennel cough in dogs, atrophic rhinitis in pigs and snuffles in rabbits (Appel and Binn 1987, Magyar et al 1988, Deeb et al 1990, Keil and Fenwick 1998). Although human infections have been documented, they have been associated with severely compromised hosts (Dworkin et al 1999, Tamion et al 1996).

Host infection and induction of respiratory disease
B. bronchiseptica colonize the ciliated respiratory mucosa, a surface designed to eliminate foreign particles, thereby making the adherence and persistence mechanisms of these bacteria crucial. Infections are typically chronic, often asymptomatic, and notoriously difficult to clear even with antibiotic therapy (Goodnow 1980). Furthermore, there is increasing evidence of resistance to certain antibiotics including tetracyclines and ampicillin (Speakman et al 1997). B. bronchiseptica appears to occupy a position along a continuum with "pathogen" at one end and "commensal" at the other. Its ability to establish long-term asymptomatic infection seems to be an adaptive feature and may represent a balance between immuno-stimulatory events associated with infection and immuno-modulatory events mediated by the bacteria (Yuk et al 2000).

Under certain circumstances, which, in field infections seem to involve factors such as host stress, (Coutts et al 1996) respiratory disease may occur via the expression of a range of virulence factors. Damage and loss of tracheal epithelial cells containing adherent bacteria probably contributes to respiratory disease symptoms and possibly also to transmission by the aerosol route. Ciliostasis, destruction of the cilia and failure of the mucociliary clearance mechanism together facilitate further colonisation, persistence, and transmission of bacteria.

The release of toxins following colonisation is responsible for local and systemic inflammatory damage for the first 3-5 days after infection. The first clinical signsmay be noticed after this time. After onset of the local immune response the bacteria are gradually eliminated (Bemis et al 1977). In cats most illness appears self-limiting with spontaneous resolution occurring after about 10-14 days. However, severe bronchopneumonia associated with B. bronchiseptica may occur, particularly in kittens, and can be lethal.


Role of B. bronchiseptica in feline URTD
B. bronchiseptica  can induce respiratory signs in experimentally infected Chlamydophila felis/ FHV/ FCV/ B. bronchiseptica-free cats (Elliot 1991, Jacobs et al 1993, Coutts et al 1996, Hoskins et al 1998). This demonstrates that B. bronchiseptica is able to induce respiratory disease in the absence of other pathogens. However, although B. bronchiseptica can act as a primary pathogen and cause URTD in cats it is highly likely that in many circumstances other factors are involved including stress and concurrent infection with respiratory viruses. B. bronchiseptica may also act as a secondary pathogen, particularly in cases of URTD which progress to more lethal bronchopneumonia.

Virulence factors and their regulation
B. bronchiseptica express a common set of surface associated and secreted molecules involved in colonization and virulence including adhesins such as filamentous hemagglutinin (FHA), fimbriae (Fim) and pertactin (Prn), as well as toxins such as a bifunctional adenylate cyclase/haemolysin, dermonecrotic toxin (DNT), tracheal cytotoxin (TCT),  lipopolysaccharide (LPS) and a type III secreted protein. Expression of nearly all of these virulence factors is positively regulated by the products of the bvgAS locus such that B. bronchiseptica exist in at least three identifiable phases, a virulent phase (Bvg+ ), an avirulent phase (Bvg-) and an intermediate phase (Bvgi). Transition between the three phases occurs in response to specific environmental signals, the true nature of which remains unknown.

The virulence factors and the bvgAS control system of B. bronchiseptica are almost identical to that found in B. pertussis, B. parapertussis and B. bronchiseptica (Scarlato et al 1991, Weiss and Falkow 1984). Despite these similarities, however, there are some important differences in the behaviour of B. bronchiseptica  as compared to these other subspecies including host range specificity (the other two species are confined to one or two species), severity of disease, the ability to establish persistent infection and perhaps pathways for transmission. B. bronchiseptica also differs from the other subspecies in its ability to survive nutrient limiting conditions, at least in vitro, suggesting that in addition to transmission by the aerosol route, this organism may be able to transmit via environmental reservoirs (Porter et al 1991, Porter and Wardlaw 1993). Research is currently aimed at differential gene expression and species polymorphism. Some differences have now been found. For example, the gene encoding a type III secretion system is unique to B.bronchiseptica (Yuk et al 1998). Such findings will help us to determine fundamental features of the bacterium which ultimately are important in causing disease.


Role of virulence factors in disease
Bordetella species interact with their mammalian hosts primarily, and perhaps exclusively, at respiratory surfaces. Several scanning electron micrographic studies have demonstrated that Bordetella bind specifically to the cilia of respiratory epithelia (Matsuyama and Takino 1980, Nakai et al 1988, Yokomizo and Shimizu 1979). In the nasal cavity, requirements for colonization appear to be few; B. bronchiseptica strains deficient in the expression of FHA, Fim, Prn, and adenylate cyclase toxin (ACT) are capable of persisting in the nasal cavities of rats for at least 60 days, albeit at levels lower than wild type. Establishment of infection in the trachea, however, requires that bacteria be able to resist or overcome the clearance action of the mucociliary escalator as well as the killing effects of defensins, complement and other antimicrobial factors. FHA, in its secreted as well as surface associated form, serves as a strong adhesin and appears to be essential for overcoming mucociliary clearance (Cotter et al 1998). LPS may be important for resistance to complement (Harvill et al 2000). TCT, released by Bordetella growing among the cilia, and bacterial LPS are proposed to stimulate NO production causing several cytopathological changes along the mucosal surface including: damage and loss of tracheal epithelial cells, ciliostasis and a failure of the mucociliary clearance mechanism.

The inflammatory response to B.bronchiseptica infection is initiated by damage to the respiratory epithelium causing the release of inflammatory cytokines. Inflammatory cells, predominantly neutrophils, are recruited into the lungs of mice within three days following intranasal inoculation with B. bronchiseptica (Harvill et al 1999, Gueirard et al 1996). Experiments with mice (Weingart et al 2000) have shown that ACT, by targeting neutrophils and macrophages, is an important factor in resisting constitutive host defense mechanisms allowing Bordetella to resist the killing action of phagocytic cells.