sign in sign up
<<
Home , Bordetella

SWINE TECHNICAL ARTICLES

BORDETELLA BRONCHISEPTICA AND RESPIRATORY DISEASE IN SWINE Samantha J. Hau 1, Susan L. Brockmeier1 1 National Animal Disease Center, ARS, USDA, Ames, IA Corresponding Author ([email protected]) ABSTRACT

Bordetella bronchiseptica is an ubiquitous pathogen of swine Bordetella bronchiseptica is an aerobic, Gram negative, rod- causing respiratory infections including rhinitis, tracheitis, shaped bacterium that is capable of causing respiratory bronchitis, and pneumonia. It spreads quickly between infections in a wide range of mammalian species (1). It is a animals, especially during commingling of naïve animals with member of the class and closely related to subclinical carriers. B. bronchiseptica causes disease through the human pathogen . B. bronchiseptica is the production of virulence factors, such as adhesins and an important cause of respiratory infections in swine, where it toxins, which is coordinated by the BvgAS system. In addition to can cause a range of diseases from asymptomatic colonization causing primary disease, B. bronchiseptica can exacerbate viral to severe pneumonia (2, 3). The prevalence of B. bronchiseptica respiratory infections and predispose animals to other bacterial in swine is high and it is globally distributed within the swine respiratory pathogens, which increases the clinical signifi cance industry (4-10). of B. bronchiseptica colonization. Disease is currently managed with antibiotic treatments and vaccination strategies; however, colonization is diff icult to clear and animals can remain colonized and shed B. bronchiseptica long term, acting as a source of infection for naïve animals within a herd.

5 DISEASES

Bordetella bronchiseptica causes respiratory disease in swine cause more severe atrophy of the turbinates, which can result that can impact both the upper and lower respiratory tracts. in septal deviation (25, 28). Rhinitis presents with clinical Disease has a rapid onset, with clinical signs developing 2-3 signs of sneezing, nasal discharge, and ocular discharge. As days post-exposure (11). B. bronchiseptica is associated with a atrophic rhinitis progresses, atrophy of the turbinates can be high morbidity and low mortality, spreading rapidly within visualized at necropsy and during coinfection with P. multocida, a group of animals but resulting in low death loss (12-14). can lead to brachygnathia, lateral deviation of the snout (Figure Swine diseases caused by B. bronchiseptica include: rhinitis, 1), and/or epistaxis (11). bronchitis, tracheitis, and pneumonia. Bordetella bronchiseptica is also capable of causing inflammation of the airways resulting in tracheitis and Bordetella bronchiseptica is the causal agent of Non bronchitis. Similar to disease associated with the nasal Progressive Atrophic Rhinitis, and it causes tracheitis, mucosa, B. bronchiseptica interacts with the ciliated epithelial bronchitis and pneumonia. cells in the trachea and bronchi causing ciliostasis and epithelial changes (15, 16). This reduces the clearance by the mucociliary Bordetella bronchiseptica is a primary cause of rhinitis in escalator causing accumulation of mucus in the airways, which pigs, which can present as mild rhinitis, nonprogressive may provide a niche for secondary and predispose the atrophic rhinitis, when B. bronchiseptica is the sole animal to pulmonary infection (11). Uncomplicated tracheitis etiologic agent, or progressive atrophic rhinitis, when and bronchitis present with a dry, non-productive cough that B. bronchiseptica infects with toxigenic Pasteurella can be paroxysmal in nature (11). multocida. The interaction of B. bronchiseptica with the nasal mucosa leads to inflammation (rhinitis) and epithelial Pulmonary infection with Bordetella bronchiseptica results changes including squamous metaplasia, ciliostasis, or loss of in suppurative bronchopneumonia (29)(Figure 2). It can ciliated cells (15, 16). Over time, disease progresses to atrophic act as the primary etiologic agent in young pigs and in older rhinitis, in which the boney trabeculae of the turbinates is pigs it generally contributes to the severity of the Porcine replaced with fibrous connective tissue through the action of Respiratory Disease Complex (PRDC) through interaction with the dermonecrotic toxin (DNT) produced by B. bronchiseptica other bacteria and viruses in mixed infections (6, 29-33). The (17-19). With B. bronchiseptica as the sole etiologic agent, necrosis and tissue damage associated with B. bronchiseptica the disease is nonprogressive, affecting predominantly the pneumonia is induced by the action of DNT, without which ventral scrolls and turbinates, which can take weeks to resolve pneumonia does not develop (18, 19). Pneumonia caused by (15, 20-24); however, when B. bronchiseptica interacts with B. bronchiseptica results in red-to-plum areas of cranioventral toxigenic strains of P. multocida, disease is more severe (25-27). consolidation in the lungs that are associated with hemorrhage, The P. multocida toxin (PMT) and DNT act synergistically to necrosis, and neutrophil infiltration (29). Over time, the lesions undergo fibrosis and become grey-to-tan in color and more firm (29). The most prevalent clinical sign of B. bronchiseptica pneumonia is coughing and it can be difficult to discern the cause without further diagnostics.

Figure 1. Fattening pig with lateral deviation of the snout. Source: HIPRA.

6 colonization and disease with other bacterial agents (25, 27, 31). The association between B. bronchiseptica and P. multocida has been well studied as it relates to progressive atrophic rhinitis, where toxigenic P. multocida is better able to colonize and contribute to disease in animals with established B. bronchiseptica infection (25, 27). Additionally, P. multocida is less capable of causing pneumonic lesions as the sole agent or during PRRSV coinfection; however, when P. multocida is associated with PRRSV and B. bronchiseptica, more severe pneumonia develops (37). B. bronchiseptica also predisposes animals to disease with Streptococcus suis, promotes colonization with Haemophilus parasuis, and may contribute to the persistence of Actinobacillus pleuropneumoniae in the respiratory tract (31, 38-40). Coinfection of pigs with B. bronchiseptica and S. suis increases the prevalence of pneumonia as well as increasing the incidence of systemic infection with S. suis (38, 39). Coinfection of B. bronchiseptica and H. parasuis increases the burden of H. parasuis in the nasal cavity (31). Finally, biofi lms produced by B. bronchiseptica may provide a niche for the survival of other in the nasal passageways, as has been seen with A. pleuropneumoniae in vitro (40).

Although Bordetella bronchiseptica is ubiquitous within the Figure 2. Turbinate and lung lesions in a nursery pig aff ected by swine industry, this organism is not a commensal and the Bordetella bronchiseptica. Source: Histology and Anatomical Pathology, B. bronchiseptica Faculty of Veterinary Medicine, University of Murcia. diff erences in severity of disease are associated with the age and immune status of the animal, environmental conditions, coinfections, and variations in B. bronchiseptica Bordetella bronchiseptica is a predisposing factor for other isolates. Younger animals tend to develop more severe nasal diseases. and pulmonary lesions during B. bronchiseptica infection (11, 41). B. bronchiseptica disease is also impacted by immune status Bordetella bronchiseptica is also capable of increasing the and passive immunity, with piglets from vaccinated or naturally severity of respiratory disease caused by viral pathogens infected sows having delayed onset and/or reduced severity of and predisposing pigs to secondary infection with other lesions; however, these animals still become colonized with bacterial pathogens. The impact of B. bronchiseptica on B. bronchiseptica (29, 41, 42). Environmental conditions, such as respiratory disease associated with PRDC has been investigated poor air quality, can exacerbate disease with B. bronchiseptica using coinfection models with several viral agents (12, 32, 34, 35). as well as coinfections with other pathogens, both bacterial and Disease associated with Porcine Reproductive and Respiratory viral. Diff erences in isolate virulence also contribute to diff erences Syndrome Virus (PRRSV), infl uenza A virus (IAV), and Porcine in disease presentation and a broad range of virulence has been Respiratory Corona Virus (PRCV) is exacerbated by coinfection detected (lethal dose 50 variation of 100,000 fold in inbred mice) with B. bronchiseptica (32, 34-37). B. bronchiseptica was found (43, 44). These diff erences have been attributed to variation in to increase lesion severity and prolong disease resolution virulence factor production (43-45); however, even with less when contributing to a viral respiratory infection, which may virulent isolates, B. bronchiseptica predisposes animals to be associated with elevated and sustained cytokine response secondary infections and, when present, B. bronchiseptica during coinfection of viral agents and B. bronchiseptica (12, should not be considered a commensal. 32, 34-36). B. bronchiseptica has also been shown to enhance

7 PATHOGENESIS

Bordetella bronchiseptica infection begins with attachment of mutations prevent the expression of BvgAS and the transition the bacterium to the respiratory epithelium, with preferential of the bacterium to the pathogenic state (11). These Bvg- locked adherence to ciliated cells in the mucosa (15, 46). Through bacteria are readily cleared by the innate immune system and this interaction and toxin production, B. bronchiseptica causes do not establish infections in the swine host (14). ciliostasis and the extrusion of ciliated epithelial cells (15, 16, 29), which contributes to mucus accumulation within the respiratory tract. B. bronchiseptica causes inflammation of the Bordetella bronchiseptica virulence factors epithelium, leading to epithelial metaplasia and necrosis and the infiltration of immune cells (15, 16, 29), which B. bronchiseptica Bordetella bronchiseptica produces a host of virulence factors combats through being cytotoxic to phagocytes (33, 47). This that function in adherence, host tissue damage, and immune allows the bacterium to persist during tissue inflammation and evasion. Adhesion is mediated by a group of adhesins that evade the host immune response. Additionally, while they are work in concert to promote B. bronchiseptica colonization. not the preferred cell type, the interaction of B. bronchiseptica Filamentous hemagglutinin (FHA), fimbrial proteins, and with nonciliated epithelial cells is thought to play a role in pertactin are all thought to contribute to adherence through establishing microcolonies or biofilms, especially within the multiple binding specificities that extend the range of ligands nasal cavity (48). Biofilms are communities of microorganisms (48, 56-61). Toxin production by B. bronchiseptica contributes within a complex matrix that function in adherence, protect the to tissue damage and immune evasion. One prominent toxin organisms from the environment, and contribute to persistent is DNT, which is essential for the bony changes associated infections in bacteria such as B. bronchiseptica (49). with nonprogressive atrophic rhinitis and the necrosis associated with pneumonia (17-19, 62, 63). The production of The pathogenesis of B. bronchiseptica infection is associated DNT is essential for B. bronchiseptica to cause disease in swine with the coordinated implementation of various virulence and many swine isolates of B. bronchiseptica have enhanced factors that are regulated by the BvgAS (Bordetella virulence DNT production due to the presence of mutations in the coding gene) system (50). This system functions as an on/off switch sequence upstream of the gene (64). This genetic change may regulating the virulence genes of B. bronchiseptica and enabling represent host-adaption of swine isolates to causing disease phenotypic modulation that allows the bacterium to succeed in pigs. Another important B. bronchiseptica toxin is tracheal as it cycles between the environment and the host (11, 50, cytotoxin (TCT). TCT is produced by the bacteria during 51). The Bvg+ state is induced by an elevation in temperature cellular proliferation as a breakdown product of during the transition of B. bronchiseptica from the environment remodeling (65). When released from the cell, TCT interacts to infecting a host (50, 51). The virulence factors induced by with lipopolysaccharide in the outer to induce the BvgAS system are generated in two phases: “early” and ciliostasis and extrusion of ciliated epithelial cells from the “late”. Early genes induced by BvgAS function predominantly in mucosa (16, 29, 65). Because TCT is produced during cell wall adherence and aid the bacterium in establishing host infection. remodeling, it is constitutively produced and its production is not Late genes induced by BvgAS include toxins and virulence factors impacted by the BvgAS system. The last major B. bronchiseptica which cause tissue damage and are involved in host evasion. At toxin is (ACT). ACT has adenylate cyclase environmental temperatures in the Bvg- state, B. bronchiseptica activity and induces cellular lysis through pore formation (66, 67). has elevated expression of genes involved in motility and urease ACT can lyse many cell types, but the primary targets of ACT are production, while virulence factors are repressed (52, 53). phagocytes (68). Through its interaction with immune cells, ACT Bvg- B. bronchiseptica also show greater adherence to swine is able to modulate cytokine production and alter the serum and epithelial cells than Bvg+ cells (54, 55), this is thought to assist in secretory antibody response (58, 69, 70). Immune modulation the persistence of Bvg- cells in the respiratory tract until BvgAS and tissue damage are also mediated by effectors of the type can be induced. The BvgAS system can also become locked in 3 secretion system (T3SS) produced by B. bronchiseptica. The the “off” condition through phase variation, in which frameshift T3SS functions in the translocation of effector proteins from

8 the bacterium into the host cell cytosol (71). The effector and the tissue damage associated with rhinitis (76). Second, proteins contribute to immune evasion and tissue necrosis ciliostasis associated with B. bronchiseptica infection inhibits (72-74), and the T3SS is important in the progression and mucociliary clearance leading to the accumulation of mucus persistence of pneumonia (13, 74, 75). within the respiratory tract (16, 29). This provides a niche for secondary bacterial pathogens to adhere and thrive during The presence of B. bronchiseptica in the respiratory tract and B. bronchiseptica infection. Additionally, the epithelial the progression of disease contributes to the development of damage associated with B. bronchiseptica infection leads secondary bacterial infections through several mechanisms. to increased loss of nutrients that can be utilized by First, the interaction of Bordetella bronchiseptica with other bacterial pathogens during colonization. Finally, epithelial cells is mediated through the production of multispecies biofilms can be generated byB. bronchiseptica adhesins, which can be pirated by other bacteria, such as and other bacteria, such as A. pleuropneumoniae, to provide P. multocida, to enable attachment to the nasal epithelium added protection and nutrients within the nasal cavity (40), (11). For the interaction between B. bronchiseptica and thereby increasing the survival and risk of infection with P. multocida, this occurs independently of DNT production both bacterial species.

TRANSMISSION

Bordetella bronchiseptica is highly infectious and spreads also able to persist in the environment with a half-life of 1-2 rapidly throughout a herd to infect most animals (12- hours at ambient temperatures and 75% relative humidity and 14). The bacterium spreads through direct contact between is known to survive weeks in soil or water (77, 79, 80), which infected sows and their piglets as well as between pigs after indicates fomites may also play a role in transmission. Although comingling. B. bronchiseptica can also spread via aerosols there are no documented cases of transmission to swine from between animals without direct contact (12-14, 77), which other animal species, B. bronchiseptica has been isolated from is promoted by the sneezing and coughing associated with wildlife found in close proximity to swine (81) and is a common the progression of disease. After acute disease resolves, cause of disease in other domesticated mammals (1), which B. bronchiseptica colonization persists for several months may allow them to act as a reservoir for B. bronchiseptica and infected animals can serve as a reservoir for newly infection. introduced, naïve animals (78). Bordetella bronchiseptica is

9 DIAGNOSTICS

Bordetella bronchiseptica grows readily on blood agar plates; however, because B. bronchiseptica is a slower-growing organism, it can be difficult to identify without the use of a more restrictive media to prevent overgrowth of contaminating bacteria. Assessing the role of B. bronchiseptica in the disease process can also be difficult due to the mixed nature of many infections. B. bronchiseptica can be detected through isolation and biochemical identification from nasal swabs, or in cases of pneumonia from lung tissue samples or washes from pigs with pneumonia. Additionally, a polymerase chain reaction (PCR) target has been developed that has shown 100% specificity and sensitivity for B. bronchiseptica (82). More recently the use of Figure 3. Routine evaluation of the nasal turbinates in the slaughterhouse oral fluids has compared favorably to the use of nasal swabs and in nursery animals is now the best way of confirming or ruling out Progressive or Non-Progressive AR, respectively. Source: HIPRA. for detecting B. bronchiseptica via PCR at the herd level, improving the ease of sample collection (83, 84). Collection cards that lyse the bacteria and capture and stabilize the DNA for transport and storage at room temperature have also been used successfully to detect B. bronchiseptica in oral fluids (85). Atrophic rhinitis prevention programs can also be assessed using a snout scoring system, in which turbinate atrophy is quantified using a transverse sectioned snout (11) (Figure 3).

10 TREATMENT AND PREVENTION

Control of Bordetella bronchiseptica has been accomplished Vaccination as prevention and control of AR primarily with antibiotic treatments and vaccination to develop protective immunity. B. bronchiseptica tends to Vaccination against Bordetella bronchiseptica in swine be susceptible to chlortetracycline, oxytetracycline, and typically utilizes whole cell bacterins often including enrofloxacin, all antibiotics approved for the treatment of inactivated P. mutocida toxin to provide better control of bacterial agents associated with PRDC, but not specifically progressive atrophic rhinitis. Although vaccination with B. bronchiseptica (86). Resistance to β-lactams, including bacterins does not provide sterilizing immunity, it can ampicillin and ceftiofur, is widespread making them prevent clinical signs, lower bacterial numbers, and limit ineffective in treating B. bronchiseptica (8, 87, 88). While the severity of disease with B. bronchiseptica (89-91). Only antibiotics have been useful in reducing pneumonia and natural infection has been shown to provide total resistance clinical signs associated with B. bronchiseptica infection, to reinfection, probably due to induction of both serum IgG they are not effective in clearing the upper respiratory tract and mucosal IgA, which are important for clearance of the of infection and animals continue to shed B. bronchiseptica lung and upper respiratory tract respectively (92-96). Modified after treatment (11). Atrophic rhinitis control often utilizes live vaccines are not widely available for swine but may be antibiotic treatment using a combination of tetracycline more likely to mimic natural immunity through induction and trimethoprim-sulfonamide of the piglets and/or sow of a mucosal immune response; however, this would be around weaning or farrowing; however, resistance to dependent on the mechanism of attenuation and length of trimethoprim-sulfa antibiotics is becoming more common in persistence in the respiratory tract and thus is strain/vaccine B. bronchiseptica, making this treatment less effective (87). dependent. In addition, attenuated B. bronchiseptica strains In addition, the trend to reduce antibiotic usage in animal colonize the nasal cavity and may still predispose animals to production in general, and more specifically as a disease infection with other respiratory pathogens (76, 97). Systemic prevention measure, may result in a reemergence of overt antibody responses tend to be higher in animals parenterally atrophic rhinitis lesions in herds. vaccinated with bacterins compared to naturally infected animals or animals given intranasally administered attenuated vaccines (89). Thus bacterins are preferred for sow vaccination protocols, which involve vaccinating animals pre-farrow and rely on passively acquired maternal immunity to limit the severity of disease in piglets (98). Reduction of the prevalence of infection, bacterial load, and severity of nasal lesions, as well as increased weight gains have been demonstrated in piglets from B. bronchiseptica bacterin vaccinated sows. As is often the case, active vaccination of piglets can be complicated by the presence of maternal antibodies and vaccination at one and four weeks of age in maternally immune piglets has been employed with mixed results (89, 99). It is reasonable to suggest that vaccination against B. bronchiseptica may also reduce infection or severity of disease with secondary pathogens, nevertheless additional research into the effectiveness of vaccination in preventing enhanced disease with coinfection models using B. bronchiseptica and other respiratory pathogens is needed.

11 CONCLUSION

Bordetella bronchiseptica is a widespread, highly infectious difficult to discern. Vaccination can improve clinical health and cause of respiratory disease in swine. Disease varies from improve performance, but control of B. bronchiseptica can be mild, subclinical infections to severe pneumonia or atrophic challenging due to the difficulty in fully clearing the bacterium rhinitis. The presence of mild and subclinically infected animals using vaccines and antibiotics. Further research should aim to causes B. bronchiseptica to be an underreported contributor to better understand the mechanisms by which B. bronchiseptica respiratory disease in pigs. B. bronchiseptica also exacerbates contributes to enhanced disease with other respiratory viral respiratory infection and enhances colonization and/ pathogens and to determine whether vaccination can improve or disease with other bacterial pathogens, which makes the our ability to control both B. bronchiseptica infection and its full impact of B. bronchiseptica on swine respiratory health contribution to secondary disease.

12 REFERENCES

1. Ferry NS. 1912. Bacillus bronchisepticus (bronchicanis): The 11. Brockmeier SL, Register KB, Nicholson TL, Loving CL. 2012. cause of distemper in dogs and a similr disease in other Bordetellosis, p 670-679. In Zimmerman JJ, Karriker LA, animals. Vet J 19:376-391. Ramirez A, Schwartz KJ, Stevenson GW (ed), Diseases of Swine, 10 ed. John Wiley & Sons, Inc, West Sussex, UK. 2. Goodnow RA. 1980. Biology of Bordetella bronchiseptica. Microbiol Rev 44:722-738. 12. Brockmeier SL, Lager KM. 2002. Experimental airborne transmission of porcine reproductive and respiratory 3. Mattoo S, Cherry JD. 2005. Molecular pathogenesis, syndrome virus and Bordetella bronchiseptica. Vet Microbiol epidemiology, and clinical manifestations of respiratory 89:267-275. infections due to Bordetella pertussis and other Bordetella subspecies. Clin Microbiol Rev 18:326-382. 13. Nicholson TL, Brockmeier SL, Loving CL, Register KB, Kehrli ME, Jr., Shore SM. 2014. The Bordetella bronchiseptica type 4. Kumar S, Singh BR, Bhardwaj M, Singh V. 2014. Occurrence III secretion system is required for persistence and disease of Bordetella infection in pigs in northern India. Int J severity but not transmission in swine. Infect Immun Microbiol 2014:238575. 82:1092-1103. 5. Kureljusic B, Weissenbacher-Lang C, Nedorost N, 14. Nicholson TL, Brockmeier SL, Loving CL, Register KB, Kehrli Stixenberger D, Weissenbock H. 2016. Association between ME, Jr., Stibitz SE, Shore SM. 2012. Phenotypic modulation Pneumocystis spp. and co-infections with Bordetella of the virulent Bvg phase is not required for pathogenesis bronchiseptica, Mycoplasma hyopneumoniae and and transmission of Bordetella bronchiseptica in swine. Pasteurella multocida in Austrian pigs with pneumonia. Vet Infect Immun 80:1025-1036. J 207:177-179. 15. Duncan JR, Ross RF, Switzer WP, Ramsey FK. 1966. Pathology 6. Palzer A, Ritzmann M, Wolf G, Heinritzi K. 2008. Associations of experimental Bordetella bronchiseptica infection in between pathogens in healthy pigs and pigs with swine: atrophic rhinitis. Am J Vet Res 27:457-466. pneumonia. Vet Rec 162:267-271. 16. Duncan JR, Ramsey FK. 1965. Fine structural changes in the 7. Rutter JM, Taylor RJ, Crighton WG, Robertson IB, Benson porcine nasal ciliated epithelial cell produced by Bordetella JA. 1984. Epidemiological study of Pasteurella multocida bronchiseptica rhinitis. Am J Pathol 47:601-612. and Bordetella bronchiseptica in atrophic rhinitis. Vet Rec 115:615-619. 17. Horiguchi Y, Okada T, Sugimoto N, Morikawa Y, Katahira J, Matsuda M. 1995. Effects of Bordetella bronchiseptica 8. Zhao Z, Xue Y, Wang C, Ding K, Wu B, He Q, Cheng X, dermonecrotizing toxin on bone formation in calvaria of Chen H. 2011. Antimicrobial susceptibility of Bordetella neonatal rats. FEMS Immunol Med Microbiol 12:29-32. bronchiseptica isolates from pigs with respiratory diseases on farms in China. J Vet Med Sci 73:103-106. 18. Brockmeier SL, Register KB, Magyar T, Lax AJ, Pullinger GD, Kunkle RA. 2002. Role of the dermonecrotic toxin of 9. Sweeney MT, Lindeman C, Johansen L, Mullins L, Murray Bordetella bronchiseptica in the pathogenesis of respiratory R, Senn MK, Bade D, Machin C, Kotarski SF, Tiwari R, Watts disease in swine. Infect Immun 70:481-490. JL. 2017. Antimicrobial susceptibility of Actinobacillus pleuropneumoniae, Pasteurella multocida, Streptococcus 19. Magyar T, Glavits R, Pullinger GD, Lax AJ. 2000. The suis, and Bordetella bronchiseptica isolated from pigs in the pathological effect of the Bordetella dermonecrotic toxin in United States and Canada, 2011 to 2015. J Swine Health mice. Acta Vet Hung 48:397-406. Prod 25:106-120. 20. Cross RF. 1962. Bordetella bronchiseptica-induced porcine 10. Shin EK, Seo YS, Han JH, Hahn TW. 2007. Diversity of swine atrophic rhinitis. J Am Vet Med Assoc 141:1467-1468. Bordetella bronchiseptica isolates evaluated by RAPD analysis and PFGE. J Vet Sci 8:65-73.

14 21. Ross RF, Switzer WP, Duncan JR. 1967. Comparison of 33. Brockmeier SL, Register KB. 2000. Effect of temperature pathogenicity of various isolates of Bordetella bronchiseptica modulation and bvg mutation of Bordetella bronchiseptica in young pigs. Can J Comp Med Vet Sci 31:53-57. on adhesion, intracellular survival and cytotoxicity for swine alveolar macrophages. Vet Microbiol 73:1-12. 22. Tornoe N, Nielsen NC. 1976. Inoculation experiments with Bordetella bronchiseptica strains in SPF pigs. Nord Vet Med 34. Kowalczyk A, Pomorska-Mol M, Kwit K, Pejsak Z, Rachubik 28:233-242. J, Markowska-Daniel I. 2014. Cytokine and chemokine mRNA expression profiles in BALF cells isolated from pigs 23. Rutter JM. 1981. Quantitative observations on Bordetella single infected or co-infected with swine influenza virus and bronchiseptica infection in atrophic rhinitis of pigs. Vet Rec Bordetella bronchiseptica. Vet Microbiol 170:206-212. 108:451-454. 35. Loving CL, Brockmeier SL, Vincent AL, Palmer MV, Sacco 24. Magyar T, Donko T, Repa I, Kovacs M. 2013. Regeneration of RE, Nicholson TL. 2010. Influenza virus coinfection with toxigenic Pasteurella multocida induced severe turbinate Bordetella bronchiseptica enhances bacterial colonization atrophy in pigs detected by computed tomography. BMC and host responses exacerbating pulmonary lesions. Vet Res 9:222. Microb Pathog 49:237-245. 25. de Jong MF, Nielsen JP. 1990. Definition of progressive 36. Brockmeier SL, Palmer MV, Bolin SR. 2000. Effects of atrophic rhinitis. Vet Rec 126:93. intranasal inoculation of porcine reproductive and 26. Harris DL, Switzer WP. 1968. Turbinate atrophy in young respiratory syndrome virus, Bordetella bronchiseptica, pigs exposed to Bordetella bronchiseptica, Pasteurella or a combination of both organisms in pigs. Am J Vet Res multocida, and combined inoculum. Am J Vet Res 29:777- 61:892-899. 785. 37. Brockmeier SL, Palmer MV, Bolin SR, Rimler RB. 2001. Effects 27. Pedersen KB, Barfod K. 1981. The aetiological significance of intranasal inoculation with Bordetella bronchiseptica, of Bordetella bronchiseptica and Pasteurella multocida in porcine reproductive and respiratory syndrome virus, or a atrophic rhinitis of swine. Nord Vet Med 33:513-522. combination of both organisms on subsequent infection 28. Nair SP, Meghji S, Wilson M, Reddi K, White P, Henderson B. with Pasteurella multocida in pigs. Am J Vet Res 62:521-525. 1996. Bacterially induced bone destruction: mechanisms 38. Vecht U, Arends JP, van der Molen EJ, van Leengoed LA. and misconceptions. Infect Immun 64:2371-2380. 1989. Differences in virulence between two strains of 29. Duncan JR, Ramsey RK, Switzer WP. 1966. Pathology of Streptococcus suis type II after experimentally induced experimental Bordetella bronchiseptica infection in swine: infection of newborn germ-free pigs. Am J Vet Res 50:1037- pneumonia. Am J Vet Res 27:467-472. 1043.

30. Dunne HW, Kradel DC, Doty RB. 1961. Bordetella 39. Vecht U, Wisselink HJ, van Dijk JE, Smith HE. 1992. Virulence bronchiseptica (Brucella bronchiseptica) in pneumonia in of Streptococcus suis type 2 strains in newborn germfree young pigs. J Am Vet Med Assoc 139:897-899. pigs depends on phenotype. Infect Immun 60:550-556.

31. Brockmeier SL. 2004. Prior infection with Bordetella 40. Loera-Muro A, Jacques M, Avelar-Gonzalez FJ, Labrie J, bronchiseptica increases nasal colonization by Haemophilus Tremblay YD, Oropeza-Navarro R, Guerrero-Barrera AL. parasuis in swine. Vet Microbiol 99:75-78. 2016. Auxotrophic Actinobacillus pleurpneumoniae grows in multispecies biofilms without the need for nicotinamide- 32. Brockmeier SL, Loving CL, Nicholson TL, Palmer MV. 2008. adenine dinucleotide (NAD) supplementation. BMC Coinfection of pigs with porcine respiratory coronavirus Microbiol 16:128. and Bordetella bronchiseptica. Vet Microbiol 128:36-47. 41. Harris DL. 1970. Resistance to Bordetella bronchiseptica infection in swine. Ph.D. Iowa State University, Ames, Iowa.

15 REFERENCES

42. Giles CJ, Smith IM, Baskerville AJ, Brothwell E. 1980. Clinical 53. Akerley BJ, Monack DM, Falkow S, Miller JF. 1992. The bvgAS bacteriological and epidemiological observations on locus negatively controls motility and synthesis of flagella infectious atrophic rhinitis of pigs in southern England. Vet in Bordetella bronchiseptica. J Bacteriol 174:980-990. Rec 106:25-28. 54. Brockmeier SL. 1999. Early colonization of the rat upper 43. Buboltz AM, Nicholson TL, Parette MR, Hester SE, Parkhill J, respiratory tract by temperature modulated Bordetella Harvill ET. 2008. Replacement of adenylate cyclase toxin in bronchiseptica. FEMS Microbiol Lett 174:225-229. a lineage of Bordetella bronchiseptica. J Bacteriol 190:5502- 55. Register KB, Ackermann MR. 1997. A highly adherent 5511. phenotype associated with virulent Bvg+-phase swine 44. Gueirard P, Guiso N. 1993. Virulence of Bordetella isolates of Bordetella bronchiseptica grown under bronchiseptica: role of adenylate cyclase-hemolysin. Infect modulating conditions. Infect Immun 65:5295-5300. Immun 61:4072-4078. 56. Cotter PA, Yuk MH, Mattoo S, Akerley BJ, Boschwitz J, 45. Buboltz AM, Nicholson TL, Weyrich LS, Harvill ET. 2009. Role Relman DA, Miller JF. 1998. Filamentous hemagglutinin of the type III secretion system in a hypervirulent lineage of of Bordetella bronchiseptica is required for efficient Bordetella bronchiseptica. Infect Immun 77:3969-3977. establishment of tracheal colonization. Infect Immun 66:5921-5929. 46. Yokomizo Y, Shimizu T. 1979. Adherence of Bordetella bronchiseptica to swine nasal epithelial cells and its 57. Edwards JA, Groathouse NA, Boitano S. 2005. Bordetella possible role in virulence. Res Vet Sci 27:15-21. bronchiseptica adherence to cilia is mediated by multiple adhesin factors and blocked by surfactant protein A. Infect 47. Forde CB, Shi X, Li J, Roberts M. 1999. Bordetella Immun 73:3618-3626. bronchiseptica-mediated cytotoxicity to macrophages is dependent on bvg-regulated factors, including pertactin. 58. Hibrand-Saint Oyant L, Bourges D, Chevaleyre C, Raze D, Infect Immun 67:5972-5978. Locht C, Salmon H. 2005. Role of Bordetella bronchiseptica adenylate cyclase in nasal colonization and in development 48. Irie Y, Yuk MH. 2007. In vivo colonization profile study of local and systemic immune responses in piglets. Vet Res of Bordetella bronchiseptica in the nasal cavity. FEMS 36:63-77. Microbiol Lett 275:191-198. 59. Mattoo S, Miller JF, Cotter PA. 2000. Role of Bordetella 49. Cattelan N, Dubey P, Arnal L, Yantorno OM, Deora R. bronchiseptica fimbriae in tracheal colonization and 2016. Bordetella biofilms: a lifestyle leading to persistent development of a humoral immune response. Infect infections. Pathog Dis 74:ftv108. Immun 68:2024-2033. 50. Beier D, Gross R. 2008. The BvgS/BvgA phosphorelay 60. Scheller EV, Melvin JA, Sheets AJ, Cotter PA. 2015. system of pathogenic Bordetellae: structure, function and Cooperative roles for and filamentous evolution. Adv Exp Med Biol 631:149-160. hemagglutinin in Bordetella adherence and immune 51. Cotter PA, Miller JF. 1994. BvgAS-mediated signal modulation. MBio 6:e00500-00515. transduction: analysis of phase-locked regulatory mutants 61. Nicholson TL, Brockmeier SL, Loving CL. 2009. Contribution of Bordetella bronchiseptica in a rabbit model. Infect Immun of Bordetella bronchiseptica filamentous hemagglutinin 62:3381-3390. and pertactin to respiratory disease in swine. Infect Immun 52. McMillan DJ, Shojaei M, Chhatwal GS, Guzman CA, Walker 77:2136-2146. MJ. 1996. Molecular analysis of the bvg-repressed urease of 62. Magyar T, Chanter N, Lax AJ, Rutter JM, Hall GA. 1988. Bordetella bronchiseptica. Microb Pathog 21:379-394. The pathogenesis of turbinate atrophy in pigs caused by Bordetella bronchiseptica. Vet Microbiol 18:135-146.

16 63. Roop RM, 2nd, Veit HP, Sinsky RJ, Veit SP, Hewlett EL, 72. Medhekar B, Shrivastava R, Mattoo S, Gingery M, Miller Kornegay ET. 1987. Virulence factors of Bordetella JF. 2009. Bordetella Bsp22 forms a filamentous type III bronchiseptica associated with the production of infectious secretion system tip complex and is immunoprotective in atrophic rhinitis and pneumonia in experimentally infected vitro and in vivo. Mol Microbiol 71:492-504. neonatal swine. Infect Immun 55:217-222. 73. Kuwae A, Momose F, Nagamatsu K, Suyama Y, Abe A. 2016. 64. Okada K, Abe H, Ike F, Ogura Y, Hayashi T, Fukui-Miyazaki A, BteA Secreted from the Bordetella bronchiseptica Type Nakamura K, Shinzawa N, Horiguchi Y. 2015. Polymorphisms III Secetion System Induces Necrosis through an Actin influencing expression of dermonecrotic toxin inBordetella Cytoskeleton Signaling Pathway and Inhibits Phagocytosis bronchiseptica. PLoS One 10:e0116604. by Macrophages. PLoS One 11:e0148387.

65. Cookson BT, Cho HL, Herwaldt LA, Goldman WE. 1989. 74. Yuk MH, Harvill ET, Cotter PA, Miller JF. 2000. Modulation Biological activities and chemical composition of purified of host immune responses, induction of apoptosis and tracheal cytotoxin of Bordetella pertussis. Infect Immun inhibition of NF-kappaB activation by the Bordetella type III 57:2223-2229. secretion system. Mol Microbiol 35:991-1004.

66. Hanski E. 1989. Invasive adenylate cyclase toxin of 75. Pilione MR, Harvill ET. 2006. The Bordetella bronchiseptica Bordetella pertussis. Trends Biochem Sci 14:459-463. type III secretion system inhibits gamma interferon production that is required for efficient antibody-mediated 67. Basler M, Masin J, Osicka R, Sebo P. 2006. Pore-forming bacterial clearance. Infect Immun 74:1043-1049. and enzymatic activities of Bordetella pertussis adenylate cyclase toxin synergize in promoting lysis of monocytes. 76. Brockmeier SL, Register KB. 2007. Expression of the Infect Immun 74:2207-2214. dermonecrotic toxin by Bordetella bronchiseptica is not necessary for predisposing to infection with toxigenic 68. Harvill ET, Cotter PA, Yuk MH, Miller JF. 1999. Probing the Pasteurella multocida. Vet Microbiol 125:284-289. function of Bordetella bronchiseptica adenylate cyclase toxin by manipulating host immunity. Infect Immun 77. Stehmann R, Rottmayer J, Zschaubitz K, Mehlhorn G. 67:1493-1500. 1992. [The tenacity of Bordetella bronchiseptica in the air]. Zentralbl Veterinarmed B 39:546-552. 69. Henderson MW, Inatsuka CS, Sheets AJ, Williams CL, Benaron DJ, Donato GM, Gray MC, Hewlett EL, Cotter 78. Backstrom LR, Brim TA, Collins MT. 1988. Development PA. 2012. Contribution of Bordetella filamentous of turbinate lesions and nasal colonization by Bordetella hemagglutinin and adenylate cyclase toxin to suppression bronchiseptica and Pasteurella multocida during long- and evasion of interleukin-17-mediated inflammation. term exposure of healthy pigs to pigs affected by atrophic Infect Immun 80:2061-2075. rhinitis. Can J Vet Res 52:23-29.

70. Skinner JA, Reissinger A, Shen H, Yuk MH. 2004. Bordetella 79. Porter JF, Parton R, Wardlaw AC. 1991. Growth and survival type III secretion and adenylate cyclase toxin synergize to of Bordetella bronchiseptica in natural waters and in drive dendritic cells into a semimature state. J Immunol buffered saline without added nutrients. Appl Environ 173:1934-1940. Microbiol 57:1202-1206.

71. Deng W, Marshall NC, Rowland JL, McCoy JM, Worrall LJ, 80. Porter JF, Wardlaw AC. 1993. Long-term survival of Bordetella Santos AS, Strynadka NCJ, Finlay BB. 2017. Assembly, bronchiseptica in lakewater and in buffered saline without structure, function and regulation of type III secretion added nutrients. FEMS Microbiol Lett 110:33-36. systems. Nat Rev Microbiol 15:323-337.

17 REFERENCES

81. Farrington DO, Jorgenson RD. 1976. Prevalence of 91. Brandenburg AC. 1978. Bordetella rhinitis in pigs: serum Bordetella bronchiseptica in certain central Iowa. J Wildl Dis and nasal antibody response to Bordetella bacterins. Can J 12:523-525. Comp Med 42:23-28.

82. Hozbor D, Fouque F, Guiso N. 1999. Detection of Bordetella 92. Harris DL, Switzer WP. 1969. Nasal and tracheal resistance bronchiseptica by the polymerase chain reaction. Res of swine against reinfection by Bordetella bronchiseptica. Microbiol 150:333-341. Am J Vet Res 30:1161-1166.

83. Maldonado J, Valls L, Camprodon A, Riquelme R, Riera P. 93. Gopinathan L, Kirimanjeswara GS, Wolfe DN, Kelley 2014. Improvement of surveillance of atrophic rhinitis in ML, Harvill ET. 2007. Different mechanisms of vaccine- pigs by using qPCR on oral fluid samples from individual induced and infection-induced immunity to Bordetella and grouped pigs, abstr International Pig Veterinary Society bronchiseptica. Microbes Infect 9:442-448. Congress, León, Mexico, 94. Yoda H, Nakagawa M, Muto T, Imaizumi K. 1972. 84. Nofrarias M, Alba A, Valls L, Blanch M, Acal L, Lopez R, Development of resistance to reinfection of Bordetella Maldonado J. 2015. The use of oral fluid from pigs for the bronchiseptica in guinea pigs recovered from natural diagnosis of atrophic rhinitis, abstr European Symposium infection. Nihon Juigaku Zasshi 34:191-196. of Porcine Health Management, Nantes, France, 95. Wolfe DN, Kirimanjeswara GS, Goebel EM, Harvill ET. 85. Maldonado J, Sanchez A, Valls L. 2017. Feasibility of using 2007. Comparative role of immunoglobulin A in protective dried porcine oral fluid for the diagnosis of Porcine Atrophic immunity against the Bordetellae. Infect Immun 75:4416- Rhinitis, abstr Asian Pig Veterinary Society Congress, 4422. Wuhan, China, 96. Kirimanjeswara GS, Mann PB, Harvill ET. 2003. Role of 86. Kadlec K, Kehrenberg C, Wallmann J, Schwarz S. 2004. antibodies in immunity to Bordetella infections. Infect Antimicrobial susceptibility of Bordetella bronchiseptica Immun 71:1719-1724. isolates from porcine respiratory tract infections. 97. Zhang Q, Hu R, Hu J, He H, Tang X, Jin M, Chen H, Wu B. 2013. Antimicrob Agents Chemother 48:4903-4906. aroA deleted Bordetella bronchiseptica inspiring robust 87. Pruller S, Rensch U, Meemken D, Kaspar H, Kopp PA, mucosal immune response and provide full protection Klein G, Kehrenberg C. 2015. Antimicrobial Susceptibility against intranasal challenge. Res Vet Sci 94:55-61. of Bordetella bronchiseptica Isolates from Swine and 98. Riising HJ, van Empel P, Witvliet M. 2002. Protection of Companion Animals and Detection of Resistance Genes. piglets against atrophic rhinitis by vaccinating the sow PLoS One 10:e0135703. with a vaccine against Pasteurella multocida and Bordetella 88. Dayao DA, Gibson JS, Blackall PJ, Turni C. 2014. Antimicrobial bronchiseptica. Vet Rec 150:569-571. resistance in bacteria associated with porcine respiratory 99. Smith IM, Giles CJ, Baskerville AJ. 1982. Immunisation disease in Australia. Vet Microbiol 171:232-235. of pigs against experimental infection with Bordetella 89. Farrington DO. 1974. Evaluation of nasal culturing bronchiseptica. Vet Rec 110:488-494. procedures and immunization as applied to the control of Bordetella bronchiseptica rhinitis in swine. Ph.D. Iowa State University, Ames, IA.

90. Farrington DO, Switzer WP. 1979. Parenteral vaccination of young swine against Bordetella bronchiseptica. Am J Vet Res 40:1347-1351.

The article was prepared by a U.S. Department of Agriculture employee as part of his/her official duties. Articles and other publications prepared as part of a Federal employee’s official duties are property of the U.S. Government. Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture. This article has been done in collaboration with LABORATORIOS HIPRA, S.A.