Pasteurella and Mannheimia spp. infections

Pasteurella and Mannheimia spp. infections

Historically, the term pasteurellosis has been used to signify disease caused by bacteria of the genus Pasteurella.10 In the context of respiratory disease of cattle, the term pneumonic pasteurellosis has been used conveniently and extensively to embrace disease caused by Pasteurella multocida and/or Pasteurella haemolytica without specifying which agent is of greater importance. Although the recent reclassification of bacteria in the Pasteurella haemolytica complex into five named species in the new genus Mannheimia makes continued use of the term pasteurellosis awkward, an acceptable replacement term with the same clinical implications has not emerged.2, 13, 34, 36

The family Pasteurellaceae is a large group of bacteria with phenotypic and genomic similarities and currently includes the genera Pasteurella, Actinobacillus, Haemophilus, Mannheimia and Lonepinella with other less well-defined groups.2, 3, 40 The pasteurellas and allied bacteria are Gram negative, chemo-organotrophic, facultatively anaerobic, fermentative bacteria liked by DNA affiliation. Despite these similarities, it is a heterogeneous group.3, 40, 48 DNA hybridization studies, in particular, have emphasized the heterogeneity of the species within the group.3, 40 Consequently, the taxonomic position of many of the species within the family Pasteurellaceae is the topic of debate: a debate that has prompted nomenclatural changes and reclassification of some species.3

The genus Pasteurella comprises a number of species, of which Pasteurella multocida, P. granulomatis, P. lymphangitidis, P. caballi and P. mairi are of significance in disease processes in domestic livestock.10, 50, 52, 60 Although P. multocida was finally accepted as the type species only as recently as 1985, its nomenclatural origin goes back to the 1800s.24, 40 The causative agent of a disease in poultry (subsequently referred to as fowl cholera) first described by Rivolta in 1877 and then by Revolee in 1879, was named Micrococcus gallicidus by Burrill in 1883. The microorganism underwent several name changes until 1887, when an Italian, Count Trevisan, named the genus Pasteurella to honour Louis Pasteur’s efforts in elucidating the aetiology of fowl cholera in turkeys.40 In spite of this signal occurrence, inconsistency in its nomenclature prevailed. Kitt is credited with the introduction of the species epithet when the microorganism was designated Bacterium (bipolare) multocidum in his Bacterienkunde II Auflage, 1893.24 In 1900, the name Bacterium (bipolare) multocidum was used synonymously with Bacterium bovisepticum by Migula24 and Bacillus boviseptica by Lignieres39 in their texts on bacterial systematics. The latter two names referred to the causative agent of haemorrhagic septicaemia in cattle.39 The genus name of Pasteurella was apparently accepted thereafter, but isolates of the microorganism were named according to their origin: P. bovicida orP. boviseptica from cattle, for example.48 The name P. septica, mooted by Topley and Wilson in 1929, was used until 1939, after which the combination P. multocida, proposed by Rosenbusch and Merchant, gained wide acceptance. 24, 40, 48

Species with phenotypic similarities were either separated from the type species (Pasteurella haemolytica in 1932,40 [reclassified as Mannheimia haemolytica in 19993]) or added to the genus (Pasteurella pneumotropica in 1950, Pasteurella gallinarum in 1955, Pasteurella ureae in 1962, [since reclassified as Actinobacillus ureae7] and Pasteurella aerogenes in 1974, among others).40 Several Pasteurella species of clinical significance have subsequently been added to this genus. Pasteurella lymphangitidis, a cause of lymphangitis in cattle in southern India,58 has never been isolated in South Africa.26 Pasteurella caballi causes primarily respiratory and uterine infections in horses. In South Africa it has been isolated from cases of uterine infections, abortions, abscesses and other purulent infections in horses.26 Pasteurella mairi has been cultured from cases of abortion in sows and septicaemia in piglets and may cause infection in other animal species.58 In South Africa the bacterium has been isolated from aborted pig foetuses and piglet septicaemia.26 The different species may be distinguished by their biochemical characteristics. 2, 11

Pasteurella multocida is a species that exhibits heterogeneity in several respects.48 The microorganism measures 0,6–2,5 × 0,2–0,4 μm and is a non-motile, non-sporogenous, Gram-negative, encapsulated, facultatively anaerobic coccobacillus or short rod. Bipolar staining is evident in Giemsa- or Wright-stained preparations of young cultures.

Based on the passive haemagglutination test, five capsular serotypes: A, B, D, E and F, and 16 somatic types of P. multocida are recognized.46 In addition, untypable isolates are also encountered. While not the only factor involved, the polysaccharide constituent of the capsule plays a role in adherence, colonization, invasiveness and virulence, and is therefore an important determinant of pathogenicity. Encapsulated strains of P. multocida belonging to serogroups A, D and F are not readily phygocytosed in non-immunized animals.47 Other chemical determinants of pathogenicity identified to date include:

  • the lipopolysaccharide (LPS) of the outer cell membrane, which has endotoxic activity—an activity indistinguishable from that of LPS derived from other Gram-negative bacteria (see below);
  • the protein (dermonecrotic) toxin elaborated by certain serotypes, serotype D in particular, that plays an integral role in the pathogenesis of progressive atrophic rhinitis in pigs;
  • a secreted neuraminidase that may serve to enhance colonization and adhesion;38, 63 and
  • other toxins common to the genera Haemophilus, Actinobacillus and Pasteurella, such as the RTX (repeats in toxin) family of toxins and outer membrane proteins, also play a role in virulence but are less well studied.43

The remaining (chemical) determinants of pathogenicity await elucidation. Plasmids that encode for antibiotic resistance have been identified in P. multocida.31

Pasteurella multocida has a wide geographic distribution and an almost unlimited host range among mammals and birds in both terrestrial and aquatic environments.10, 48 The biological behaviour of the microorganism varies, however. It may exist as a commensal in the upper respiratory tract (nasopharynx) or it may act as a primary or secondary pathogen in different animals. Most strains of the microorganism are, interestingly, singularly pathogenic for laboratory mice.10 An association between the different serotypes and the different disease syndromes in domestic livestock is apparent.10, 20 Thus serotypes B and E are considered the causative agents of haemorrhagic septicaemia (epidemic pasteurellosis) of cattle and water buffaloes (Bubalus bubalis), serotype A is occasionally associated with pneumonic pasteurellosis in cattle and pigs, while serotype D is most frequently implicated in the aetiology of progressive atrophic rhinitis in pigs and occasionally with pneumonic pasteurellosis in pigs, sheep and goats.

The first report of haemorrhagic septicaemia, called ‘wild und rinderseuche’ because of the involvement of deer as well as cattle, emanated from Germany in 1878.12 This disease was reproduced experimentally in cattle. In 1892, Nocard reproduced acute fibrinous pneumonia in a juvenile bovine, using bacteria isolated from cattle that had died acutely with similar lesions following transhipment to France from North America.53, 54 Nocard appreciated the distinction between this disease and haemorrhagic septicaemia. 53 Nevertheless, around this period, the similarities between the aetiological agents responsible for haemorrhagic septicaemia and acute fibrinous pneumonia in cattle (bipolar staining among other features), led to the hypothesis that the latter disease was merely the pectoral (pneumonic) form of haemorrhagic septicaemia.39, 54 Although cultural differences between the microorganisms associated with haemorrhagic septicaemia and its socalled pectoral variant were recognized in 1921, it was only in the 1930s that separation of haemorrhagic septicaemia and pneumonic pasteurellosis into distinct disease entities was finally accepted.39, 53, 54 This coincided with recognition of Bacillus (Pasteurella) boviseptica as a distinct species, the name P. haemolytica materializing in 1932, while the remaining bacteria were grouped into P. multocida in 1939.40

Since then, bacteria belonging to the species Pasteurella haemolytica were reclassified.3 Trehalose fermenting serotypes (formerly Pasteurella haemolytica biotype T; serotypes 3, 4, 10 and 15) have been reclassified as Bibersteinia trehalosi.3, 4, 58 This species causes pneumonia in sheep of all ages and a distinct syndrome in six- to ten-month-old lambs, called ‘systemic pasteurellosis’ in the UK.19

The non-trehalose fermenting biogroups have been placed in a new genus, Mannheimia, that consists of at least five genera.3 Mannheimia haemolytica (formerly P. haemolytica biogroup 1) has a global distribution but is restricted to ruminants. Sporadic reports of isolation of this bacterium from non-ruminant species are most likely cases of misidentification.6, 25, 40 It is most commonly implicated as a cause of bronchopneumonia in especially feedlot cattle. Besides its involvement in pneumonic disease, M. haemolytica is also associated with septicaemic conditions, acute localized infections (pericarditis, pleuritis and peritonitis) and mastitis in ruminants, and abortion in cattle.10, 20, 23 Mannheimia granulomatis (formerly Pasteurella granulomatis) causes a focal proliferative fibrogranulomatous panniculitis in cattle in Brazil known as ‘lechiguana’.45 It has also been isolated from rabbits and hares. Mannheimia varigena (formerly Pasteurella haemolytica biogroup 6) is found in cattle and pigs and causes sepsis, pneumonia and other diseases.3, 4 Mannheimia glucosida (formerly Pasteurella haemolytica biogroups 3 and 9) is mostly isolated from the nasal cavity of sheep and rarely causes disease. Isolates of M. glucosida belong to serotype 11. Mannheimia ruminalis occurs in the rumen of cattle and does not cause disease.

Until there is further clarification, the previous serotyping scheme for the 12 serotypes 1, 2, 5–9, 12–14, 16 and 1765 in the former Pasteurella haemolytica serotyping is no longer valid for the members of the genus Mannheimia as the same serotype can be found in more than one species of Mannheimia.4

Because of its pivotal role in pneumonic pasteurellosis of cattle and the economic importance of this disease, the determinants of pathogenicity for M. haemolytica serotype 1 have been subjected to the most intensive investigation.1, 15, 23, 64 In vitro cultivation of the microorganism is characterized by an initial period of exponential proliferation (the logarithmic phase or log-phase of bacterial growth) that is succeeded by a stationary phase during which replication is minimal.61 During the log-phase of growth, factors which determine bacterial virulence are produced in large quantities. 5, 14, 16, 21, 22, 30, 44, 49, 61 It is unclear whether all the virulence factors identified in M. haemolytica serotype 1 are shared with the other serotypes of the species or with Bibersteinia trechalosi, although Bibersteinia trechalosi is known to produce a leukotoxin and the lipopolysaccharide (LPS) of the outer cell membrane is a major virulence factor.29 The pathogenicity of M. haemolytica serotype 1 rests with certain cellular components (virulence factors)15, 27, 32, 41 that include:

  • fimbriae (cell-surface pili);
  • proteolytic enzymes, neuraminidase in particular;
  • capsular polysaccharides;
  • leukotoxin (cytotoxin);
  • LPS (endotoxin); and
  • outer membrane proteins.

Each factor fulfils a specific function or set of functions that subserve initiation and amplification of the infectious and inflammatory process in the bovine respiratory tract. The fimbriae may act as specific adhesins facilitating bacterial attachment to, and colonization of, the upper and lower respiratory tract; the former an essential prelude to the pneumonic process.1, 21, 22, 37 The purported action of the proteolytic enzymes is two-fold.1, 5, 16 Firstly, enzymatic breakdown of mucus in the airways with a consequent loss of viscosity and adhesiveness may interfere with the mucociliary clearance function. Secondly, enzymatic removal of fibronectin from the surface of the epithelial cells lining the airways may facilitate bacterial attachment and colonization.

Production of capsular polysaccharides and leukotoxin is maximal during the logarithmic growth phase of M. haemolytica serotype 1.17, 52 Capsular polysaccharides and leukotoxin are released into the inflammatory exudate but remain localized within the alveolar lumen.64 The putative pathogenic functions of the capsular polysaccharides15, 16 include:

  • facilitation of bacterial adherence to bronchiolar and alveolar epithelium;
  • chemotaxis of neutrophils;
  • inhibition of the phagocytic and microbicidal mechanisms of neutrophils and macrophages; and
  • inhibition of complement-mediated microbicidal mechanisms.

These functions are largely owed to the net negative surface charge and hydrophilic properties of capsular polysaccharides. 16 Leukotoxin is an exotoxin that is heat-labile, antigenic and specifically toxic for alveolar macrophages and circulating blood lymphocytes, neutrophils and platelets of ruminants.14, 28, 35, 51 In low concentrations it may induce inappropriate activation of alveolar macrophages and neutrophils, resulting in pro-inflammatory effects while inhibiting phagocytosis of the microorganisms.1, 15, 64 In higher concentrations it causes death of the target cells, due to formation of membrane pores and osmotic lysis, or apoptosis. 33, 59, 62 Release of lysosomal enzymes from alveolar macrophages and neutrophils lysed by leukotoxin may augment local tissue injury,23, 60, 64 while fibrinogenesis may ensue after the release of procoagulant mediators from escaped blood platelets which are then subsequently damaged by leukotoxin.15 The pathogenic effects of leukotoxin are therefore indirect.15, 23, 60, 64

The pathogenic effects of LPS are attributable to its endotoxic activity,1, 15 and it is estimated that between 12 and 25 per cent of the dry weight of M. haemolytica consists of LPS.32 The route of administration is the major determinant of the host response to LPS,55, 57 of which both systemic and local effects are recognized.15 The onset of LPS mediated effects is rapid (within 15 minutes) following intravenous administration but is considerably longer (up to six hours) when administered by other routes.8, 55, 60 Systemic effects are characterized by biphasic pyrexia, activation of complement, alterations in clotting homeostasis with resultant disseminated intravascular coagulopathy (DIC), progressive leukopenia (granulocytopenia in particular), progressive thrombocytopenia and alterations in systemic and pulmonary haemodynamics and function.8, 55–57 The haemodynamic and functional deficits in the lungs that follow intratracheal instillation of LPS are biphasic: phase I consists of eicosanoid-dependent hypertension (and either ventilation-perfusion mismatching or diffusion impairment leading to hypoxaemia), and phase II is characterized by neutrophil-dependent pulmonary oedema.55, 60 The progressive nature of the leukopenia and thrombocytopenia with M. haemolytica is attributable to the combined effects of LPS and leukotoxin.8 An immunohistochemical study found that LPS is released into the inflammatory exudate and is present on epithelial surfaces and in the cytoplasm of alveolar macrophages and neutrophils in experimental pneumonic pasteurellosis in cattle and, in contrast to capsular polysaccharides and leukotoxin, may cross the alveolar wall and be present within the cytoplasm of endothelial cells, monocytes and neutrophils in vascular sites of the interstitium. 64 The pathogenic effects of LPS at the alveolar level9, 15, 42, 64 include:

  • direct damage to endothelial cells, with induction of increased vascular permeability and oedema;
  • activation of the clotting mechanism, resulting in fibrinogenesis;
  • activation of complement, resulting in activation of alveolar macrophages as well as chemotaxis and activation of neutrophils, and activation of platelets; and
  • complex formation with surfactant leading to increased surface tension that predisposes to atelectasis, oedema and haemorrhage.

However, the discrepancies noted between the pathogenic effects of purified LPS and live M. haemolytica serotype 1 in experimental models emphasize that LPS, albeit an important component, is but one of several potential virulence factors.55 In addition, plasmids that encode for resistance to certain antibiotics have been identified that may be spread between the species and genera.1, 18, 31

Thus, the family Pasteurellaceae represents a diverse group of bacteria. They are associated with a variety of clinical syndromes in domestic animals, many of which have significant economic impact on animal agriculture. This has sustained a long history of research on virulence and host response and is reflected in the dynamic nomenclature of members of the family Pasteurellaceae. Research has led to improved methods for diagnosis, management and control of pasteurellosis but much remains to be learned.


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