*2.1.3 Bacterial agents*

The main bacterial pathogens associated with BRD are *M. haemolytica, P. multocida, H. somni* and *M. bovis* [10]. *M. haemolytica* is the principal bacterial agent of BRD and has a considerable economic impact on the North American feedlot industry. It is a small, Gram-negative and facultative anaerobic bacterium that commonly exists as a part of nasopharyngeal and tonsillar crypt microbiota in healthy cattle and sheep [23]. To date, 12 different (1, 2, 5–9, 12–14 and 16–17) capsular serotypes have been identified within *M. haemolytica* [23]. Among these serotypes, serotype 1 (S1), serotype 2 (S2) and serotype 6 (S6) are most frequently isolated from feedlot cattle, with the S1 and S6 being the most prevalent in bovine infection [24, 25]. *M. haemolytica* residing in the upper respiratory tract of healthy cattle maintains a commensal relationship with the host due to the containment by the local microbiota and host immunity [23]. However, when the local microbiota and host immunity get disrupted by stress and viral infections, this opportunistic bacterium proliferates in the upper respiratory tract and then translocates into the lung where it induces acute infection characteristics to fibrinous pneumonia [23]. *M. haemolytica*-induced pathogenesis is accomplished through a combination of virulence factors including outer membrane proteins, leukotoxin (Lkt), lipopolysaccharide (LPS) and lipoproteins [23]. The outer membrane proteins, such as adhesion protein, facilitate attachment and colonization of *M. haemolytica* to the bovine respiratory cells. The Lkt, being the most important virulence factor, attracts neutrophils and macrophages to the site of infection when it is present in low concentration. High levels of Lkt, however, induce cell death of leukocytes and phagocytes, allowing *M. haemolytica* to evade the detection and destruction by the host immune system. The other virulent factors, including LPS and lipoproteins, are involved in hemorrhage, edema, hypoxemia and acute inflammation [10]. The virulence factors of *M. haemolytica* differ among different serotypes, and such difference has been reported to attribute to the genetic differences among serotypes [25].

*P. multocida* and *H. somni* are also opportunistic BRD pathogens and are involved in the development of bronchopneumonia in cattle with clinical signs indistinguishable from pneumonia caused by *M. haemolytica*. The isolation rate of *P. multocida* and *H. somni* from clinically healthy cattle at feedlot entry is relatively high ranging from 15% up to 60% [10], suggesting they predominately exist as part of normal nasopharyngeal flora in healthy cattle. However, the isolation rate of these two pathogens is higher in the lower respiratory tract of feedlot cattle affected by BRD compared to healthy cattle [13]. The main virulence factors identified in *P. multocida* include a LPS, a cytotoxin, and iron acquisition proteins [10]. *H. somni* virulence factors include expression of immunoglobulin-binding proteins, survival in phagocytic cells, induction of apoptosis in endothelial cells, antigenic phase variation and endotoxic activity of the LPS and biofilm formation [10].

Compared to the other three BRD bacterial pathogens*, M. bovis* is the least characterized BRD pathogen. This bacterium lacks a cell wall and is fastidious, requiring specialized media and techniques for its isolation and culture. *M. bovis* is often associated with chronic pneumonia, and its mechanism of actions remains poorly understood [10].
