The fundamental concept of the pathogenesis of BRD in newly arrived feedlot cattle is relatively well defined. Stress and adverse environmental conditions predispose the animal to infection with a virus or other agent that damages respiratory mucosa and alters host immunity, so that commensal bacteria become pathogens and produce fibrinopurulent bronchopneumonia. The purpose of this brief review is to highlight a few specific topics of current interest regarding the environment, infectious agents, and the host that are relevant to the pathogenesis of BRD.
Environment
Intensive management contributes to many of the stressors that predispose cattle to BRD (e.g. crowding, shipping, food and water access, and exposure to multiple pathogens). Feedlot capacity has progressively shifted toward larger feedlots (>31,999 head) compared with smaller feedlots (MacDonald and McBride, Reference MacDonald and McBride2009). Concurrently, global consumption and demand for beef is projected to increase over the next 10 years (Westcott and Trostle, Reference Westcott and Trostle2014). These trends suggest that there will be continued pressures for intensive management, which will possibly increase exposure of cattle to known and unforeseen management stressors in the future.
Extreme weather (e.g. very high temperatures, decreased or excessive rainfall, and severe storms) has increased during the past 10–30 years and is projected to continue to increase (Coumou and Rahmstorf, Reference Coumou and Rahmstorf2012). Extreme events could increase challenges to cattle due to heat stress, dust or mud, high or low humidity, changes in pest and disease distribution, and altered impacts on services that support the feedlot industry (e.g. cattle inventories, and feed and water quality and supply; Henry et al., Reference Henry, Charmley, Eckard, Gaughan and Hegarty2012).
Regulatory issues related to climate change, environmental quality, and antimicrobial use could also impact the feedlot environment. Livestock reportedly account for 18% of the total climate change-associated global anthropogenic greenhouse gas emissions and contribute substantially to air and water pollution, land degradation and water shortages, and loss of biodiversity (Steinfeld et al., Reference Steinfeld, Gerber, Wassenaar, Castel, Rosales and de Haan2006). Antimicrobial use in animal production is considered to contribute to antimicrobial resistance of human pathogens (Anonymous, 2014). Regulations to reduce greenhouse gas emissions, or to reduce emergence of antimicrobial resistance, could have substantial impacts on the characteristics of the feedlot industry and the stressors encountered by feedlot cattle.
Agents
‘Stressed’ cattle are more susceptible to the influence of contagious or commensal agents associated with BRD. Common viral components of BRD (e.g. bovine herpesvirus-1 (BHV-1), bovine parainfluenza virus 3, bovine respiratory syncytial virus (BRSV), bovine viral diarrhea virus (BVDV), and possibly bovine coronavirus), typically contribute to pathogenesis by damaging respiratory mucosa and by modifying the host innate and adaptive immune responses (Hodgins et al., Reference Hodgins, Conlon, Shewen, Brogden and Guthmiller2002). Many virus infections are self-limiting and predominately serve to promote secondary bacterial infection, but others may cause severe disease due to differences in host susceptibility and the heterogeneity that exists between strains of some BRD-associated viruses.
Common BRD-associated bacteria (e.g. Mannheimia haemolytica (MH), Pasteurella multocida (PM), Histophilus somni (HS), and Mycoplasma bovis (MB)) are commensals that most likely exist in healthy cattle as biofilms (Panciera and Confer, Reference Panciera and Confer2010). Some combinations of BRD-associated bacteria occur together in commensal polymicrobial biofilms, most notably HS and PM (Elswaifi et al., Reference Elswaifi, Scarratt and Inzana2012). The cooperative community of the biofilm creates an environment in which the bacteria co-exist with the host and are protected against toxins, antimicrobials, and other adverse substances, or agents (McDougald et al., Reference McDougald, Rice, Barraud, Steinberg and Kjelleberg2012). Bacteria in biofilms often down-regulate virulence factor production, but alteration of the biofilm microenvironment (e.g. changes in nutrient concentrations, hypoxia, high or low temperatures, and other stressors), can trigger dispersal of large numbers of planktonic (free-living) forms, which quickly convert to a virulent phenotype (Landini et al., Reference Landini, Antoniani, Burgess and Nijland2010; McDougald et al., Reference McDougald, Rice, Barraud, Steinberg and Kjelleberg2012). Biofilm dispersal is one mechanism by which commensal BRD-associated bacteria could become pathogenic and colonize deeper portions of the lung. Colonization of the upper respiratory tract by HS is the most efficient when phosphorylcholine is expressed on its surface lipooligosaccharides (LOS) (Elswaifi et al., Reference Elswaifi, Scarratt and Inzana2012). However, when phase-variable loss of phosphorylcholine expression occurs, the bacteria disperse from the biofilm and invade systemically. A similar situation may occur with capsular expression by MH. The capsular characteristics of typically non-virulent MH serotype 2 from the nasal cavity of normal calves may reflect a colonizing phenotype more likely to exist in a commensal biofilm. In contrast, the capsular characteristics of more virulent MH serotype 1 isolated from pneumonic lungs may represent a planktonic form dispersed from the biofilm.
Once established in the lung, bacteria are responsible for inflammation and bronchopneumonia associated with severe BRD. Bacteria associated with BRD damage the host by virtue of a variety of virulence factors and the host response to these factors (Panciera and Confer, Reference Panciera and Confer2010). Notable among the virulence factors are leukotoxin and lipopolysaccharide of MH (Singh et al., Reference Singh, Ritchey and Confer2011), LOS and immunoglobulin-binding protein A of HS (Agnes et al., Reference Agnes, Zekarias, Shao, Anderson, Gershwin and Corbeil2013), and variable surface proteins of MB (Caswell et al., Reference Caswell, Bateman, Cai and Castillo-Alcala2010). Similar to BRD-associated viruses, there is considerable strain variation within these bacteria which is sometimes reflected in differences in disease severity.
The polymicrobial nature of BRD determines many events in the pathogenesis of pneumonia. Enhanced or altered pathogenesis can occur due to the synergistic effects of various combinations of BRD-associated agents to cause more severe disease than that caused by either agent alone. Some combinations of agents that result in enhanced disease include MH with MB, BHV-1 or BVDV (Leite et al., Reference Leite, Kuckleburg, Atapattu, Schultz and Czuprynski2004; Caswell et al., Reference Caswell, Bateman, Cai and Castillo-Alcala2010; Ridpath, Reference Ridpath2010), HS and BRSV (Gershwin et al., Reference Gershwin, Berghaus, Arnold, Anderson and Corbeil2005), and MB and BHV-1 (Prysliak et al., Reference Prysliak, van der Merwe, Lawman, Wilson, Townsend, van Drunen Littel-van den Hurk and Perez-Casal2011). The various combinations of virulence factors can cause direct host injury, but these synergisms also alter host responses involved in pathogenesis (e.g. enhancement or inhibition of cytokine production, alteration of cell surface receptors, activation or inhibition of neutrophil and macrophage functions, and immunosuppression and interference with immune functions) (Srikumaran et al., Reference Srikumaran, Kelling and Ambagala2008; Caswell, Reference Caswell2014).
Host
There are inherent anatomical, physiological, and immunological features of the bovine that make it more prone to pneumonia, such as a large amount of respiratory dead space volume and poor collateral ventilation, pulmonary intravascular macrophages, and high numbers of circulating gamma–delta T cells (Ackermann et al., Reference Ackermann, Derscheid and Roth2010). Within the lung, antimicrobial peptides, cytokines, activities of epithelial and inflammatory cells, and other innate or acquired immune responses are the resources available to prevent BRD (Ackermann et al., Reference Ackermann, Derscheid and Roth2010). However, these responses can fail or create adverse effects in response to a multitude of environmental and infectious pulmonary challenges (Caswell, Reference Caswell2014).
Innate responses are often considered an important source of damage to the lung during the pathogenesis of BRD. Most commonly incriminated is an excessive and poorly regulated pro-inflammatory response to BRD agents that can cause extensive cell and tissue injury. However, in some cases it may be the lack of an anti-inflammatory balance in the host response that enhances disease. In a mouse model of viral–bacterial synergism, viral involvement caused fatal disease even when the bacterial infection was controlled by the immune system (Jamieson et al., Reference Jamieson, Pasman, Yu, Gamradt, Homer, Decker and Medzhitov2013). Fatality and severe disease in this study was proposed to be due to an impaired ability to tolerate and manage tissue damage partially due to down-regulation of genes involved in tissue protection and repair. In bovine bronchial epithelial cells co-infected with BHV-1 and MH, a gene involved in wound healing, fibrosis, and apoptotic functions of inflammatory cells (CYR61), was up-regulated less than pro-inflammatory genes by the co-infection compared with either agent alone (N'jai et al., Reference N'jai, Rivera, Atapattu, Owusu-Ofori and Czuprynski2013). The inhibition of pro-inflammatory NF-kappa B signaling and stimulation of secretion of anti-inflammatory substances by macrolide antibiotics is considered to be one reason for their effectiveness in treatment of BRD (Fischer et al., Reference Fischer, Duquette, Renaux, Feener, Morck, Hollenberg, Lucas and Buret2014). The complex interactions between the pro- and anti-inflammatory components of the host response are critical aspects of BRD pathogenesis. The optimal situation is to strike a balance between a pro-inflammatory host response that eliminates the agents of BRD, without causing excessive tissue injury that could overwhelm anti-inflammatory responses that are necessary for healing and repair of the damaged lung.
Multi-institutional and United States Department of Agriculture Agricultural Research Service projects using large numbers of cattle are underway to determine the genetics of resistance to BRD, the results of which could have major implications for improving host responses to BRD in the future. Observational phenotypes (e.g. breed, treatment rates, lung lesions, and production parameters) are generally associated with low heritability for resistance to BRD (Snowder et al., Reference Snowder, Van Vleck, Cundiff and Bennett2005). However, more specific criteria based on host response or accurate estimates of disease incidence could be more powerful indicators of resistance. Loci on bovine chromosomes 2, 20, and 26 were linked with BRD, and these loci also had associations with incidence of other infectious diseases (Casas and Snowder, Reference Casas and Snowder2008; Neibergs et al., Reference Neibergs, Zanella, Casas, Snowder, Wenz, Neibergs and Moore2011). Immune responses to vaccination with viral and bacterial agents of BRD had moderately high heritability (Leach et al., Reference Leach, Chitko-McKown, Bennett, Jones, Kachman, Keele, Leymaster, Thallman and Kuehn2013). These and other studies suggest that targeting animals with the best immunity could provide inherited resistance to BRD as well as other infectious diseases. Selection for other traits such as heat tolerance, and good temperament may also improve the ability of the host to respond to BRD challenges (Burdick et al., Reference Burdick, Randel, Carroll and Welsh2011).
Although the basic features of BRD pathogenesis are relatively well defined, the multiple factors involved create combinations and complex interactions between the environment, infectious agents, and the host which will continue to provide challenges to our understanding and management of BRD.
