Review

Veterinary Pathology
2014, Vol. 51(2) 393-409
Failure of Respiratory Defenses in the The Author(s) 2013
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Pathogenesis of Bacterial Pneumonia of Cattle DOI: 10.1177/0300985813502821
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J. L. Caswell1

Abstract
The respiratory system is well defended against inhaled bacteria by a dynamic system of interacting layers, including mucociliary
clearance, host defense factors including antimicrobial peptides in the epithelial lining fluid, proinflammatory responses of the
respiratory epithelium, resident alveolar macrophages, and recruited neutrophils and monocytes. Nevertheless, these manifold
defenses are susceptible to failure as a result of stress, glucocorticoids, viral infections, abrupt exposure to cold air, and poor air
quality. When some of these defenses fail, the lung can be colonized by bacterial pathogens that are equipped to evade the
remaining defenses, resulting in the development of pneumonia. This review considers the mechanisms by which these predis-
posing factors compromise the defenses of the lung, with a focus on the development of bacterial pneumonia in cattle and
supplemented with advances based on mouse models and the study of human disease. Deepening our understanding of how the
respiratory defenses fail is expected to lead to interventions that restore these dynamic immune responses and prevent disease.

Keywords
innate immunity, cattle, bacterial pneumonia, antimicrobial peptides, lung, Mannheimia haemolytica, viral infection, stress

As metabolism requires absorption of oxygen and elimination
of carbon dioxide, the high metabolic rates of mammals have
forced an expansion of ventilatory capacity and surface area
for gas exchange. This, along with the need to keep the gas
exchange region moist and covered only by a simple epithelium,
creates a vulnerability in the system with respect to protection
from inhaled gases, particles, and pathogens. Some components
of the respiratory defenses have been recognized for many years:
entrapment of particles in the mucus that lines the airways,
cough and mucociliary clearance to eliminate these trapped
particles, the bactericidal and immunomodulatory effects of resi-
dent alveolar macrophages and recruited leukocytes, antibody
and complement as soluble mediators of bacterial recognition
and elimination, and helper T cells for activation of macro-
phages. More recent advances in the understanding of respira-
tory defenses include the diversity of innate immune proteins
and peptides within the epithelial lining fluid of the lung, the
Duox/lactoperoxidase system, the role of T helper (Th)17 cells,
the polarization of macrophage functions, and improved under-
standing of the extracellular and intracellular signals that regu-
late the system.45,54,84,127,154 Finally, an important conceptual
advance is the recognition of extensive cross-talk or integration
between these components of the respiratory defenses, such that
the system is considered to operate as a layered series of
defenses with extensive interrelationships between the layers.
Clearly, gas exchange is critical for life, and an advanced system
has evolved to sustain this function.
It might seem incredible that such an integrated system
could fail, yet pneumonia caused by opportunistic bacterial
pathogens is common and important in all domestic animal
species and in humans. The bovine respiratory disease (BRD)
complex is a paradigm for the interactions among predisposing
factors and causative pathogens. BRD occurs as shipping fever
pneumonia of feedlot cattle, enzootic pneumonia of dairy and
veal calves, and pneumonia of adult cows but also affects cattle
in other production systems. Direct causes of respiratory
disease in cattle include the bacterial pathogens Mannheimia hae-
molytica, Bibersteinia trehalosi, Histophilus somni, Pasteurella
multocida, Mycoplasma bovis, and Trueperella (formerly Arca-
nobacterium) pyogenes, as well as the viral pathogens bovine
herpesvirus 1 (BHV-1), bovine respiratory syncytial virus
(BRSV), bovine parainfluenza 3 virus (BPIV-3), and bovine
coronavirus (BCV).28,65 Other infectious agentsincluding
Dictyocaulus viviparus and Mycobacterium boviscause pneu-
monia in cattle but are not included in the present review. It is
notable that most bacterial pathogens causing pneumonia in cattle
can also be detected in healthy animals.
Risk factors for the development of bacterial pneumonia in
cattle are well recognized and include infection with bovine viral
diarrhea virus (BVDV) or the viruses listed above, abrupt wean-
ing, transportation, sale through auction barns, mixing of social
groups, low body weight of recently purchased beef calves,
adverse climatic conditions including precipitation and rapid
1
Department of Pathobiology, University of Guelph, Guelph, ON, Canada
Corresponding Author:
J. L. Caswell, Department of Pathobiology, University of Guelph, Guelph, ON
N1G 2W1, Canada.
Email: jcaswell@uoguelph.ca
394
change in environmental temperatures, and poor air quality in
calf barns.10,30,31,108,130,197 Comparable risk factors predispose
humans to bacterial pneumonia, including the effects of viral
infection, psychological stress, and concurrent diseases.13,36
Thus, BRD can be considered analogous to human
community-acquired pneumonia, most frequently caused by
Streptococcus pneumoniae (pneumococcus), Haemophilus
influenzae, or Mycoplasma pneumoniae. As an animal model,
BRD cannot compare to mouse models with respect to genetic
manipulation, ease of experimentation, and the wide availabil-
ity of reagents. Nonetheless, cattle offer advantages in under-
standing the pathogenesis of opportunistic infection in the
lung: experimental infections are feasible and well character-
ized, their large size facilitates sampling, certain interventions
can be inexpensively tested on large groups of animals, cattle
and humans share certain immunologic (eg, interleukin 8) and
anatomic features (eg, bronchial glands, cartilaginous airways)
that differ from rodents, and, most important, the natural dis-
ease is of high prevalence and involves infection of outbred
animals with evolutionarily host-adapted pathogens. BRD is
clearly not equivalent to bacterial pneumonia of humans, yet
the findings in mice, cattle, and humans each contribute to an
improved general understanding of these disease processes.
This review focuses on the mechanisms by which the respira-
tory defense system is compromised by factors that predispose to
bacterial pneumonia. Specific considerations include the effects
of these predisposing factors on bacterial colonization of the nasal
cavity; effects on the epithelium of the lower respiratory tract,
including mucociliary clearance, receptor expression, and signal
transduction; effects on the production and function of host
defense molecules and antibody in the epithelial lining fluid; and
effects on leukocyte responses, including alveolar macrophages
and neutrophils. The nature of these defenses is mentioned only
superficially, as these are already well described.45,54,132,154 This
analysis is supplemented where possible with comparative infor-
mation from the human disease or from animal models, along
with a synopsis of how the bacterial pathogens themselves have
virulence attributes that allow them to evade the respiratory
defenses (Fig. 1).
Effects of Predisposing Factors on Bacterial
Colonization of the Nasal Cavity
Most discussions of innate immunity in the respiratory system
focus on the lungs, yet the upper respiratory tract clearly plays
an important yet poorly understood role in the pathogenesis of
bacterial pneumonia. M. haemolytica is known to colonize the
nasal mucosa61 and tonsil60 of clinically normal calves but is
not uniformly present. Indeed, the number of these bacteria iso-
lated from swabs of the nasal cavity increases as calves move
from the farm of origin through auction barns and subsequently
to feedlots. This increase in pathogen load is accompanied by a
shift in the predominant serotype: serotype A2 is more
frequently isolated from nonstressed pastured cattle, whereas
the more pathogenic serotype A1 is more often isolated from
stressed cattle soon after arrival to feedlots.64
Veterinary Pathology 51(2)
Viral infection may also play a role in these changes, as most
viruses that predispose to bacterial pneumonia replicate in the
nasal cavity before reaching the lung.210 In calves experimentally
infected with M. haemolytica, subsequent challenge with
BHV-163 or BPIV-361 leads to greater number of M. haemolytica
in nasal swabs, longer duration of bacterial shedding in nasal
secretions, reactivation of shedding in quiescent infections,62 and
increased severity of clinical signs.63,224 The effect of these viral
infections seems unique to nasal populations of M. haemolytica,
since comparable changes in tonsillar populations are not
observed.60 Similar to the effect of viruses, exposure to colder
environmental temperatures also increases the prevalence of
nasal colonization with M. haemolytica.94,96 Thus, viral infection
and exposure to cold air seem to selectively trigger M. haemoly-
tica serotype A1 to colonize and grow to greater numbers in the
nasal cavity.
The mechanisms of this effect in cattle are not known, but find-
ings in a mouse model may be relevant. Hemagglutinin (H)3
subtypes of influenza virus replicate to high titer in the middle ear
of mice, and the ensuing inflammatory response promotes repli-
cation of S. pneumoniae at this site.181 This effect is dependent
on hemagglutinin subtype, with greater replication of H3 than
H1 subtypes in the middle ear,181 and on anatomic site, with no
differences between hemagglutinin subtypes in the nasophar-
ynx.133 Although influenza in mice is not equivalent to viral infec-
tions of the cattle, the concept that virus-induced inflammation
can trigger bacterial replication may be informative.
M. haemolytica can be cultured from samples of tracheal air
of recently weaned and transported cattle, at levels ranging
from 67 to 441 colony-forming units/m3,74 and M. haemolytica
is isolated from bronchoalveolar lavage fluid of healthy calves
within 2 weeks of arrival to the feedlot but is rare at later
times.25 Paired M. haemolytica isolates from nasal swabs and
transtracheal aspirates had the same genotype in 77% of cases
(based on pulsed field gel electrophoresis), with significant
agreement between the presence and absence of M. haemoly-
tica in these 2 sites.200 Thus, the presence of M. haemolytica
in the nasal cavity likely influences the likelihood of bacteria
reaching the lung, although the number of M. haemolytica in
the nasal cavity and trachea is not well correlated.74 Together,
these findings indicate that weaning, transport, viral infections,
and cold air stimulate colonization of the nasal cavity by bac-
terial pathogens, and this in turn challenges the lung by inhala-
tion of infected droplets. In the context of M. haemolytica in
cattle, the mechanisms of these effects remain unknown, but
they represent a promising target for prevention of this disease.
Epithelial Cell Responses in the Lower
Respiratory Tract
Effects of Predisposing Factors on Clearance of Inhaled
Particles
Pulmonary clearance depends on deposition of inhaled particles,
quality of the mucus layer and periciliary layer, ciliary beat fre-
quency, and coordinated function of the ciliary apparatus.
Caswell 395

Figure 1. Mechanisms of failure of the respiratory defenses. The center column illustrates the layered arrangement of the respiratory defenses.
At left is a partial summary of causes and mechanisms whereby each of these respiratory defenses is compromised by factors that predispose to
bacterial pneumonia. At right is a partial summary of how bacterial pathogens further contribute to failure of the lung defenses. BVDV, bovine
viral diarrhea virus; IFN, interferon; TLR, Toll-like receptor.

Altered mucus quality is well recognized in cystic fibrosis.
Several explanations are proposed to link the causative CFTR
mutation to excessive secretion of tenacious mucus and subse-
quent airway obstruction: direct effects of the abnormal electro-
lyte conductance on physicochemical qualities of the secreted
mucus, reduced fluid secretion or increased absorption by airway
epithelial cells leading to dehydration of the mucus layer and
thinning of the periciliary layer, and excessive mucus secretion
with goblet cell hyperplasia as a consequence of airway inflam-
mation.57,89,106,168 The viscosity of the mucus interferes with
clearance, leading to airway obstruction, colonization with
bacteria, and impaired migration and bactericidal activity of
neutrophils.128
The shrinkage or weight loss experienced by recently
weaned and transported cattle is partly attributed to dehydra-
tion. Although dehydration is a potential cause for reduced
thickness of the periciliary layer and increased tenacity of
airway mucus, this has not been studied in cattle.
Ciliary dysfunction is a consequence of viral infection in
cattle,224 and BHV-1, BRSV, BPIV-3, and BCV are the
396
important viruses infecting airway epithelial cells. Mucociliary
clearance in normal calves eliminates 75% of aerosolized
M. haemolytica from the lung within 2 hours of exposure and
90% by 4 hours.114 BRSV infection causes loss of cilia as early
as 1 to 2 days postinfection (DPI), with cellular necrosis at
about 4 to 7 DPI, hyperplasia with undifferentiated or immature
cells at 7 DPI, and repair by 10 DPI.21,26,27,189 Reduced
pulmonary clearance is documented at 7 DPI, taking 50% more
time to clear ovalbumin after BRSV infection,67 and retention
of as much as 90% of inhaled cobalt particles after BPIV-3
infection.184 In these respects, respiratory viral infections in
cattle are comparable to human infection or mouse models of
influenza.158 Despite these abnormalities in airway epithelial
cell morphology and function, delayed mucociliary clearance
has been considered less important than defective bactericidal
activity in the pathogenesis of bacterial pneumonia.224
The effect of cold air on mucociliary clearance has been
studied in ruminants. Calves held at 3 C compared with 17 C
had a 24% reduction in nasal mucus velocity.47 Similarly, for
bovine and sheep trachea studied ex vivo, reducing the air
temperature from 37 C to 34 C or 30 C induced a marked
reduction in ciliary beat frequency and mucus transport, with
ciliary clumping and reduced height of the epithelium observed
at 30 C.47,100,186,187 Since cold-adapted animals are not at great
risk of pneumonia, the mechanisms of adaptation to cold air
and the detrimental effects of whole-body hypothermia155 also
merit consideration.
Particulates and xenobiotics are known to affect mucociliary
clearance. Inhaled particles are likely relevant to reduced air
quality in intensively housed calves and swine, but the effect
on ciliary function is not straightforward: swine barn dust
extracts increased ciliary beat frequency in primary cultures
of bovine bronchial epithelial cells, whereas they quelled the
enhancing effects of sympathetic stimulation with a b-ago-
nist.221 Elevated ammonia levels are associated with reduced
ventilation and use of solid partitions in crowded calf barns
in the autumn and winter and are thus another potential reason
for susceptibility to pneumonia. Chronic exposure to ammonia
is reported to cause ciliary dysfunction, degeneration of nasal
epithelium, and rhinitis in mice,211 as well as exacerbate the
lesions of mycoplasmal infection in rats,19 but its effects have
not been studied in cattle. Although the above conditions are
associated with increased frequency of respiratory dis-
ease,20,49,108,126 ammonia levels in 1 study were inversely cor-
related with BRD prevalence.118 Indeed, a study of swine
suggests that organic particulates may be of more importance
than ammonia in explaining the effects of poor air quality on
growth and feed conversion.137 Cigarette smoke,212,220 nitro-
gen dioxide,46 and sulfite34,142although not of relevance to
BRDare other xenobiotics causing reduced ciliary function.
Inflammation and sex hormones may also affect ciliary
function, but this is based on only scant evidence. Using in
vitro systems, acute exposure to inflammatory cytokines
increased ciliary beat frequency, while this was reduced with
chronic exposure to interleukin 8.4,163,179 In vitro ciliary beat
frequency was inhibited by progesterone treatment but restored
Veterinary Pathology 51(2)
with estrogen,90 a preliminary finding of potential relevance to
feedlot cattle treated with growth promotants. Thus, reasons for
failure of mucociliary clearance in cattle include infection with
viruses and cold exposure, with more poorly characterized
contributions from dehydration, exposure to organic particu-
lates or noxious gases in the barn environment, and chronic
airway inflammation.
In addition to the above predisposing factors, several bacterial
pathogens are known to impede ciliary function, both by secre-
tion of bacterial toxins and by the physical effect of adhering to
cilia. Ciliostatic effects are important in the pathogenesis of
M. pneumoniae in humans and mouse models, as well as Myco-
plasma hyopneumoniae in swine. Ciliostasis is also induced by
infection of bovine tracheal explants with Mycoplasma dispar
but not with certain other BRD-associated mycoplasmas, includ-
ing M. bovis and Acholeplasma laidlawii.5,86,107 Cilia-associated
respiratory bacillus isolates from cattle cause loss of cilia from
tracheal explants, but this pathogen is a minor contributor to
BRD.81,141 Bordetella bronchiseptica adheres to canine cilia,
causes ciliostasis and reduced clearance of particles within 1
hour of infection, stimulates mucus secretion by 4 to 8 hours, and
later induces epithelial cell cytotoxicity at 36 hours from secre-
tion of tracheal cytotoxin.7,15 Therefore, ciliary dysfunction is a
well-recognized effect of several bacterial pathogens but is not
known to occur with any of the bacteria causing BRD.
Effects of Predisposing Factors on Receptors on the
Surface of Airway Epithelial Cells
Toll-like receptors (TLRs) 1, 2, 4, 5, and 6 are cell surface
receptors recognizing bacterial products,154 and their genes are
expressed in bovine airway epithelial cells (Kawashima et al97
and unpublished data). Various factors that predispose to bac-
terial pneumonia are known to alter expression of these recep-
tors. TLR2 expression in airway epithelial cells is decreased in
patients with chronic obstructive pulmonary disease, and
TLR2/ mice have defective lactotransferrin (lactoferrin) pro-
duction following bacterial challenge.218 On the other hand,
TLR2 expression and subsequent functional responses are
increased by treatment of airway epithelial cells with tumor
necrosis factor (TNF)a, interferon (IFN)g, or corticoster-
oid.216 TLR4 expression in nasal epithelium and cultured
airway epithelial cells is reduced by corticosteroid or exposure
to cigarette smoke, with subsequent adverse effects on antimi-
crobial peptide production.120 Human respiratory syncytial
virus induces TLR3 expression in airway epithelial cells, with
increased cytokine responses when these cells are then stimu-
lated with TLR3 agonists.76 Thus, altered TLR expression in
airway epithelium is 1 mechanism whereby viral infections,
corticosteroids, and inflammatory cytokines alter the suscept-
ibility to bacterial infection.
Bacterial adhesins bind to host cell ligands, and altered
expression of these ligands affects colonization of the lung
by pathogens. BHV-1 is reported to promote adhesion of
M. haemolytica to airway epithelial cells in vitro,41,66 and similar
effects are well studied in human virus-bacterial interactions.
Caswell
Human influenza A virus, respiratory syncytial virus, and
parainfluenza virus enhance adhesion of S. pneumoniae and
H. influenzae to cultured bronchial epithelial cells by at least
2 mechanisms: altering the cell-surface expression of receptors
for bacterial adhesins (eg, platelet activating factor receptor,
which binds both the lipooligosaccharide of H. influenzae and
phosphorylcholine in the cell wall of S. pneumoniae), as well
as cleavage of host sialic acid by influenza viral neuraminidase,
thus exposing receptors on epithelial cells.9,39 Whether bovine
viruses induce similar changes remains unknown.
In addition to the above direct effects of viral infection, the
ensuing host inflammatory response may alter expression of
receptors for bacterial adhesins on respiratory epithelial cells,
potentially promoting colonization of the lung by bacteria.39,180
Since bacterial peptidoglycans in barn dusts induce TLR2-
dependent inflammatory responses in mouse lung,159 these
findings may have relevance to the pathogenesis of enzootic
pneumonia in intensively housed dairy and veal calves.108,137
Inflammation induced by short-term exposure to cold air44
could have similar effects, although specific evidence is
lacking.
Effects of Predisposing Factors on Epithelial Cell Signal
Transduction
Respiratory epithelial cells have elaborate mechanisms to sense
and eliminate viral infection, including recognition by TLR3,
TLR7/9, RIG-I, MDA-5, and Nlrp3, leading to activation of
type I interferon and induction of a range of antiviral
responses.174,208 Successful viral pathogens have evolved
diverse mechanisms to evade these recognition and effector
mechanisms,205,208 and some of these evasion strategies alter
the immuno-inflammatory response to bacterial infection of the
lung.
Several bovine respiratory viruses dysregulate the expres-
sion of IFN-a and IFN-b. BHV-1 encodes the viral proteins
ICP0 and ICP27, which block induction of IFN-b gene expres-
sion.42 BRSV also appears to inhibit type I interferon
responses.190,193 In vitro infection of macrophages with BVDV
has both stimulatory and inhibitory effects on these responses;
the in vivo situation is further complicated by effects of virus
strain and time after infection.152,193 Although BVDV also
infects airway epithelial cells, the effect on type I interferon
responses in these cells is unknown.3,37
This viral manipulation of host cells impairs specific aspects
of pulmonary defenses against bacteria, as described in later
sections, and also has broader effects on regulation of inflam-
mation and immunity in the lung. For example, nuclear factor
(NF)kB signaling is essential for a protective immuno-
inflammatory response to Pseudomonas aeruginosa in mice,35
and viral infections are known to modulate this signaling
pathway.170,203 Similarly, viral infections affect RIG-I,
MDA-5, and TLR3-induced signaling through the type I inter-
feron pathway.13,140 These effects seem to vary among different
viruses, time points after infection, and details of the host cells
analyzed. Consequently, it is difficult to make general inferences
397
about how the virus-manipulated epithelial cells respond to
inflammatory stimuli to induce innate defense proteins, vascular
changes in inflammation, and recruitment and activation of
leukocytes.
Some virus-induced defects in the host immuno-
inflammatory response promote bacterial survival and prolif-
eration in the lung,178 but viral meddling with the host response
may also exacerbate the immuno-inflammatory reaction to bac-
terial infection. For example, influenza virus infection induces
glucocorticoid, IL-10, or transforming growth factor (TGF)b,
which are immunosuppressive factors that predispose to
bacterial infection.13,93 BRSV infection of lambs induces gene
expression of IFN-b, IFN-g, TNF-a, IL-8, and MCP-1,190 and
BHV-1 infection of bronchial epithelium elicits IL-1, IL-8,
and TNF-a expression.165 These findings are similar to the
above-described influenza models in mice, but ovine BRSV
infection differs from the mouse model in a reduced production
of IFN-a, IL-10, and TGF-b.65 Thus, the findings in mouse
models of influenza-bacterial coinfection may not mirror the
viral-bacterial synergy that occurs in BRD.
In addition to these immunosuppressive effects, mice coin-
fected with influenza virus and Legionella pneumophila have
defective production of tissue-repairing growth factors that is
associated with more severe damage to airway and alveolar
epithelium and increased mortality.92 Thus, consideration
should be given not only to virus-induced failure of antibacter-
ial immunity but also to defective repair and tolerance of
injured tissues.
Bacteria that cause pneumonia are also known to modulate
epithelial signaling pathways. For example, virulence factors
of Moraxella catarrhalis and Neisseria meningitidis adhere
to carcinoembryonic antigen-related cell adhesion molecule 1
(CEACAM1) on airway epithelial cells, and this interaction
interferes with signaling through the TLR2 pathway.78
N-acyl homoserine lactone is produced by P. aeruginosa and
functions in quorum sensing, but this bacterial small molecule
also inhibits I-kB kinase to interfere with NF-kBinduced sti-
mulation of innate immune responses.105 Commensal bacteria
may play a similar role in pathogenesis: Streptococcus salivar-
ius suppresses NF-kB responses in epithelial cells and thereby
represses the production of neutrophil-recruiting chemokines
when the epithelial cells are subsequently exposed to the patho-
gen P. aeruginosa.38 Other examples involve the production of
immunosuppressive cytokines, such as the cAMP-mediated
expression of IL-10 that is triggered by the adenylate cyclase
toxin of Bordetella pertussis.78
Host Defense Molecules in the Epithelial
Lining Fluid
Host defense molecules in the epithelial lining fluid of the respira-
tory tract are derived from the epithelium, macrophages and other
leukocytes, and plasma. These factors function as opsonins, kill or
limit the growth of microbes, protect tissues against oxidative and
proteolytic injury, modulate the immuno-inflammatory response,
and promote tissue repair.77,132,154 Although it is helpful to
398
classify innate defense factors into these functional categories,
this is certainly a simplification because each of these molecules
generally has multiple functions that contribute to the health of the
respiratory system. Antibacterial molecules include defensins,
cathelicidins, lactotransferrin, hypothiocyanite, and hypoiodous
acid (products of the Duox/lactoperoxidase system); anionic
antimicrobial peptides; and lipocalins. Opsonins include immu-
noglobulins (Ig), complement proteins, the surfactant proteins
A and D, and pentraxins. Most of the above factors are immuno-
modulatory and contribute to tissue repair, as do annexins,
odorant binding protein, Clara cell secretory protein, haptoglobin,
and SPLUNC.132,154,167 Despite the relatively short time since
their discovery, much has been discovered of how these innate
defenses fail by mechanisms including lack of production, degra-
dation or impaired function, or resistance of pathogens to their
effects.
Effects of Predisposing Factors on Production of Innate
Defense Molecules
Expression of innate defense genes may be constitutive, induci-
ble, or both. For example, human b-defensin (HBD)1 is
expressed in normal individuals, whereas HBD-2 as well as the
bovine defensins tracheal and lingual antimicrobial peptide
(TAP, LAP) are normally present at low levels, but their expres-
sion is stimulated by bacteria, inflammatory cytokines, or TLR
agonists. In contrast, lactotransferrin is constitutively present but
induced to higher levels by inflammation.3,116,134,154,171 Factors
that reduce the baseline or induce levels of these innate defense
molecules are one mechanism by which predisposing factors
lead to bacterial pneumonia.
Polymorphisms are present in the noncoding regions of
bovine b-defensin genes that are associated with somatic cell
count in milk,11,139,196,217 and promoter polymorphisms in the
lactotransferrin gene correspond to levels of this protein in milk
and with somatic cell count.12,87,144 Thus, genetic variations in
these and upstream regulatory genes are a potential explanation
for differing levels of innate defense molecules among individ-
uals and are of potential utility with respect to genetic improve-
ment of disease resistance.113 Although human b-defensin
genes have copy number polymorphisms that show some asso-
ciation with a variety of diseases, in silico analysis of the
bovine genome has so far not revealed such polymorphisms
in cattle (unpublished data).
Corticosteroids impair the lipopolysaccharide (LPS)indu-
cible expression of tracheal antimicrobial peptide expression
in cattle134 and of HBD-2201 and HBD-3 in humans,51 perhaps
by interfering with TLR4/NF-kB signaling. Inhalation of corti-
costeroid presents little risk to otherwise healthy human
asthmatics as they have few bacteria reaching the lung, but this
is a risk factor for patients with chronic obstructive pulmonary
disease (COPD) or community-acquired pneumonia, in which
bacterial challenge of the lung is greater.6,93,143,213 Since corti-
costeroid levels are elevated in calves that are stressed by
disruption of social groups and transportation or by exposure
to cold,82,117,187 this is a plausible mechanism contributing to
Veterinary Pathology 51(2)
disease in calves exposed to these stressors. Weaning stress
is also associated with lower levels of blood lactotransferrin
in cattle, and glucocorticoids reduce secretion of lactotransfer-
rin from human bronchial epithelial cells.101,166 Thus, impaired
secretion of innate defense factors from the airway epithelium
is 1 way that corticosteroids and stress predispose to bacterial
pneumonia.
Viruses can also cause failure of expression of innate
defense factors. Noncytopathic BVDV is a major predisposing
cause of bacterial pneumonia in feedlot cattle164 and infects
bronchial epithelial cells in vivo without causing morphologic
change.37 Infection of bovine tracheal epithelial cells with this
virus does not affect baseline expression of host defense factors
but abrogates the LPS-stimulated expression of tracheal anti-
microbial peptide and lactotransferrin.3 Human influenza virus
and herpes simplex virus each suppress baseline expression of
human b-defensin-1 in bronchial epithelial cells.172 Chinchilla
airway (nasal) epithelial cells infected in vivo or in vitro with
respiratory syncytial virus have reduced b-defensin expression,
which permits colonization with H. influenzae; this effect is
blocked by prior intranasal administration of the defensin,
confirming the specificity of the effect.129 Thus, these various
models provide evidence that impaired defensin expression due
to respiratory viral infection predisposes to bacterial pneumo-
nia. In contrast, infection of lambs with BRSV had no effect
on expression of sheep b-defensin-1, while infection with para-
influenza virus induced expression of this gene, albeit late in
the disease course.97 The effect on subsequent challenge with
bacteria or LPS was not examined.
Th17 cells produce IL-17A, IL-17F, IL-22, and IL-23. In
addition to eliciting neutrophil recruitment, these cytokines
induce defensin gene expression on mucosal surfaces,54 and
IL-17A has been found to induce tracheal antimicrobial peptide
expression in bovine tracheal epithelial cells (unpublished
data). Thus, factors that skew the acquired immune response
toward a Th1 or Th2 response rather than a Th17 response can
interfere with innate immunity on the respiratory mucosa, and
indeed the Th2 cytokine IL-13 does suppress TLR2-induced
expression of human b-defensin-2 in airway epithelial cells.219
Micronutrients affect production of host defense factors.
Vitamin D, produced locally by airway epithelial cells or acti-
vated macrophages, increases expression of cathelicidin and
CD14.79 Thus, vitamin D deficiency is associated with bacter-
ial pneumonia in humans and might partly explain the season-
ality of this disease.79 However, in cattle, vitamin D levels had
no effect on response to challenge with BRSV,173 and injection
of vitamin D did not affect the prevalence of BRD.40
Iodine deficiency might also interfere with production of
host defense factors. The Duox/lactoperoxidase system of
airway epithelial cells is comparable to the NADPH oxidase/
myeloperoxidase system of neutrophils. Tracheobronchial
epithelial gland cells secrete lactoperoxidase. In the presence
of hydrogen peroxide from the airway surface epithelium, lacto-
peroxidase catalyzes formation of hypothiocyanite from thiocya-
nate and hypoiodous acid from iodine. These factors have
antibacterial and antiviral activity. The Duox/lactoperoxidase
Caswell
system is defective in cystic fibrosis, where epithelial cells fail to
secrete thiocyanate.136,160 Administration of iodine enhances
production of hypoiodous acid.58 However, observations of
diagnostic case material suggest that pneumonia is uncommon
in ruminants with iodine deficiency, so the negative effects of
iodine deficiency on respiratory defenses are presumably minor.
Chromium, copper, selenium, vitamin E, vitamin A, cobalt, and
zinc are reported to affect immune function, but dietary levels
have not shown a clear association with the development of
BRD.24,40,50,191
Other reported causes for failed regulation of host defense
factors may not be relevant to bovine respiratory disease.
Vanadium pentoxide and sulfate (air pollutants from diesel
exhaust) inhibit LPS-induced expression of tracheal antimicro-
bial peptide in bovine tracheal epithelial cells.102 Cigarette
smoke reduces b-defensin expression in airway epithelium and
may thus play a role in the pathogenesis of COPD.151 Finally,
of possible relevance to the nasal cavity, the normal flora is
thought to constantly induce production of innate defense
factors, including defensins, thereby protecting the mucosa
against colonization by pathogens. There is limited evidence
that disruption of this commensal flora may lead to failure of
local innate defenses and colonization by pathogens.204
Together, these findings imply that failure to synthesize host
defense factors, including b-defensins, is a likely mechanism
by which stress and viral infection predispose to bacterial pneu-
monia. Nutritional factors, induction of a skewed immune
responses, and environmental toxins may have similar effects.
In addition to these host and viral effects, several bacterial
pathogens have evolved mechanisms to evade these antimicro-
bial factors, although none are directly relevant to BRD.104,157
Binding of Klebsiella pneumoniae to TLR2 and TLR4 triggers
a signaling pathway in host epithelial cells that interferes with
NF-kB and MAP kinasemediated production of 2 b-defen-
sins. Thus, this provides an example of a bacterial pathogen
actively suppressing the antimicrobial peptide response that it
would otherwise stimulate.135 Salmonella typhimurium simi-
larly suppresses a-defensin production by Paneth cells in the
duodenum by an unknown mechanism.175 Finally, procyanin
is a metabolite of P. aeruginosa that appears to inhibit Duox
and thereby evade the Duox/lactoperoxidase defenses of the
airways.160
Effects of Predisposing Factors on the Function of Innate
Defense Molecules
In addition to the aforementioned effects of genetic polymorph-
isms on the levels of secreted innate defense molecules, genetic
variations affecting the function of these molecules may permit
bacterial infection of the lung.113 For example, a nonsynon-
ymous polymorphism has been detected in the coding region
of bovine tracheal antimicrobial peptide, which appears to
influence the function of the corresponding peptides.196
Polymorphisms have also been identified in the coding region
of genes for cathelicidins,68 complement proteins,223 and
surfactant protein D.70
399
Even when innate defense molecules are secreted appropri-
ately, other substances in the epithelial lining fluid of the lung
may interfere with their function. The best studied of these
effects is the sensitivity of b-defensin to increased salt concen-
tration, such as that found in the airway fluid of patients with
cystic fibrosis.71 Cathepsins secreted by macrophages cause
proteolytic cleavage and inactivation of b-defensins, and neu-
trophil elastase cleaves lactotransferrin.195 Thus, the tissue
microenvironment may compromise the function of secreted
antimicrobial proteins.
Some pathogens are able to evade these defenses directly,
either by resisting the effects of antimicrobial factors or by
inciting their destruction.104,157 Group A streptococci such as
Streptococcus pyogenes produce the protease SpeB that cleaves
and inactivates the human cathelicidin LL-37.95 Similarly, a
protease of Aspergillus fumigatus cleaves several complement
proteins and thereby prevents complement activation,14 while
protease IV of P. aeruginosa degrades surfactant proteins.122
Several Gram-positive pathogens alter the acetylation patterns
of peptidoglycan in their cell wall, as a mechanism to resist
degradation by lysozyme.43 The bacterial capsule is important
in evading complement80 but also confers resistance to catheli-
cidins among some pathogens, including N. meningitidis.192
Finally, Staphylococcus aureus, Streptococcus agalactiae, and
others modify their teichoic acids, phosphatidylglycerol, or
lipid A to make the normally anionic bacterial surface more
neutral and therefore less attractive to cationic antimicrobial
peptides.157
Despite this diversity of mechanisms by which bacterial
pathogens evade antimicrobial peptide defenses, M. haemolytica,
H. somni, and P. multocida have uniformly similar sensitivity as
Escherichia coli, to the levels of tracheal antimicrobial peptide
expected to be induced in vivo.196 In contrast, Mycoplasma bovis
was resistant under the conditions tested.
Effects of Predisposing Factors on Antibody Defenses
In addition to the above innate defense factors, IgM, IgGpar-
ticularly IgG2and IgA are effective in defense of the bovine
respiratory tract against bacterial pathogens by activating com-
plement, opsonizing for enhanced recognition by macrophages
and neutrophils, neutralizing bacterial toxins, and blocking
sites of colonization. Lack of prior exposure is 1 reason for
failure of this defense mechanism. At the time of arrival to
feedlots, the prevalences of serum antibody titers to M. haemo-
lytica and H. somni vary considerably but are generally high,
presumably because of prior exposure or vaccination. In
several studies, high on-arrival antibody titers to bacterial patho-
gens were associated with lower incidence of BRD, although that
finding was not demonstrated in other studies.123125,198 In con-
trast, generally low titers to Mycoplasma bovis prior to mixing
of calf groups suggests that prior exposure is infrequent, and titers
have not been correlated with later frequency of disease.8,25
Maternal antibody is considered important in defense
against BRD in the first 3 months of life. Failure to acquire
colostral immunoglobulin is associated with an increased
400
prevalence of respiratory disease in this age group and may
result from inadequate levels of protective antibodies in colos-
trum, poor quality or inadequate storage of colostrum, or
failure of the neonatal calf to ingest colostrum.209
Viral infections may interfere with an adequate immune
response after exposure to a bacterial pathogen. Even if the
acquired immune response develops too slowly to influence the
course of acute disease in an immunologically naive calf, develop-
ment of an antibody response may influence the longer term course
of disease. The evidence that BHV-1 and BVDV negatively affect
humoral immune responses has been previously reviewed.22,33,193
The bacterial pathogens causing BRD have several mechan-
isms to limit antibody-mediated immunity, although it should be
emphasized that induction of humoral immunity does confer
protection in challenge models of the disease. The capsule of
M. haemolytica confers partial resistance to antibody, whereas
an acapsular mutant had similar sensitivity to complement as the
parent strain.131 Formation of biofilm is described for H. somni
and several other bovine respiratory pathogens,148,176 although
the functional role in resisting the host immune response during
development of BRD has not been tested. M. haemolytica
secretes a protease that cleaves IgG1, and this pathogen also
encodes genes homologous to IgA protease of other Pasteurella-
ceae bacteria even though IgA proteolytic activity has not been
detected.69,109 H. somni secretes immunoglobulin-binding pro-
teins, including 3 IgG2-binding proteins, which are associated
with serum resistance.182 Thus, degradation or binding of anti-
body and formation of a capsule are mechanisms by which these
pathogens may evade the host antibody response.
Leukocyte Responses
Effects of Predisposing Factors on Pulmonary Alveolar
Macrophages
Alveolar macrophagesconsidered distinct from other
histiocytes in the lung, including intravascular and interstitial
macrophages as well as dendritic cellshave considerable het-
erogeneity in function. Research in mice has revealed plasticity
of macrophage responses and diversity of macrophage subsets;
evidence for the validity of these concepts in cattle remains lim-
ited. Resident alveolar macrophages form a self-renewing cell
population supplemented at a low level by immigration of blood
monocytes. These resident cells in mice are quiescent, with low
major histocompatibility complex (MHC) II expression, weak
antigen-presenting function, and low production of inflamma-
tory cytokines. In contrast, an inflammatory stimulus elicits a
more substantial influx of monocytes to form so-called exuda-
tive macrophages and monocyte-derived dendritic cells in the
lung tissue; these cells present antigen effectively and activate
T cells, produce nitric oxide and TNF-a, and stimulate injury
to lung tissue.199
Macrophages of mice and other species have functional
differences depending on the stimuli they encounter during dif-
ferentiation. Classically activated (M1) macrophages develop
in response to IFN-g and TNF-a; stimulate inflammation by
Veterinary Pathology 51(2)
secreting TNF-a, IL-12, and chemokines; and have substantial
bactericidal activity by undergoing an oxidative burst as well as
generating nitric oxide from arginine. In contrast, alternately acti-
vated (M2) macrophages develop in response to IL-13 and IL-4,
express arginase I, and promote tissue repair and restoration by
secreting IL-10, TGF-b, and IL-6.2,206 Comparable subsets have
been suggested in cattle, although they have not been extensively
characterized.52 Thus, macrophages in the lung maintain alveolar
homeostasis by recycling surfactant, phagocytose particulates
including bacteria, generate reactive oxygen and nitrogen species,
and secrete cytokines and proteases, yet the spectrum of these
functions depends on the monocyte subpopulation from which
they were derived, the method of recruitment, and the stimuli
encountered in the lung microenvironment.2,206
Most research on alveolar macrophages of cattle, particu-
larly the effects of viral infection and corticosteroids, predated
these concepts of macrophage heterogeneity, which are of
considerable relevance to understanding the findings. For
example, if viral infections elicit exudative macrophages, then
macrophages isolated from infected calves would be expected
to respond differently than normal resident macrophages
infected in vitro, yet this difference would not represent a direct
effect of viral infection on macrophage function. Furthermore,
the diversity of methods used to probe macrophage function
over the years has probably contributed to the conflicting data
in the published literature.
Noncytopathic BVDV has a suppressive effect on alveolar
macrophage function. Infection reduces expression of receptors
for immunoglobulin and complement; interferes with phagocy-
tosis and fusion of phagosomes to lysosomes; reduces bacteri-
cidal activity; reduces the secretion of TNF-a, IL-1b, IL-6, and
neutrophil chemoattractants; and enhances secretion of prosta-
glandin E2. However, it has no effect or a stimulatory effect on
production of IL-12 and type I interferon.110,115,207,215 Simi-
larly, BPIV-3 and BHV-1 have shown mainly suppressive
effects on alveolar macrophage function, including reductions
in phagocytosis and oxidative burst,53,112,185 although TNF-a
production in response to LPS was enhanced by BPIV-3 infec-
tion,17 and BHV-1 infection enhanced TLR2 and TLR4 gene
expression in blood mononuclear cells.83
In contrast to the situation with BVDV and BPIV-3, BRSV
infection has shown more variable effects on alveolar macro-
phages. BRSV infection recruits macrophages into the lung,
resulting in increased levels of nitrate in lung tissue (of postna-
tal lambs).189 Alveolar macrophages infected in vitro show
early induction of IL-1b, IL-6, and IL-8 gene expression, as
well as more minor expression of TNF-a, IL-12, IL-4, and
IL-10.56,161 The level of induction was less than for other TLR
agonists, consistent with the mild but significant neutrophil
infiltrates within the resulting lesions.29,56 Phagocytosis of
nonopsonized and of opsonized particles is reported to either
increase or decrease depending on the study.27,98,145,202 BRSV
infection has generally had no effect on the oxidative burst of
alveolar macrophages.145 Thus, BRSV induces production of
inflammatory mediators by alveolar macrophages, but the
effects of this infection on macrophage function are not clear.
Caswell
Table 1. Summary of Some Positive and Negative Effects of Acute Stress and Glucocorticoids on Measures of Innate Immunity Relevant to Bovine
Respiratory Disease. It is erroneous to think of stress as immunosuppressive: glucocorticoids and the body s response to acute stress have
stimulatory and suppressive effects on various elements of the innate immune response, with differing outcomes in different models of disease.
Immunostimulatory and Disease-Resisting Effects
59
Increased production of nitric oxide from macrophages
Enhanced TNF-a production by leukocytes55
Increased IL-8elicited neutrophil response134
Increased expression of proinflammatory cytokines by blood
leukocytes146
Improved survival of mice after influenza virus challenge48
Transiently improved survival of mice after Streptococcus pneumoniae Increased load of Mannheimia haemolytica serotype A1 in the nasal
challenge73
Negative association of glucocorticoid-regulated proteins with
177
BRD
BRD, bovine respiratory disease; IL-8, interleukin 8; LPS, lipopolysaccharide; TLR, Toll-like receptor; TNF-a, tumor necrosis factora.
Studies in mouse models of influenza inform our understand-
ing of how viruses affect pulmonary alveolar macrophage
function. Nasal infection with influenza virus triggered type I
interferon production that interfered with production of the che-
mokine CCL2, thus reducing recruitment of macrophages to the
lung and predisposing to colonization by S. pneumoniae.138
Pulmonary infection with influenza virus also induced IFN-g
production by T lymphocytes, which reduced expression of the
scavenger receptor MARCO on pulmonary alveolar macro-
phages, thereby impairing phagocytosis and elimination of
S. pneumoniae.194 Finally, influenza infection in mice reduces
recruitment, activation, and TNF-a production by NK cells, and
this deficiency in TNF-amediated activation of alveolar macro-
phages increases the susceptibility to infection with S. aureus.188
These studies in mice thus provide detailed examples of how the
host antiviral response abrogates defenses against bacteria.
The effects of stress on alveolar macrophage function have
been difficult to study. There is a widespread assumption that
stress impairs the function of these innate immune cells, but
much evidence suggests that acute stressorswhich are of
most relevance to recently arrived feedlot cattleenhance
many aspects of the innate immune response.1,59 For example,
in a rat model, stress induces release of heat shock protein 72
from cells, which acts similarly to a damage-associated mole-
cular pattern (DAMP) to enhance production of nitric oxide
from macrophages.59 This idea of stress-associated enhance-
ment of innate immunity is clearly sensible in an evolutionary
context, yet contradicts the observed occurrence of respiratory
disease in stressed cattle. These observations suggest that the
vague concept of immunosuppression must be abandoned
and more appropriately focused on specific elements of innate
immune responses (Table 1).48,73,149
Effects of Predisposing Factors on Neutrophils
Adverse effects of stress and viral infections on neutrophil
responses include neutropenia, altered neutrophil recruitment
to the lung, effects on sensitivity to leukotoxin, and effector
401
Immunosuppressive and Disease-Promoting Effects
Reduced LPS-induced expression of antimicrobial peptide134 and
lactoferrin101,166
Reduced expression of TLR4 by airway epithelial cells120
Reduced L-selectin expression on neutrophils23
Reduced TLR2 and TLR4 messenger RNA expression on leukocytes55
Reduced neutrophil phagocytosis and oxidative burst55
cavity64
Reduced pulmonary clearance of Staphylococcus in mice149
responses to bacterial infection. Neutropenia is the most readily
measured effect on neutrophil responses in the lung and predis-
poses to pneumonia, such as that caused by P. aeruginosa in
humans. Noncytopathic BVDV infection induces a sustained
neutropenia, in part due to reduced production in the bone mar-
row.99 The effect of other respiratory viral infections, including
BHV-1, on blood neutrophil counts is less consistent. Conver-
sely, abrupt weaning stress results in a slight increase in the
number of blood neutrophils.119
Stress and viral infections may interfere with neutrophil
recruitment to the lung. This is observed in mouse models of
influenza, where the virus-triggered type I interferon response
limits the production of CXC chemokines, thus increasing the
susceptibility to pulmonary S. pneumoniae challenge.178 Simi-
lar findings have not been reported with viral infections of
cattle.
Stress or glucocorticoid treatment reduces expression of
L-selectinand to a lesser degree CD18on bovine neutro-
phils,23,119,214 reduces TLR2 and TLR4 messenger RNA
(mRNA) expression,55 and delays apoptosis.121 Despite these
effects, dexamethasone-treated cattle had greater numbers of
neutrophils after administration of IL-8 into the lung or
uterus,103,134 with similar findings in the mammary gland of
cows experiencing transport stress.222 These findings surpris-
ingly suggest that either recruitment or survival of neutrophils
is increased by glucocorticoid.
Glucocorticoids induce synthesis of the anti-inflammatory
protein annexin A1 and stimulate release of this protein from
the secondary granules of neutrophils.16,156 Calves with lower
levels of annexin A1 at the time of arrival to the feedlot are
more likely to later develop pneumonia;177 this finding, along
with the observation that weaning stress induces expression
of proinflammatory cytokines,146 may suggest that calves that
are better able to downregulate these neutrophil inflammatory
responses are less likely to develop disease.
Viral infections sensitize neutrophils to the damaging
effects of M. haemolytica leukotoxin. Bovine mononuclear
cells infected with BHV-1 produce IL-1b and other cytokines
402
that upregulate expression of CD18 (LFA-1) on neutrophils.
Since CD18 is the receptor for M. haemolytica leukotoxin, this
increases the binding of this toxin and exacerbates the cyto-
toxic effect on bovine neutrophils.111
Laboratory studies of the phagocytic and bactericidal
functions of neutrophils are complex and often contradictory,
perhaps because of the diversity of analytical methods and the
considerable variability among individual animals. Abrupt
weaning has relatively minor adverse effects on phagocytic
activity of neutrophils and no effect on oxidative burst.119
Weaning stress induces gene expression of IL-1b, TNF-a,
IFN-g, IL-8, and other chemokines in whole-blood leukocytes
of calves.146,147 Castration of calves (by the Burdizzo method)
results in higher numbers of blood neutrophils and a mild
increase in respiratory burst.153 Neutrophils from temperamen-
tal bulls (which have elevated serum levels of cortisol) have
slightly lower levels of oxidative burst and phagocytosis than
do neutrophils from calm bulls.88 Glucocorticoid treatment has
been shown to inhibit phagocytosis, oxidative burst, and
antibody-dependent cell-mediated cytotoxicity in bovine neu-
trophils.103,150,162,169 Although these studies show significant
influences of stress and glucocorticoids on neutrophil function,
the effects are generally not large, usually affect only one of
several time points, and differ between studies.
BRSV infection induces neutrophil and macrophage infiltra-
tion of airways and alveoli,189 associated with increased levels
of IL-8.29 However, these BRSV-elicited neutrophils have
lower myeloperoxidase levels as assessed by immunohisto-
chemistry (IHC), suggesting dysfunction or immaturity.189
Similarly, cattle infected with BPIV-3 or BHV-1, or mice
infected with influenza, have evidence of reduced neutrophil
phagocytosis or bactericidal activity.13,18,224
Of relevance to dairy cows experiencing negative energy bal-
ance, b-hydroxybutyrate has adverse effects on neutrophil func-
tion, including reduced phagocytosis and formation of
neutrophil extracellular traps.75 Thus, many factors affect neutro-
phil recruitment and function, including stress, glucocorticoids,
viral infection, and negative energy balance. However, these
effects are neither uniformly negative nor positive (Table 1), and
their contribution to development of pneumonia is uncertain.
Bacterial pathogens use diverse mechanisms to evade killing
by neutrophils and macrophages. The capsule of M. haemolytica
and P. multocida confers resistance to phagocytosis.32,80
H. somni is capable of inhibiting the oxidative burst in neutrophils
and alveolar macrophages, and the immunoglobulin-binding
protein A inhibits phagocytosis and induces cytotoxicity of
bovine monocytes.72,85 The M. haemolytica leukotoxin induces
apoptotic or oncotic death of ruminant neutrophils and macro-
phages.183 Thus, the pathogens causing BRD are well equipped
to interfere with the bactericidal effector functions of neutrophils
and macrophages.
Conclusions
The mechanisms by which the risk factors for BRD affect lung
defenses are complex. Earlier reviews of this topic focused
Veterinary Pathology 51(2)
mainly on the impact on mucociliary clearance and phagocytes,
as well as considered which of these effects were more impor-
tant.91,224 Since that time, the recognized mechanisms of lung
defense have flourished, leading to the following conceptual
model of how such a multifarious system could fail.
Respiratory defenses can be considered a layered system,
albeit one with considerable functional interaction among the
layers. Specifically, for a bacterial pathogen to infect the lung,
it must either evade or take advantage of the failure of these
sequential defenses, including those of the nasal cavity, antimi-
crobial molecules in the airway lining fluid, mucociliary clear-
ance, alveolar resident and exudate macrophages, and
neutrophils (Fig. 1). In cattle that develop aspiration pneumo-
nia, these barriers are still functioning but are overwhelmed
by multitudinous bacteria. In contrast, for shipping fever
or community-acquired bronchopneumonia in cattle and
humans, it is likely that many of these defenses must be over-
come before opportunistic pathogens are able to colonize the
lung and cause bronchopneumonia. But pneumonia in cattle
is not caused by common environmental bacteria or mucosal
commensalsthe example of aspiration pneumonia notwith-
standingimplying that simultaneous failure of all respiratory
defenses is uncommon. Instead, the risk factors for BRD cause
failure of some respiratory defenses, while the bacterial patho-
gens that take advantage of this opportunity to colonize the
lung are those that have virulence attributes allowing them to
overcome the remaining defenses.
There are 2 major implications of this model. First, it raises
the opportunity for collaboration between infecting pathogens.
Most cases of bacterial pneumonia in cattle are polymicrobial,
including various Pasteurellaceae, Trueperella pyogenes, and a
diversity of Mycoplasma spp. This may reflect the importance
of the predisposing factors that weaken the lung defenses, as
infection with the causative bacteria is so common. It is, in the-
ory, possible that each pathogen could interfere with different
respiratory defenses, allowing 2 or more bacteria to colonize
the lung together when either pathogen alone would be unable.
However, mechanisms of polymicrobial pneumonia are little
studied in humans and less in cattle.
Second, this model implies that disease prevention does not
require that all of the failed lung defenses be cured. Instead,
restoration of one or a few of these defensesparticularly
those that the pathogens are ill-equipped to evademay be
adequate to eliminate bacterial infection and prevent disease.
This concept is important for developing alternatives to anti-
biotics for prevention of BRD in feedlot, veal, and dairy calves.
Bacterial bronchopneumonia in cattle results from complex
interactions among the stresses of weaning, transport and
disruption of social groups, adverse climatic conditions, poor
air quality, and viral and mycoplasmal infections, as well as
infection with the bacteria that ultimately elicit the disease-
causing host response. This complexity leads to challenges in
investigating the mechanisms by which the respiratory defense
system fails, yet it is this complexity of interacting causes that
is lacking in mouse models of bacterial pneumonia. Nonethe-
less, a limitation of in vivo studies of BRD is the difficulty in
Caswell
measuring the inducible responses. A major criticism of past
research is the focus on static parameters: blood neutrophil
counts, baseline levels of cytokines and antimicrobial factors
in body fluids, and ex vivo studies of leukocyte function. Most
of the innate and acquired defenses of the lung are dynamic,
inducible, and dependent on the microenvironment in the lung;
such studies fail to capture the true nature of these immune
responses. Thus, advancing this understanding will require
synthesis of knowledge acquired from cell culture systems,
mouse models, experiments in cattle, and observations of
natural disease in cattle and other species, including humans.
Understanding how host factors and pathogens interact to cause
bovine respiratory disease clarifies the pathogenesis and may
lead to improved strategies for disease prevention.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship and/or publication of this article: This work
was supported by the Natural Sciences and Engineering Research
Council (NSERC) of Canada, the Ontario Cattlemens Association,
and the Ontario Ministry of Agriculture and Food.
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