Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

III. Virulence Factors Preventing Neutrophil-Mediated Killing
339
( Levy et al. , 1999 ). This selective deficiency of BPI may
explain the increased incidence of Gram-negative sepsis
among newborns.
Granulocytes also contain a variety of proteases and
acid hydrolases, the most notable of which are cathepsin
G, elastase, collagenase, lysozyme, acid phosphatase, aryl
sulfatase, neuramidase, and nuclease. Elastase degrades
bacterial cell wall proteins and potentiates the lytic activity
of lysozyme and the microbicidal activity of cathepsin
G. Lysozyme is a cationic protein that hydrolyzes bacterial
cell walls by attacking the β 1-4 glycosidic linkage that
joins N-acetyl muramic acid and N-acetyl glucosamine
of peptidoglycan. Although a wide variety of bacteria are
sensitive to the action of lysozyme, group A Streptococcus ,
Staphylococcus , and most Gram-negative organisms resist
the action of lysozyme.
Lactoferrin has bacteriostatic activity that is associated
with its capacity to sequester iron. However, lactoferrin
also exerts a bactericidal effect independent of its bacteriostatic
effects ( Lehrer and Ganz, 1990 ).
Few deficiencies of oxygen-independent mechanisms
have been described. A specific granule deficiency has been
described in humans in which specific granules lack lactoferrin,
vitamin B 12 binding protein, and defensins ( Gallin,
1985 ). Affected individuals have recurrent severe bacterial
infections. Neutrophils have small, elongated granules that
appear late in maturation.
D . Neutrophil-Mediated Amplification of
Inflammation
Neutrophils secrete a variety of proinflammatory mediators
that amplify the inflammatory process. These include leukotrienes,
prostaglandins, cytokines, and chemokines.
1 . Prostaglandins and Leukotrienes
Arachidonic acid and other C20 polyunsaturated fatty
acids containing four and five carbon-carbon double bonds
are the immediate precursors of prostaglandins and leukotrienes.
They are released from phospholipids by the action
of phospholipase A, phospholipase C, and diacylglycerol
lipase. Among the leukocytes, macrophages appear to be
the major producers of prostaglandins, whereas neutrophils,
monocytes, macrophages, eosinophils, and mast cells are
major producers of leukotrienes ( Lewis and Austen, 1984 ).
Leukotriene (LTB) synthesis begins when 5-lipoxygenase
catalyzes the production of 5-monohydroperoxy-eicosatetraenoic
acid (5-HPETE) from arachidonic acid. 5-HPETE
is converted to 5-hydroxyeicosatetraenoic acid (5-HETE).
In addition, 5-lipoxygenase converts 5-HPETE to LTA 4 .
Separate pathways synthesize LTB 4 and sulfidopeptide
leukotrienes (LTC 4 , LTD 4 , LTE 4 ). Neutrophils synthesize
mostly LTB 4 ( Lewis and Austen, 1984 ). LTB 4 has both
priming and direct activating effects on neutrophils. It is
a potent chemotactic and chemokinetic agent for neutrophils,
monocytes, and eosinophils. It also stimulates neutrophil
aggregation, superoxide production, and integrin
expression.
2 . Cytokines and Chemokines
Neutrophils secrete a broad spectrum of cytokines. Most
of these are involved in the innate immune response, however,
neutrophils also secrete cytokines that affect adaptive
immunity ( Petrofsky and Bermudez, 1999 ; Tacchini-Cottier
et al. , 2000 ). Activated neutrophils release a variety of
proinflammatory cytokines including tumor necrosis factor-
α (TNF- α ), IL-1 β , and IL-6. At sites of inflammation,
release of these cytokines amplifies the inflammatory process.
Neutrophils also produce interferon- γ (IFN- γ ), IL-12,
and transforming growth factor- β (TGF- β ), known to affect
adaptive immunity. Several studies indicate that neutrophils
may modulate the adaptive immune response to infectious
agents. For example, in a mouse model of leishmaniasis,
depletion of neutrophils 6 h before infection prevented the
early Th2-type immune response suggesting a role of neutrophils
in initiating this response ( Tacchini-Cottier et al. ,
2000 ).
Neutrophils also have cell surface receptors for many
cytokines. These include TNF- α , IL-1, IL-4, IL-6, IL-8,
IL-10, G-CSF, and GM-CSF ( Lapinet et al. , 2000 ; Lavkan
et al. , 1998 ; Skoutelis et al. , 2000 ). Although most of these
cytokines activate neutrophils, IL-4 and IL-10 are potent
inhibitors of neutrophil function ( Lapinet et al. , 2000 ).
Neutrophils secrete both CC and CXC chemokines
( Lapinet et al. , 2000 ). CC chemokines include macrophage
inflammatory protein-1 α (MIP-1 α ) and MIP-1 β . CXC
chemokines include IL-8 and IFN- γ -inducible protein-10.
Therefore, neutrophils at a site of inflammation amplify
the inflammatory response by attracting more inflammatory
cells to the site.
III . VIRULENCE FACTORS PREVENTING
NEUTROPHIL-MEDIATED KILLING
Many pathogenic organisms have developed the capacity to
evade killing by neutrophils and macrophages. Each pathogen
has developed its own group of evasion tactics that
provide a competitive advantage for survival and growth
( Allen, 2003 ; Mayer-Scholl et al. , 2004 ).
Staphylococcus aureus is resistant to neutrophil phagocytosis.
This is largely due to the capsule. A slime layer
is composed of capsular polysaccharide. Like other Grampositive
bacteria, S. aureus is resistant to defensins, probably
as a result of the composition of the cell wall.
Anaplasma phagocytophilum survives and replicates
within neutrophils. The organism has the capacity to block