Immune Defense against Bacterial Pathogens: Innate Immunity (page 6)
(This chapter has 6 pages)
© Kenneth Todar, PhD
Macrophages, dendritic cells,
and epithelial cells have a set of transmembrane receptors that
recognize different types of molecular determinants associated with
both pathogenic and non pathogenic bacteria. Foremost among
these are Toll-like
In macrophages and dendritic cells, a pathogen is exposed to a TLR
when it is engulfed within the phagosome membrane. Depending on
which TLR it binds to will
determine what the response will be. In this way, the TLRs identify the
nature of the pathogen and turn on a response appropriate for
dealing with it, generally by expression of
various cytokines. Humans have 12 different TLRs, each of which
specializes in a slightly different response to a pathogen (be it a
bacterium, virus or protozoa).
For example TLR-2 binds to the peptidoglycan of Gram-positive
bacteria such as streptococci and staphylococci; TLR-3 binds to
double-stranded RNA; TLR-4 is activated by the lipopolysaccharide
(endotoxin) in the outer membrane of Gram-negative such as Salmonella and E. coli; TLR-5
binds to the flagellin of motile bacteria like Listeria; TLR-6 forms a heterodimer
with TLR-2 and responds to peptidoglycan and certain bacterial
TLR-7 binds to the single-stranded RNA genomes of viruses such as
as influenza, mumps and measles.
In all these cases, binding of the pathogen to the TLR initiates a
signaling pathway that leads to the activation of a transcription
factor that turns on cytokine genes such as those for tumor necrosis
factor-alpha (TNF-α), Interleukin-1 (IL-1), and chemotactic attractants
that attract white blood cells to the site. These effector molecules
lead to inflammation at the site. Even before these late events
occur, the binding of Gram-positive bacteria to TLR-2 and Gram-negative
bacteria to TLR-4
enhances phagocytosis and the fusion of the phagosomes with lysosomes.
Formation of the phagolysosome
The phagosome migrates into the cytoplasm and collides with lysosomal
which explosively discharge their contents into the membrane-enclosed
(phagosome). Membranes of the phagosome and lysosome actually fuse
in a digestive vacuole called the phagolysosome. Other
will fuse with the phagolysosome. It is within the phagolysosome that
and digestion of the engulfed microbe take place. Some of the
constituents of the lysosomes of neutrophils and macrophages include
cationic proteins, various proteases and hydrolyases and
The killing processes are confined to the phagolysosome, such that none
of the toxic substances
lethal activities of the phagocytes are turned against themselves.
Intracellular killing of organisms
After phagolysosome formation the first detectable effect on bacterial
physiology, occurring within a few minutes after engulfment, is loss of
viability (ability to reproduce). The exact mechanism is unknown.
of macromolecular synthesis occurs later. By 10 to 30 minutes after
many pathogenic and nonpathogenic bacteria are killed followed by lysis
and digestion of the bacteria by lysosomal enzymes. The microbicidal
of phagocytes are complex and multifarious. Metabolic products, as well
as lysosomal constituents, are responsible. These activities differ to
some extent in neutrophils, monocytes and macrophages.
The microbicidal activities of phagocytes are usually divided into oxygen-dependent and oxygen-independent events.
Lysosomal granules contain a variety of extremely basic proteins that
inhibit bacteria, yeasts and even some viruses. A few molecules of any
one of these cationic proteins appear able to inactivate a bacterial
by damage to their permeability barriers, but their exact modes of
are not known. The lysosomal granules of neutrophils contain
an extremely powerful iron-chelating protein, which withholds potential
needed for bacterial growth. The pH of the phagolysosome may be as low
as 4.0 due to accumulation of lactic acid, which is sufficiently acidic
to prevent the growth of most pathogens. This acidic environment
optimizes the activity of many degradative lysosomal enzymes including
lysozyme, glycosylases, phospholipases, and nucleases.
Liganding of Fc receptors (on neutrophils, monocytes or macrophages)
mannose receptors (on macrophages) increases their O2
called the respiratory burst. These receptors activate a
oxidase that reduces O2 to O2-
Superoxide can be reduced to OH. (hydroxyl radical) or
to H2O2 (hydrogen peroxide) by superoxide
O2-, OH., and H2O2
are activated oxygen species that are potent oxidizing agents in
systems which adversely affect a number of cellular structures
membranes and nucleic acids. Furthermore, at least in the case of
these reactive oxygen intermediates can act in concert with a lysosomal
enzyme called myeloperoxidase to function as the
system, or MPO.
Myeloperoxidase is one of the lysosomal enzymes of neutrophils which
is released into the phagocytic vacuole during fusion to form the
Myeloperoxidase uses H2O2 generated during the
burst to catalyze halogenation (mainly chlorination) of phagocytosed
Such halogenations are a potent mechanism for killing cells.
When the NADPH oxidase and myeloperoxidase systems are operating in
concert, a series of reactions leading to lethal oxygenation and
of engulfed microbes occurs.
Dead microbes are rapidly degraded in phagolysosomes to low
components. Various hydrolytic enzymes are involved including lysozyme,
proteases, lipases, nucleases, and glycosylases. Neutrophils die and
after extended phagocytosis, killing, and digestion of bacterial cells.
This makes up the characteristic properties of pus.
Macrophages egest digested debris and allow insertion of microbial
components into the plasma membrane for presentation to lymphocytes in
the immunological response.
Figure 7. Phagocytosis of
pyogenes by a macrophage. CELLS
Bacterial Defense Against Phagocytosis
Pathogenic bacteria have a variety of defenses against phagocytes.
In fact, most successful pathogens have some mechanism(s) to contend
the phagocytic defenses of the host. These mechanisms will be discussed
in detail later as part of the determinants of virulence of pathogens.
However, in general, pathogens may resist phagocytosis by:
Evading phagocytes by growing in regions of the body which
not accessible to them
Avoiding engulfment by phagocytes after contact
Being able to kill phagocytes either before or after
Being able to survive inside of phagocytes (or other types
cells) and to persist as intracellular parasites
END OF CHAPTER
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