Mechanisms of Bacterial Pathogenicity (page 5)
(This chapter has 8 pages)
© Kenneth Todar, PhD
EVASION OF HOST DEFENSES
Some pathogenic bacteria are inherently able to resist the
components of host tissues. For example, the poly-D-glutamate capsule
anthracis protects the organisms against cell lysis by cationic
in sera or in phagocytes. The outer membrane of Gram-negative bacteria
is a formidable permeability barrier that is not easily penetrated by
compounds such as bile salts which are harmful to the bacteria.
mycobacteria have a waxy cell wall that resists attack or digestion by
most tissue bactericides. And intact lipopolysaccharides (LPS) of
pathogens may protect the cells from complement-mediated lysis or the
Most successful pathogens, however, possess additional structural or
biochemical features which allow them to resist the main lines of host
internal defense against them, i.e., the phagocytic and immune
of the host.
Overcoming Host Phagocytic Defenses
Microorganisms invading tissues are first and foremost exposed to
Bacteria that readily attract phagocytes, and that are easily ingested
and killed, are generally unsuccessful as parasites. In contrast, most
bacteria that are successful as parasites interfere to some extent with
the activities of phagocytes or in some way avoid their attention.
Microbial strategies to avoid phagocytic killing are numerous and
but are usually aimed at blocking one or of more steps in the
process. Recall the steps in phagocytosis:
1. Contact between phagocyte and microbial cell
3. Phagosome formation
4. Phagosome-lysosome fusion
5. Killing and digestion
Avoiding Contact with Phagocytes
Bacteria can avoid the attention of phagocytes in a number of ways.
1. Invade or remain confined in regions inaccessible to phagocytes.
Certain internal tissues (e.g. the lumen of glands) and surface tissues
(e.g. the skin) are not patrolled by phagocytes.
2. Avoid provoking an overwhelming inflammatory response. Some
induce minimal or no inflammation required to focus the phagocytic
3. Inhibit phagocyte chemotaxis. e.g. Streptococcal streptolysin
also kills phagocytes) suppresses neutrophil chemotaxis, even in very
concentrations. Fractions of Mycobacterium tuberculosis are
to inhibit leukocyte migration. Clostridium ø toxin
4. Hide the antigenic surface of the bacterial cell. Some pathogens
can cover the surface of the bacterial cell with a component which is
as "self" by the host phagocytes and immune system. Phagocytes cannot
bacteria upon contact and the possibility of opsonization by antibodies
to enhance phagocytosis is minimized. For example, pathogenic Staphylococcus
aureus produces cell-bound coagulase which clots fibrin on the
surface. Treponema pallidum binds fibronectin to its surface.
A streptococci are able to synthesize a capsule composed of hyaluronic
Inhibition of Phagocytic Engulfment
Some bacteria employ strategies to avoid engulfment (ingestion)
if phagocytes do make contact with them. Many important pathogenic
bear on their surfaces substances that inhibit phagocytic adsorption or
engulfment. Clearly it is the bacterial surface that matters.
to phagocytic ingestion is usually due to a component of the bacterial
cell wall, or fimbriae, or a capsule enclosing the bacterial wall.
examples of antiphagocytic substances on the bacterial surface include:
Polysaccharide capsules of S. pneumoniae, Haemophilus
pallidum and Klebsiella pneumoniae
M protein and fimbriae of Group A streptococci
Surface slime (polysaccharide) produced by Pseudomonas aeruginosa
O antigen associated with LPS of E. coli
K antigen of E. coli or the analogous Vi antigen of Salmonella
Cell-bound or soluble Protein A produced by Staphylococcus aureus
Streptococcus pneumoniae, FA
stain showing its antphagocytic capsule (CDC). S. pneumoniae cells that possess a
capsule are virulent; nonencapsulated strains are avirulent. Although S. pneumoniae strains possess a
variety of determinants of virulence, this illustrates the essential
role of their capsule in ability to resist phagocytosis by alveolar
macrophages in order to initiate disease.
Survival Inside of Phagocytes
Some bacteria survive inside of phagocytic cells, in either
or macrophages. Bacteria that can resist killing and survive or
inside of phagocytes are considered intracellular parasites. The
of the phagocyte may be a protective one, protecting the bacteria
the early stages of infection or until they develop a full complement
virulence factors. The intracellular environment guards the bacteria
the activities of extracellular bactericides, antibodies, drugs, etc.
Most intracellular parasites have special (genetically-encoded)
to get themselves into their host cell as well as special mechanisms to
survive once they are inside. Intracellular parasites usually survive
virtue of mechanisms which interfere with the bactericidal activities
the host cell. Some of these bacterial mechanisms include:
1. Inhibition of phagosome-lysosome fusion. The bacteria
inside of phagosomes because they prevent the discharge of lysosomal
into the phagosome environment. Specifically phagolysosome formation is
inhibited in the phagocyte. This is the strategy employed by Salmonella,
tuberculosis, Legionella and the Chlamydiae.
Intracellular Mycobacterium tuberculosis in lung.
Ziehl-Neelsen acid fast stain (CDC).
2. Survival inside the phagolysosome. With some
parasites, phagosome-lysosome fusion occurs but the bacteria are
to inhibition and killing by the lysosomal constituents. Also, some
pathogens can resist killing in phagocytes utilizing similar resistance
mechanisms. Little is known of how bacteria can resist phagocytic
within the phagocytic vacuole, but it may be due to the surface
of the bacteria or due to extracellular substances that they produce
interfere with the mechanisms of phagocytic killing. Bacillus
tuberculosis and Staphylococcus aureus all possess
to survive intracellular killing in macrophages.
3. Escape from the phagosome. Early escape from the
vacuole is essential for growth and virulence of some intracellular
This is a very clever strategy employed by the Rickettsias which
a phospholipase enzyme that lyses the phagosome membrane within thirty
seconds of after ingestion.
Products of Bacteria that Kill or Damage
One obvious strategy in defense against phagocytosis is direct
by the bacteria upon the professional phagocytes. Any of the substances
that pathogens produce that cause damage to phagocytes have been
to as "aggressins". Most of these are actually extracellular enzymes or
toxins that kill phagocytes. Phagocytes may be killed by a pathogen
or after ingestion.
Killing phagocytes before ingestion. Many Gram-positive
particularly the pyogenic cocci, secrete extracellular enzymes which
phagocytes. Many of these enzymes are called "hemolysins" because their
activity in the presence of red blood cells results in the lysis of the
Pathogenic streptococci produce streptolysin. Streptolysin O binds
cholesterol in membranes. The effect on neutrophils is to cause
granules to explode, releasing their contents into the cell cytoplasm.
Pathogenic staphylococci produce leukocidin, which also acts on the
neutrophil membrane and causes discharge of lysosomal granules.
Other examples of bacterial extracellular proteins that inhibit
include the Exotoxin A of Pseudomonas aeruginosa which kills
and the bacterial exotoxins that are adenylate cyclases (e.g. anthrax
EF and pertussis AC) which decrease phagocytic activity.
Gram stain of a pustular exudate from a
mixed bacterial infection. Pus is the usual outcome of the battle
between phagocytes and bacterial strategies to kill them.
Killing phagocytes after ingestion. Some bacteria exert their
toxic action on the phagocyte after ingestion has taken place. They may
grow in the phagosome and release substances which can pass through the
phagosome membrane and cause discharge of lysosomal granules, or they
grow in the phagolysosome and release toxic substances which pass
the phagolysosome membrane to other target sites in the cell. Many
which are the intracellular parasites of macrophages (e.g.
usually destroy macrophages in the end, but the mechanisms are not
Antibodies that are bound to bacterial surfaces will activate
by the classical pathway and bacterial polysaccharides activate
by the alternative pathway. Bacteria in serum and other tissues,
Gram-negative bacteria, need protection from the antimicrobial effects
of complement before and during an immunological response.
One role of capsules in bacterial virulence is to protect
bacteria from complement activation and the ensuing inflammatory
Polysaccharide capsules can hide bacterial components such as LPS or
which can induce the alternate complement pathway. Some bacterial
are able to inhibit formation of the C3b complex on their surfaces,
avoiding C3b opsonization and subsequent formation of C5b and the
attack complex (MAC) on the bacterial cell surface. Capsules that
sialic acid (a common component of host cell glycoproteins), such as
in Neisseria meningitidis, have this effect.
One of the principal targets of complement on Gram-negative bacteria
is LPS. It serves as the attachment site for C3b and triggers the
pathway of activation. It also binds C5b.
LPS can be modified by pathogens in two ways that affects its
First, by attachment of sialic acid residues to the LPS O antigen,
a bacterium can prevent the formation of C3 convertase just as capsules
that contain sialic acid can do so. Both Neisseria meningitidis
and Haemophilus influenzae, which cause bacterial meningitis,
able to covalently attach sialic acid residues to their O antigens
in resistance to MAC. Second, LPS with long, intact O antigen
can prevent effective MAC killing. Apparently the MAC complex is held
far from the vulnerable outer membrane to be effective.
Bacteria that are not killed and lysed in serum by the complement
are said to be serum resistant. As might be expected many of
Gram-negative bacteria that cause systemic infections, (bacteremia or
are serum resistant. Gram-positive bacteria are naturally
since their cells are not enclosed in an outer membrane.
Other ways that pathogens are able to inhibit the activity of
is to destroy one or more of the components of complement. Pseudomonas
aeruginosa produces an extracellular elastase enzyme that
components of complement.