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Transcript
Pathogenesis of Bacterial Infection
Microbial Pathogenicity
• Initiation the infectious
• Mechanism that lead to the development of signs
and symptoms of disease
• If a microorganism is capable of causing disease, it
is called a pathogen.
• Fortunately, only a minority of the microorganisms
in nature are pathogenic.
• Whereas some organisms are highly virulent and
cause disease in healthy individuals, even with a
small inoculum.
• Others cause disease only in compromised
individuals when their defense are weak. The latter
are called opportunistic organisms, as they
take the opportunity offered by reduced host
defenses to cause disease. These opportunists are
frequently members of the body’s normal flora.
General aspects of infection
Virulence:-
is a quantitative measure of pathogenicity and
is related to an organism’s toxigenic potential and invasiveness
Virulence can be measured
by the number of organisms required to cause disease and is
designated as LD50 or ID50: the
LD50 (50% lethal dose)
is the number of organisms needed to kill half the hosts.
ID50 (50% infectious dose)
is the number needed to cause infection in half the hosts.
These values are determined by inoculation of laboratory
animals.
Communicable diseases
Infections are called ‘communicable diseases’
if they are spread from host to host. Many, but not
all, infections are communicable; for example,
tuberculosis is communicable, as it is spread by
airborne droplets produced by coughing,
but staphylococcal food poisoning is not, as the
exotoxin produced by the organism and present in
the contaminated food affects only those eating
that food.
If a disease is highly communicable, it is called a
‘contagious disease’ (e.g. chickenpox).
Depending on the degree of incidence and
prevalence of infectious disease in a community, it
may be called an endemic, an epidemic or a
pandemic infection.
endemic infection is constantly present at a low
level in a specific population (e.g. endemic malaria
in some African countries
An infection is an epidemic if it occurs much more
frequently than usual (e.g. an epidemic of influenza
in the winter)
An infection is a pandemic if it has a worldwide
distribution (e.g. human immunodefciency virus
(HIV) infection).
Natural history of infectious disease
An acute infection generally progresses through four stage
1-The incubation period: time between the acquisition of the
organism or the toxin and the commencement of symptoms
(this may vary from hours to days to weeks).
2. The prodromal period: non- specific symptoms such as
fever, malaise and loss of appetite appear during this
period.
3. The acute specific illness: the characteristic signs and
symptoms of the disease are evident during this period.
4. The recovery period: the illness subsides and the patient
returns to health during this final phase.
Pathogenesis can be Divided into
1- Pathogenesis of Bacterial disease.
2- Pathogenesis of Viral disease.
3- Pathogenesis of fungal disease
Pathogenesis of bacterial disease
the ways and means by which bacteria cause
disease. The major steps are
1- Transmission:Most infections are acquired by transmission from
external sources; i.e. they are exogenous in origin.
Others are caused by members of the normal flora
behaving as opportunist pathogens; i.e. they are
endogenous in origin.
Transmission
Transmission can be by:
• inhalation – the air borne route
• ingestion –fecal contamination of food and water
• inoculation –by sexual contact, contaminated
needles, skin
contact, blood transfusions or biting
insects
There are four important portals (or gates) of entry of
pathogens :1. skin
2. respiratory tract
3. gastrointestinal tract
4. genitourinary tract
Adherence to host surfaces
adherence is the first step in infection.
Some bacteria and fungi have specialized structures or
produce substances that facilitate their attachment to
the surface of human cells or prostheses (e.g. dentures,
artificial heart valves),
These adherence mechanisms are critical for organisms
that attach to mucous membranes;
mutants that lack these mechanisms are often nonpathogenic (e.g. the hair-like pili of Neisseria
gonorrhoeae and Escherichia coli mediate their
attachment to the urinary tract epithelium;
the extracellular polysaccharides of Streptococcus
mutans help it adhere to enamel surfaces)
Biofilm formation
A biofilm:- is defined as an aggregate of interactive
bacteria attached to a solid surface (such as a
denture prosthesis or an intravenous catheter) or to
each other, encased in an extracellular
polysaccharide matrix. Up to 65% of human
infections are thought to be associated with
microbial biofilms
Dental plaque on solid enamel surfaces is a classic
example of a biofilm.
Known infections associated with biofilms are
difficult to eradicate as sessile organisms in biofilms
exhibit higher resistance to antimicrobials than their
free living The reasons for this
• protection offered by the extracellular
polysaccharide matrix from the host immune
mechanisms
• poor penetration of the antimicrobials into the
deeper layers of the biofilm
• degradation of the antimicrobials as they
penetrate the biofilm
• Some examples of important
recalcitrant human infections
mediated by biofilms, difficult to
manage by antimicrobials alone,
include Pseudomonas aeruginosa
infections of the respiratory tract
in cystic fibrosis patients,
• Staphylococcus aureus infections
in central venous catheters,
chronic candidal infections of HIVinfected individuals and chronic
periodontal infections due to
dental plaque.
Invasiveness& Virulence factors
Invasiveness of bacteria plays a critical role in pathogenesis; this property is
dependent upon secreted bacterial enzymes. A few examples are:
• Collagenase and hyaluronidase degrade their respective intercellular
substances, allowing easy spread of bacteria through tissues, and are
especially important in skin infections caused by Streptococcus pyogenes.
• Coagulase, produced by Staphylococcus aureus, accelerates the formation
of a fbrin clot (from fbrinogen). It helps protect the organisms from
phagocytosis by walling off the infected area and by coating the organisms
with a fibrin layer.
• Immunoglobulin A (IgA) protease degrades protective IgA on mucosal
surfaces, allowing organisms such as N. gonorrhoeae, Haemophilus
influenzae and Streptococcus pneumoniae to adhere to mucous
membranes.
• Leukocidins can destroy both neutrophilic leukocytes and macrophages.
Bacterial infection
may lead to two categories of inflammation:
1-pyogenic (pus-producing)
2- granulomatous (granuloma-forming).
1- Pyogenic inflammation (pus-producing)
The neutrophils are the predominant cells in this
type of
inflammation. Streptococcus pyogenes,
Staphylococcus aureus and Streptococcus
pneumoniae are the common pyogenic bacteria.
categories of inflammation of Bacterial
infection
2- Granulomatous inflammation(granuloma-forming)
Macrophages and T cells predominate in this type of
inflammation. The most notable organism in this
category is Mycobacterium tuberculosis.
Here, the bacterial antigens stimulate the cellmediated immune system, resulting in sensitized Tlymphocyte and macrophage activity.
Toxigenicity
Toxins are of two categories: endotoxins and exotoxins.
Endotoxins
Endotoxins are the cell wall lipopolysaccharides of Gram negative bacteria
(both cocci and bacilli) and are not actively released from the cell. (Note: thus,
by defnition, Gram positive organisms do not possess endotoxins.)
Endotoxins
cause fever, shock and other generalized symptoms.
These are mainly due to the production of host factors such as interleukin-1
(IL-1) and tumor necrosis factor (TNF) from macrophages.
1.
Fever is due to the release of endogenous pyrogens (IL-1) by
macrophages; these act on the hypothalamic temperature regulatory
center and reset the ‘thermostat’ at a higher temperature.
2. Hypotension, shock and reduced perfusion of major organs due to
vasodilatation, are brought about bybradykinin release, increased vascular
permeability anddecreased peripheral resistance.
3. Activation of the alternative pathway of the complement cascade results in
inflammation and tissue damage.
4. Generalized activation of the coagulation system
(via factor XII) leads to disseminated intravascular
coagulation (DIC), thrombosis and tissue ischaemia.
5. There is increased phagocytic activity of
macrophages and polyclonal B cell activation (but
not T lymphocytes).
6. There is increased antibody production.
Endotoxin-like effects may also occur in Grampositive bacteremic infections. However, as
endotoxin is absent in Gram-positive bacteria, other
cell wall components, such as teichoic acid or
peptidoglycan, are thought to trigger the release of
TNF and IL-1 from macrophages
Exotoxins
• Both Gram-positive and Gram-negative bacteria
secrete exotoxins, whereas endotoxin is an
integral component of the cell wall of Gramnegative organisms.
• Exotoxins in particular can cause disease in
distant parts of the body as a result of diffusion or
carriage of the toxin via systemic route
Exotoxins
are polypeptides whose genes are frequently
located on plasmids or lysogenic bacterial viruses.
Essentially, these polypeptides consist of two
domains or subunits: one for binding to the cell
membrane and entry into the cell, and the other
possessing the toxic activity
Bacterial exotoxins can be broadly categorized as:
• neurotoxins
• enterotoxins
• miscellaneous exotoxins
Neurotoxins
Tetanus toxin, diphtheria toxin and botulinum toxin
are all neurotoxins and their action is mediated via
neuronal pathways
enterotoxins
Enterotoxins
These toxins act on the gut mucosa and cause
gastrointestinal disturbances
Miscellaneous exotoxins
An array of exotoxins are produced by C. welchii
and other species of clostridia that cause gas
gangrene.
These include the α-toxin (a phospholipase that
hydrolyses lecithin, present in all eukaryotic cell
membranes), collagenase, protease,
hyaluronidase and deoxyribonuclease (DNAase).
Pathogenesis of viral disease
Viral pathogenesis can be defined
as the methods by which viruses produce disease
in the host.
Entry of viral infections :As in bacterial infections, viruses gain entry
into the host by:
• inoculation (via the skin and mucosa)
• inhalation (via the respiratory tract)
• ingestion (via the gastrointestinal tract
Mechanisms of viral spread in the body
1-direct local spread on epithelial and sub epithelial
surfaces
2- lymphatic spread
3- viraemic spread
4- central nervous system and peripheral nerve
spread
1- Local spread on body
surfaces
A number of viruses cause disease on epithelial
surfaces without systemic spread. Such infections
are characterized by:
• their localized nature
• direct viral shedding into the exterior or lumen
(e.g. respiratory tract and alimentary tract
infections with rhinoviruses and rotaviruses,
respectively)
Lymphatic spread
The phagocytosed and free viral particles lurking
beneath the epithelium rapidly enter the
subepithelial /mucosal network of lymphatic
capillaries and are carried to regional lymph nodes
(Fig. 5.6). Lymph nodes serve two main functions:
1. They act as flters of extraneous microbes that gain
access to the lymphatic system.
2. They are the sites where immune responses are
generated
Viraemia and spread to organs
The entry of virus into the blood and its
subsequent spread is called viraemia. Once a
virus reaches the blood stream, it is effectively
disseminated within minutes. The first episode
of viral entry into the blood is called a primary
viraemia
The virus may then be seeded in various distant
organs, after which there is further replication at
these sites and a second wave of viral entry into
the blood stream – a secondary viraemia.
This is usually larger than the primary viraemia
and the virus is more easily detected in blood
samples.
The secondary viraemia often leads to infection of
other organs
Virus and host cell interactions
Once the virus enters the host cell, it can interact
with the
host cell in two main ways:
1. permissive infection, in which there is synthesis
of viral components, their assembly and release.
2. non-permissive infection, in which the infection
can result in cell transformation, often with the
integration of viral DNA into the host genome.
Permissive infection
The infection of a cell by a virus may have one or more
sequelae
The most common sequela is for the virus to replicate in
a lytic or cytocidal infection, causing the cells to die and
producing an acute illness. A virus infected cell may die
as a result of:
• ’shut-down’ of host cell protein and nucleic acid
synthesis
• cell lysis, by the release of progeny virions
• intracellular release of lysosomal enzymes
• damage to cell membranes.
Non-permissive infection
Cell death is not an inevitable accompaniment of viral
replication. Sometimes a persistent infection may ensue in
which there may be viral replication within the cell but the
cell remains alive. Many viruses can produce persistent
infections. herpesviruses and retroviruses.
Factors that favour persistence include:
• low pathogenicity of the virus
• ineffective or no antibody-mediated or cell-mediated
host immune responses
• defective or no interferon production
• infection of lymphocytes and macrophages by the virus
During the early phase of infection , befor cell
death characteristic alteration in the infected
cell membrane may occur
Hemadsorption (hemagglutinin)
In viruses leave the cell by budding through the
plasma membrane viral glycoproteins first inserted
into membrane. Acommon envelope protein is
hemaglutinin . This protein enables an infected cell
to attract red cell at the surface, aphenomena
called hemadsorption.
Hemadsorption can be used in the laberatory to
detect cell infected with certain viruses(e.g
orthoviruses &Paramyxoviruses)
2- Gaint cell formation
• Some viruses , Such as herpes simplex and Hiv
promote cell fusion in with membranes of
adjacent cell coalesce to produce multinucleated
gaint cells. Other markers of viral infection
include intra neuclear or cytoplasmic inclusion
bodies .
Pathogenesis of fungal disease
In general medically important fungi do not possess
the virulent attributes of bacteria such as exotoxin
and endotoxin( an exception is the exotoxin ,
aflatoxin, produce by Aspergillus Species) hence
they cause slowly progressive chronic infection
rather then the acute disease commonly seen in
bacterial or viral diseases. However they may cause
life – threating acute infections in
immunocomprised patients (e.g. those with
acquired immune deficiency syndrome (AIDES)
The oral fungal pathogen candida possesses
a number of virulent attributes including:1- ability to adhere to host tissue(e.g. dentures)
and form biofilms
2- the ability to form hyphae that helps in tissue
invasion
3- extracellular phospholipase and hemolysin
production which break down physical defence
barriers of the host