Pathogenesis of bacteria

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Pathogenesis of bacteria
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Original and development of Bacterial Infection
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Infection

• the invasion of a host organism's bodily
  tissues by disease-causing organisms, their
  multiplication, and the reaction of host tissues
  to these organisms and the toxins they produce.

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• Pathogen
• A disease causing microorganism.
• Nonpathogen
• A microorganism that does not cause
  disease.
• Opportunistic pathogen
• A microorganism does not cause disease
  in normal conditions,
• but is capable of causing disease under
  contain conditions.

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• A bacterial infectious disease is a
  multi-factorial event which depends on
• Nature (virulence factors) of bacterial species
  or strain.
• Immune status of bacteria invading hosts.
• Environment conditions

• Pathogenesis of microbial infection includes
• a) general process of infection
• b) mechanisms of microbes causing
  disease

transmissibility, adherence to host cells,
invasion of host cells and tissues, toxigenicity,
and ability to evade the host's immune system
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pathogenesis How a disease develops
Pathogenicity Disease-causing ability of microorganisms
virulence Degree of pathogenicity
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Pathogen-- Pathogenicity
The ability of a microorganism to cause disease

• Factors that determine bacterial pathogenicity
• Virulence The quantitative ability of a
  pathogen to cause disease that containing
  invasiveness and toxigenicity.
• The amount of entry
• The portal of entry

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• LD50 (Lethal Dose, 50)
• The number of pathogen required to cause lethal
  disease in half of the exposed hosts.
• ID50 (Infective Dose, 50)
• The number of pathogens required to cause disease
  or infection in half of the exposed hosts.

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• Adhesion (adherence, attachment) the process of
  microbes sticking to the surfaces of host cells.
• Adhesion is a key initial step during
  infection (then invasion).

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• Invasiveness The process of microbes entering
  host cells or tissues as well as spread in the
  body.

• Toxigenicity The ability of a microorganism to
  produce toxins that contributes to the
  development of disease.

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• intracellular bacteria
• capable of living and reproducing either
  inside or outside cells
• Listeria monocytogenes
• Salmonella
• Brucella
• Mycobacterium
• Yersinia
• Neisseria meningitidis
• Cryptococcus neoformans
• extracellular bacteria
• capable of replicating outside of the host
  cells

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Source of infections

• Exogenous infection
• Infections caused by infectious agents that are
  come from the external environment or other hosts
  (patient, carrier, diseased animal or animal
  carrier).
• carrier individuals infected with infectious
  agents but no clinical signs or symptoms.
• Endogenous infection
• Infections caused by normal flora under certain
  conditions (opportunistic infection)

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Transmission of bacterial infection

• Bacteria can be transmitted in airborne droplets
  to the respiratory tract, by ingestion of food or
  water or by sexual contact.
• Specific bacterial species are being transmitted
  by different routes to specific sites in the
  human body
• Respiratory tract (Mycobacterium tuberculosis)
• gastrointestinal tract (pathogenic E. coli)
• Genitourinary tract (Neisseria gonorrhoeae)
• Closely contact
• Insect bite (Rickettsia)
• Blood transfusion
• Skin and other mucosa (eye)

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Common Diseases contracted via the Respiratory
Tract

• Common cold
• Flu
• Tuberculosis
• Whooping cough
• Pneumonia
• Measles
• Strep Throat
• Diphtheria

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Mucus Membranes

• Gastrointestinal Tract
• microbes gain entrance thru contaminated food
  water or fingers hands
• most microbes that enter the G.I. Tract are
  destroyed by HCL enzymes of stomach or bile
  enzymes of small intestine

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Common diseases contracted via the
GastrointestinalTract

• Salmonellosis
• Salmonella sp.
• Shigellosis
• Shigella sp.
• Cholera
• Vibrio cholorea
• Ulcers
• Helicobacter pylori
• Botulism
• Clostridium botulinum

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Fecal - Oral Diseases

• These pathogens enter the G.I. Tract at one end
  and exit at the other end.
• Spread by contaminated hands fingers or
  contaminated food water
• Poor personal hygiene.

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Mucus Membranes of the Genitourinary System
Gonorrhea Neisseria gonorrhoeae
Syphilis Treponema pallidum
Chlamydia Chlamydia trachomatis HIV Herpes
Simplex II
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Types of bacterial infection
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According to infectious state

• Inapparent or subclinical infection The
  infection with no manifesting clinical signs and
  symptoms.
• Latent infection or Carrier state The infection
  is inactive but remains capable of producing
  clinical signs and symptoms.
• Apparent infection The infection with
  manifesting clinical signs and symptoms.

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According to infectious sites

• Local infection The infection is limited to a
  small area of the body.
• Generalized or systemic infection The infection
  is throughout the body, it can present as
• Bacteremia (???) Bacteria enter bloodstream
  without propagation in
• bloodstream (bloodstream only used as a
  channel tool for bacteria
• to spread)
• -Salmonella
• Toxemia (???) Exotoxins enter bloodstream but no
  bacteria in the blood.
• - corynebacterium diphtheriae,
  clostridium tetani

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According to infectious sites
Endotoxemia (?????) Endotoxins enter bloodstream
but no bacteria in the blood.
- Shigella Septicemia (???) Bacteria enter
bloodstream with propagation and release their
virelent substances (e.g., toxins).
- clostridium perfringens, Yersinia
pestis Pyemia (????)Pyogenic bacteria enter
bloodstream with propagation and release their
virulent substances, and spread through
bloodstream into the target organs to form
pyogenic foci. - staphylococcus
aureus
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Normal flora Opportunistic infections
Hospital acquired infections
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• All humans have bacteria (normal flora) that
  living on their external surfaces (skin) and
  their inner surfaces (Respiratory, Gastroenteric
  and Genitourinary tract mucosa). Normally due to
  our host defenses, most of these bacteria are
  harmless.
• The infectious diseases that initiated in
  hospital are referred to as nosocomial infection
  (Hospital acquired infection ).

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Normal flora

• Microorganisms that live on or in human bodies,
  and ordinarily do not cause human diseases

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Distribution of normal flora
Skin Flora Various environment of the skin
results in locally dense or sparse microbial
populations. Usually Gram-positive bacteria
(e.g., Staphylococci and Micrococci ) are
predominating. Oral and Upper Respiratory Tract
Flora Various microbial floras can be found in
the oral cavity (e.g., anaerobic bacteria) and
upper respiratory tract (e.g., Neisseria,
Bordetella and Streptococci ).
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Gastrointestinal Tract Flora In normal hosts,
flora in stomach are rare as well as transient,
flora in duodenum and jejunum are sparse, and
ileum contains moderately mixed flora. Flora in
large bowel is dense (109-1011 bacteria/g of the
content) and is predominantly composed of
anaerobes.
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Urogenital Flora Flora in vaginal (e.g.,
anaerobes and Lactobacillus) changes with the age
of the individual, pH and hormone levels. Distal
urethra contains a sparse mixed flora (e.g.,
Corynebacterium). Conjunctival
FloraConjunctiva (eye) has few or no
microorganisms. However, Haemophilus and
Staphylococcus are frequently detected.
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Physiological Role of normal flora

1. Antagonism a) Normal flora on skin and mucosa of
   hosts can form biolfilm (as a biological barrier)
   that acts as colonization resistance of exogenous
   pathogenic microbes b) Normal flora may
   antagonize exogenous pathogens through the
   production of antibiotics.
2. Trophism Normal flora in the intestinal tract
   synthesize nutrients that can be absorbed by
   human (e.g., vitamin K and vitamin B).
3. Immunoenhancement Normal flora promotes the
   development of local lymphatic tissues (e.g.,
   Peyers patches in the intestines).

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Conditions that opportunistic pathogens cause
human diseases

• Alteration of colonization sites
• Declination of the host immunity defense
• Dysbacteriosis
• -the state in which the proportion of
  bacterial species and the number of the normal
  flora colonizing in a certain site of a host
  present large-scale alteration

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Opportunistic infections (Infections caused by
normal flora)
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Opportunity for opportunistic infection
I. Low immunity of human body Normal flora that
usually don't cause disease in a person with a
healthy immune system. If a person with a poor
immunity, some of them can cause infection. II.
Translocation of normal flora Members of normal
flora removed from the original inhabitancy into
bloodstream or other tissues, these microbes may
become pathogenic. III. Suppression of normal
flora When some numbers of normal flora are
killed or inhibited, it creates a partial local
void that tends to be filled by exogenous
microbes or microbes from other parts of the
body. Such microbes behavior as opportunists and
some of them may be pathogens.
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Hospital acquired infections (Nosocomial
infections)
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• Hospital acquired infections specially indicate
  the opportunistic infections acquired during
  hospital stays. Formally, they are defined as
  infections arising after 48 hours of hospital
  admission.
• Hospital acquired infections can be bacterial,
  viral, fungal or even parasitic. The most common
  pathogens include Staphylococci, Pseudomonas,
  Escherichia coli and Saccharomyces (fungus).
• Most of microbes causing hospital acquired
  infections usually have a high resistance to
  antibiotics.
• Prevention of hospital acquired infections
  includes personal hygiene (patients and hospital
  staff), a clean and sanitary environment in
  hospital, and complete sterilization of medical
  materials and equipments.

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Generally, infection process caused by a
bacterial pathogen involves the four steps as the
following
I. Adhesion II. Penetration and spread III.
Survival and propagation in the host IV. Tissue
injury
Any bacterial factors involved in the four steps
determine the virulence of bacteria.
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i. Bacterial virulent factors (Implying of Nature
of bacterial species or strain) In step I
Adhesion
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BACTERIAL VIRULENCE FACTORS
Environmental signals often control the
expression of the virulence genes. Common signals
include Temperrature/Iron availability/low ion/
Osmolality/Growth phase/pH/Specific ions
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• The fist step of bacterial infection is the
  adhesion to a specific epithelial surface of the
  host.
• Adhesion is a specific interaction and then a
  specific combination between adhesins (virulent
  factors) of bacteria and their receptors on the
  surface of host cells.
• Adhesins include lipoteichoic acid (for G), some
  of outer membrane proteins (for G-), ordinary
  pilus (for both) and so on.

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Adhesion
E. coli fimbriae
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i. Bacterial virulent factors In step II
Penetration and spread
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• After the adherence, the bacteria may entered
  into host cells.
• Invasion is commonly used to describe the entry
  of bacteria into host cells, implying an active
  role for the organisms and a passive role for the
  host cells.
• Invasion often occurs in mucosa of intestine,
  urinary tract and respiratory tract, and much
  less in skin.

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1. reside on epithelial surface for a few of
bacteria (e.g. Vibrio
cholerae) 2. penetrate the epithelial barrier and
invade host cells but remain in local tissues for
a few of bacteria (e.g. Shigella
spp.). 3. pass into the bloodstream and/or from
there spread into systemic sites including
internal organs for many of bacteria
(e.g. Salmonella typhi spread into spleen
and liver through bloodstream).
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Degradative enzymes

• Collagenase to destroy collagen. There are a
  lot of collagens in soft tissue including
  connective tissue.
• Hyaluronidase to destroy hyaluronic acid which
  is a major component in the matrix of connective
  tissue.
• Coagulase to coagulate fibrinogen in tissue
  fluid and plasma into fibrin. (to protect
  bacteria from damage by many agents)
• Streptokinase/fibrinolysin The former activates
  fibrinogenase to thrombin, which results in the
  degradation of fibrin. And the latter directly
  lyse fibrin.
• Streptodornase it is a DNase.
• Cytolysins 1) hemolysins (to dissolve red
  blood cells)
• 2) Leukocisins (to kill
  leukocytes or tissue cells )

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i. Bacterial virulent factors In step III
Survival and propagation in the host
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• After bacteria enter hosts, they must have anti-
  phagocyte ability for surviving. Surviving is a
  basis for further propagation of bacteria.
• In human body fluids, there are phagocytes,
  antibody, complement and lysozyme, which can
  destroy extracellular bacteria.
• Some of bacteria can produce anti-phagocyte
  factors.
• Propagation is the aim of bacteria entering
  hosts. On the other hand, only certain number for
  a bacterium can cause disease!!!

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Antiphagocytic Substances

• 1. Polysaccharide capsules of S. pneumoniae,
  Haemophilus influenzae, Treponema pallidum B.
  anthracis and Klebsiella pneumoniae.
• 2. M protein and fimbriae of Group A streptococci
  
• 3. Surface slime (polysaccharide) produced as a
  biofilm by Pseudomonas aeruginosa
• 4. O polysaccharide associated with LPS of E.
  coli

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Antiphagocytic Substances

• 5. K antigen (acidic polysaccharides) of E. coli
  or the analogous Vi antigen of Salmonella typhi
• 6. Cell-bound or soluble Protein A produced by
  Staphylococcus aureus. Protein A attaches to the
  Fc region of IgG and blocks the cytophilic
  (cell-binding) domain of the Ab. Thus, the
  ability of IgG to act as an opsonic factor is
  inhibited, and opsonin-mediated ingestion of the
  bacteria is blocked.

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Protein A inhibits phagocytosis
immunoglobulin
M protein inhibits phagocytosis
Complement
fibrinogen
M protein
peptidoglycan
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i. Bacterial virulent factors In step IV
Tissue injury
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Bacteria cause tissue injury by many factors or
some special mechanisms involving

• Exotoxin
• b) Endotoxin
• c) Inducement of Immunopathological reaction

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a) Exotoxin

• Definition Exotoxin is a toxic protein or
  polypeptide that is usually secreted by living
  bacteria.
• Produced by many Gram and a few of Gram-
  bacteria.
• Most of exotoxins have strong and specific
  toxicity and frequently cause acute infection and
  serious effects (e.g. death).
• Antibody against exotoxin can neutralize the
  toxicity.
• Exotoxins become toxoids after treatment with
  formaldehyde. Toxoids lose toxic properties but
  retains antigenicity, which can be used as
  vaccines to prevent the exotoxin-mediated
  disease.

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According to the differences of the target cells
and acting mechanisms, exotoxins can be divided
into three types
Enterotoxin cause food poisoning
botulin, staphylococcal enterotoxin. Nuerotoxin
Systematic toxic effects
diphtheria, tetanus, and streptococcal
erythrogenic toxins. Cytotoxin Local toxic
effects cholera, and toxigenic E.
coli enterotoxins.
Antibodies (anti-toxins) neutralize Vaccination
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This child has diphtheria resulting in a thick
gray coating over back of throat. This coating
can eventually expand down through airway and, if
not treated, the child could die from suffocation

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neonatal tetanus patient displays sardonic smile,
lockjaw and dyspnea
Severe case of adult tetanus. The muscles in the
back and legs are very tight.
neonatal tetanus. It is completely rigid. Tetanus
kills most of the babies who get it when newly
cut umbilical cord is exposed to dirt.
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? Many exotoxins are called as A-B type toxins
because they consist of A and B subunits. A
subunit provides the toxic activity. B subunit
generally mediates the toxin complex molecule to
adhere and then enter the host cell.
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b) Endotoxins (LPS)

• Endotoxin usually released by damaged G-
  bacteria because it is a structural component of
  the cell wall.
• Endotoxin is general poisonous to all mammal
  cells but its toxicity is much lower than most of
  exotoxins.
• The toxicity of LPS from different G- bacteria
  is similar.
• Endotoxin can not become toxoids after treatment
  with formaldehyde.
• Antibody against endotoxin can not neutralize
  the toxicity.

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Pathophysiologic effects of LPS

• LPS (endotoxin) has many pathophysiologic
  effects.
• One of the effects is to cause inflammation by
  many different ways including
• Non-specific inflammation
• cytokine release
• complement activation
• B cell mitogen, polyclonal B cell activator and
  adjuvant
• Stimulation of marrow and blood vessels

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Cytokine release
LPS are able to induce macrophage and
neutrophilic leukocyte to synthesize and release
cytokines such as interleukin 1 (IL-1), tumor
necrosis factor (TNF), interferon (IFN) and so
on.
These cytokines results in inflammation reaction
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Complement activation
LPS is an activator of the complement cascade.
Certain complement by-products are the
attractants for neutrophilic leukocyte. On the
other hand, in the absence of specific antibody,
complement binding bacteria will encourage
phagocytes to kill the target bacterial cells.
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B cell mitogen, polyclonal B cell activator,
adjuvant
LPS is also a B cell mitogen, polyclonal B
cell activator and adjuvant, which plays a role
in the development of a suitable chronic immune
response in handling the microbes if they are not
eliminated acutely.
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Stimulation of marrow and blood vessels

• LPS acts on small blood vessels to increase the
  expression of adhering proteins to bind
  leukocytes in bloodstream.
• LPS is a powerful activator to stimulate marrow
  to release leukocytes.
• LPS has an effect to dilate small blood vessels.
• LPS can also activate blood coagulation system to
  cause thrombus forming in small blood vessels.

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Due to those pathophysiologic effects of
LPS, the following major phenomenon can be
observed clinically or experimentally a) Fever
(LPS is a typical pyrogen) b) Firstly leukopenia
(binding to small blood vessels) and Secondly
leukocytosis (marrow stimulation) c) Shock
(dilatation of small blood vessels) d) DIC
Disseminated intravascular coagulation (thrombus
forming ) e) Death from massive organ
dysfunction.
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Major difference between endotoxin and exotoxin
Properties Exotoxin endotoxin
Origin G and G- G-
Release Secreted from living cells or released upon bacterial lysis Released upon bacterial lysis
Composition protein LPS
Heat-resistance Sensitive resistance
Immunity High, antitoxin, toxoid Low, no toxoid
toxicity High, tissue specificity Low, no tissue specificity
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c) Inducement of Immunopathological reaction

• Human immune responses to bacteria may cause
  tissue injury by
• Over-stimulation of cytokine production and
  complement activation by endotoxin can cause
  tissue injury.
• Continuously generated bacterial antigens will
  subsequently elicit humoral antibodies and cell
  mediated immunity, which resulting in chronic
  immunopathological injury.
• Some of bacterial antigens (e.g., M protein of
  Streptococcus pyogenes) can cross-react with
  host tissue antigens. This bacterial antigens
  will cause the development of autoimmunity.

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virulence
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ii. Number of invaded bacteria iii. Route of
bacteria invading hosts
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Invaded number and invading route of bacteria

• Number of invaded bacteria 1)The more number of
  invaded bacteria, the stronger for pathogenecity
  2) diversity of different bacteria in number for
  pathogenicity (e.g., 50100 cells of Vibro
  cholerae but 30,00050,000 cells of
  Staphylococcus aureus can cause infectious
  diseases).
• Route of bacteria invading host For most of
  bacteria, they have specific invading routes
  (e.g. Clostridum tetani infects human through
  wounds and Mycobacterium tuberculosis has
  multiple invading routes to cause diseases).

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Summary

1. Concepts of virulence, normal flora, hospital
   acquired infection, latent infection, toxemia,
   septicemia, endotoxemia and pyemia.
2. The physiologic role of normal flora.
3. The conditions for generation of opportunistic
   infection.
4. The steps relative to bacterial infection.
5. The difference between exotoxin and endotoxin.
6. Virulence of bacteria.
7. Clinical characteristics of bacterial infections.