PATHOGENESIS

PHARMACEUTICAL MICROBIOLOGY
 PRINCIPLES OF PATHOGENESIS

⚫ Pathogenic microorganism is capable of causing

disease; however, some organisms are highly pathogenic
whereas others cause disease rarely.
⚫ Opportunistic pathogens are those that rarely, if
ever, cause disease in immunocompetent people but can
cause serious infection in immunocompromised patients.
⚫ The infectious dose of an organism required to
cause disease varies greatly among the pathogenic
bacteria.

For example, Shigella and Salmonella both cause diarrhea

by infecting the gastrointestinal tract, but the infectious
dose of Shigella is less than 100 organisms, whereas the
infectious dose of Salmonella is on the order of 100,000
organisms.
 Virulence factors

* pili allow them to adhere well to

mucous membranes
* exotoxins or endotoxins
* capsule to protect them from
phagocytosis
* can survive various nonspecific
host defenses such as acid in the
stomach).
 WHY DO PEOPLE GET INFECTIOUS
?DISEASES

⚫ when the balance between the organism and the host shifts in favor
of the organism.
Number and Virulence of organisms
Vs
Host defense
The result will be either ..
* infectious disease
* Asymptomatic infection
 TYPES OF BACTERIAL INFECTIONS

Bacteria cause disease by two major mechanisms:

(1) Toxin production : exotoxins and endotoxins.

(2) Invasion and inflammation

⚫ Communicable (i.e., they are spread from host to host).
⚪ For example, tuberculosis is communicable (i.e., it is spread from person to
person via airborne droplets produced by coughing).
⚪ but botulism is NOT communicable !
An infection is :
⚫ Epidemic if it occurs much more frequently than usual Pandemic if it has a
worldwide distribution.
⚫ Endemic infection is constantly present at a low level in a specific population.
⚫ Subclinical can be detected only by demonstrating a rise in antibody titer or
by isolating the organism.
⚫ Latent state, after which reactivation of the growth of the organism and
recurrence of symptoms may occur.
⚫ Chronic carrier state, in which the organisms continue to grow with or
without producing symptoms in the host. Chronic carriers (e.g., “Typhoid
Mary”) are an important source of infection of others and hence are a public
health hazard.
 .Normal flora vs Colonization

⚫ Normal flora are permanent residents of the body and vary in type according to anatomic site.

⚫ Colonization refers to the presence of a new organism that is neither a member of the normal
flora nor the cause of symptoms.
 STAGES OF BACTERIAL PATHOGENESIS

(1) Transmission from an external source into the portal of entry.

(2) Evasion of primary host defenses such as skin or stomach acid.
(3) Adherence to mucous membranes, usually by bacterial pili.
(4) Colonization by growth of the bacteria at the site of adherence.
(5) Disease symptoms caused by toxin production or invasion
accompanied by inflammation.
(6) Host responses, both nonspecific and specific (immunity), during
steps 3, 4, and 5.
(7) Progression or resolution of the disease.
Important Modes of Transmission
 DETERMINANTS OF BACTERIAL PATHOGENESIS

(1) Transmission
The mode of transmission of many infectious diseases is :

- Human-to-human
- Nonhuman sources such as soil, water, and animals
⚫ Although some infections are caused by members of the normal
flora, most are acquired by transmission from external
sources.
Pathogens exit the infected patient most frequently from the :
- Respiratory
- Gastrointestinal
- Genital
- Skin
⚫ portals of entry:
⚪ Respiratory : via airborne respiratory droplets
⚪ Gastrointestinal: fecal contamination of food and water.
⚪ Genital & body fluids: sexual contact, blood transfusions.
⚪ Skin contact: urine, contaminated needles or biting insects.

⚫ Vertical transmission : transmission from mother to offspring

⚫ Animals can be either :

- the source (reservoir) or

- the mode of transmission (vector) of certain organisms.
⚫ Diseases for which animals are the reservoirs are called

zoonoses
 Adherence to Cell Surfaces (2)

⚫ Certain bacteria have specialized structures (e.g., pili) or

produce substances (e.g., capsules or glycocalyces)
that allow them to adhere to the surface of human cells,
thereby enhancing their ability to cause disease.
⚫ After the bacteria attach, they often form a protective matrix
called a biofilm consisting of various polysaccharides
and proteins.
 Invasion, Inflammation, & Intracellular Survival(3)

Several enzymes secreted by invasive bacteria :

(1) Collagenase and hyaluronidase .. cellulitis caused by Streptococcus
pyogenes.
(2) Coagulase, which is produced by Staphylococcus aureus and
accelerates the formation of a fibrin clot
(3) Immunoglobulin A (IgA) protease, which degrades IgA, allowing
the organism to adhere to mucous membranes, and is produced chiefly
by N. gonorrhoeae, Haemophilus influenzae, and Streptococcus
pneumoniae.
(4) Leukocidins, which can destroy both neutrophilic leukocytes and
macrophages.
 Limitation of Host defense

⚫ Virulence factors contribute to invasiveness

by limiting the ability of the host
defense mechanisms, especially
phagocytosis, to operate effectively.
(1) Capsule such as S. pneumoniae and
Neisseria meningitidis , prevents the phagocyte
from adhering to the bacteria
(2) cell wall proteins of the gram-positive
cocci, such as :
- M protein of the group A streptococci (S. pyogenes)
is antiphagocytic
- Protein A of S. aureus. , and protein A binds to
immunoglobulin G (IgG) and prevents the activation of
complement
 Types of inflammation

⚫ Bacteria can cause two types of inflammation :

- Pyogenic (pus-producing) inflammation, neutrophils are the
predominant cells , like gram-positive and gram-negative cocci

- Granulomatous inflammation ( a granuloma is an organized

collection of macrophages), macrophages and helper T cells predominate
, like Mycobacterium tuberculosis.
 Intracellular survival

⚫ Intracellular survival is an important attribute of certain bacteria that

enhances their ability to cause disease.
* Mechanisms :
⚫ (1) inhibition of the fusion of the phagosome with the lysosome.
⚫ (2) inhibition of acidification of the phagosome.
⚫ (3) escape from the phagosome into the cytoplasm.
Members of the genera Mycobacterium and Legionella are known to use the first
and second mechanisms, whereas Listeria species use the third.
 Invasion of cells

⚫ The invasion of cells by bacteria is dependent

on the interaction of specific bacterial surface
proteins called invasins and specific cellular
receptors
⚫ Once inside the cell, these bacteria typically
reside within phagosomes , others migrate
into the cytoplasm, and some move from the
cytoplasm into adjacent cells through
tunnels formed from actin.
⚫ Infection of the surrounding cells in this
manner allows the bacteria to evade host
defenses.
⚫ For example, Listeria monocytogenes
aggregates actin filaments on its surface and is
propelled “ actin rockets “, from one host
cell to another .
Toxin Production (4)
Important Mechanisms of Action of Bacterial Exotoxins
Mode of action of Escherichia coli and Vibrio cholera enterotoxins
 Mode of action of endotoxin

Endotoxin is the most important cause of septic

shock, which is characterized primarily by fever,
hypotension, and disseminated
intravascular coagulation (DIC)
 Immunopathogenesis (5)

⚫ In certain diseases, such as rheumatic fever and acute

glomerulonephritis, it is not the organism itself that causes the
symptoms of disease but the immune response to the presence of the
organism.
⚫ For example, in rheumatic fever, antibodies are formed against the M
protein of S. pyogenes, which cross-react with joint, heart, and brain
tissue.
⚫ Inflammation occurs, resulting in the arthritis, carditis, and chorea that
are the characteristic findings in this disease
 Typical Stages of an Infectious Disease

⚫ The incubation period is the time between the moment the person is exposed to
the microbe (or toxin) and the appearance of symptoms.
⚫ The prodrome period is the time during which nonspecific symptoms occur.
⚫ The specific-illness period is the time during which the characteristic features of
the disease occur.
⚫ The recovery period is the time during which symptoms resolve and health is
restored.
⚫ After the recovery period, some people become chronic carriers of the organism
and in others latent infections develop.
⚫ Some people have subclinical infections during which they remain asymptomatic.
The presence of antibodies reveals that a prior infection has occurred.