Dr. ihsan edan abdulkareem alsaimary PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY ihsanalsaimary@gmail.com mobile : 009647801410838 university of basrah - college of medicine - basrah -IRAQ

1. Pathogenesis of microbial infections
prof.dr.ihsan edan alsaimary
department of microbiology – college of medicine – university
of basrah

2. Pathogenesis
of bacterial infection
Humans and animals have abundant normal
microflora.
Most bacteria do not produce disease but achieve
a balance with the host that ensures the survival,
growth, and propagation of both the bacteria and
the host.
Sometimes bacteria that are clearly pathogens
(e.g. Salmonella typhi) are present, but infection
remains latent or subclinical and the host is a
"carrier" of the bacteria.

3. It can be difficult to show that a specific
bacterial species is the cause of a particular
disease.
In 1884, Robert Koch proposed a series of
postulates in his treatise on Mycobacterium
tuberculosis and tuberculosis.
These postulates have been applied more
broadly to link many specific bacterial
species with particular diseases.

4. Koch´s postulates are summarized as follows:
The microorganism should be found in all cases of the
disease in question, and its distribution in the body
should be in accordancce with the lesions observed.
The microorganism should be grown in pure culture in
vitro (or outsite the body of the host) for several
generations.
When such a pure culture is inoculated into
susceptible animal species, the typical disease must
result.
The microorganism must again be isolated from the
lesions of such experimentally produced disease.

5. Koch´s postulates remain a mainstay of
microbiology.
However, since the late 19th century, many
microorganisms that do not meet the criteria
of the postulates have been shown to cause
disease. For example, Treponema pallidum
(syphilis) and Mycobacerium leprae (leprosy)
cannot be grown in vitro, but there are
animal models of infection with these agents.

6. In another example, Neisseria gonorrhoeae
(gonorrhea), there is no animal model of infection
even though the bacteria can readily be cultivated in
vitro.
The host´s immune responses should be considered
when an organism is being investigated as the
possible cause of a disease.
Thus, development of a rise in specific antibody
during recovery from disease is an important adjunct
to Koch´s postulates.

7. Modern-day microbial genetics has opened new
frontiers to study pathogenic bacteria and differentiate
them from non-pathogens.
The ability to study genes associated with virulence
has led to a proposed of Koch´s postulates:
The phenotype, or property, under investigation
should be associated with pathogenic members of a
genus or pathogenic strains of a species.
Specific inactivation of the gene(s) associated with
the suspected virulence trait should lead to a
measurable loss in pathogenicity or virulence.
Reversion or allelic replacement of the mutated gene
should lead to restoration of pathogenicity.

8. Analysis of infection and disease through the application
of principles such as Koch´s postulates leads to
classification of bacteria as pathogenic or non-
pathogenic.
Some bacterial species are always considered to be
pathogens, and their presence is abnormal.
– Examples include Mycobacterium tuberculosis
(tuberculosis) and Yersinia pestis (plague).
– Other species are commonly part of the normal flora of
humans (and animals) but can also frequently cause
disease. For example, Escherichia coli is part of the
gastrointestinal flora of normal humans, but it is also a
comon cause of urinary tract infection, traveller´s diarrhea,
and other diseases.

9. The infectious process
Infection indicates multiplication of microorganisms.
Prior to multiplication, bacteria (in case of bacterial
infection) must enter and establish themselves
within the host.
The most frequent portals of entry are the
respiratory (mouth and nose), gastrointestinal, and
urogenital tracts. Abnormal areas of mucous
membranes and skin (e.g. cuts, burns) are also
frequent sites of entry.

10. The infectious process
Once in the body, bacteria must attach or adhere to
host cells, usually epithelial cells.
After the bacteria have established a primary site of
infection, they multiply and spread.
Infection can spread directly through tissues or via
the lymphatic system to bloodstream. Bloodstream
infection (bacteremia) can be transient or persistent.
Bacteremia allows bacteria to spread widely in the
body and permits them to reach tissues particularly
suitable for their multiplication.

11. The infectious process
As an example of the infectious process, Streptococcus
pneumoniae can be cultured from the nasopharynx of 5-40% of
healthy people.
Occasionally, Streptococcus pneumoniae strains from the
nasopharynx are aspirated into the lungs. Infection develops in the
terminal air space of the lungs in persons who do not have
protective antibodies against that type of Streptococcus
pneumoniae. Multiplication of Streptococcus pneumoniae strains
and resultant inflammation lead to pneumonia. The strains then
enter the lymphatics of the lung and move to the bloodstream.
Between 10% and 20% of persons with Streptococcus pneumoniae
pneumonia have bacteremia at the time the diagnosis of
pneumonia is made. Once bacteremia occurs, Streptococcus
pneumoniae strains can spread to their preferred secondary sites of
infection (e.g. cerebrospinal fluid, heart valves, joint spaces). The
major resulting complications of Streptococcus pneumoniae
pneumonia include meningitis, endocarditis and septic arthritis.

12. Basic terms frequently used in
describing aspects of pathogenesis:
Infection:
– Multiplication of an infectious agent within the
body.
– Multiplication of the bacteria that are part of
normal flora of gastrointestinal tract, skin, etc, is
generally not considered an infection.
– On the other hand, multiplication of pathogenic
bacteria (e.g. Salmonella species), even if the
person is asymptomatic, is deemed an infection.

13. Basic terms frequently used in
describing aspects of pathogenesis:
Pathogenicity:
– The ability of an infectious agent to cause disease.
Virulence:
– The quantitative ability of an agent to cause disease.
– Virulent agents cause disease when introduced into the
host in small numbers.
– Virulence involves invasiveness and toxigenicity.

14. Basic terms frequently used in
describing aspects of pathogenesis:
Toxigenicity:
– The ability of a microorganism to produce a
toxin that contributes to the development of
disease.
Invasion:
– The process whereby bacteria, parasites,
fungi and viruses enter the host cells or
tissues and spread in the body.

15. Basic terms frequently used in
describing aspects of pathogenesis:
Pathogen:
– A microorganism capable of causing disease.
Non-pathogen:
– A microorganism that does not cause disease. It may be
part of the normal flora.
Opportunistic pathogen:
– An agent capable of causing disease only when the
host´s resistance is impaired (e.g. the patient is
immunocompromised).
– An agent capable of causing disease only when spread
from the site with normal bacterial microflora to the sterile
tissue or organ.

16. Commensal and Pathogenic Microbial Flora in humans
Medical microbiology is the study of interactions
between humans and microorganisms such as
bacteria, viruses, fungi and parasites.
Although the primary interest is in diseases caused by
these interactions, it must be also appreciated that
microorganisms play a critical role in human survival.
The normal microflora participates in the metabolism
of food products, provides essential growth factors,
protects against infections with highly virulent bacteria,
and stimulates the immune system.
In the absence of bacterial microflora, life as we know
it would be impossible.

17. The microbial flora is determined by a variety of
factors:
– age
– diet
– hormonal state
– health
– personal hygiene
The human fetus lives in a protected, sterile
environment, the newborn is exposed to microbes
from the mother and environment.
The infant´s skin is colonized first, followed by the
oropharynx, gastrointestinal tract, and other mucosal
surfaces.

18. Throughout the life of an individual, the microbial
population continues to change.
For example, hospitalization can lead to the
replacement of normally avirulent bacteria in the
oropharynx with gram-negative rods, e.g.
Pseudomonas aeruginosa or Klebsiella pneumoniae,
that can invade the lungs and cause pneumonia.
The growth of Clostridium difficile in the
gastrointestinal tract is controlled by the other
bacteria present in the intestines. In the presence of
antibiotics, normal (susceptible) bacteria are
eliminated and C. difficile is able to proliferate and
produce gastrointestinal disease.

19. Exposure of an individual to bacteria
can lead to one of three outcomes:
The bacteria can transiently colonize the
person.
The bacteria can permanently colonize the
person.
The bacteria can produce disease.

20. It is important to understand the
distinction between colonization and
disease.
Some medical workers use the term
infection inappropriately as a
synonym for both terms.

21. An understanding of medical microbiology
requires knowledge not only of the different
classes of bacteria but also of their propensity
for causing disease.
Strict pathogens:
– Mycobacterium tuberculosis,
Neisseria gonorrhoeae, Francisella tularensis,
Plasmodium spp., rabies virus
Opportunistic pathogens:
– e.g. bacteria that are typically members of the
human ´s normal microflora (Staphylococcus
aureus, Escherichia coli and other)

22. Mouth, oropharynx, nasopharynx
The upper respiratory tract is colonized with
numerous bacteria, with 10 to 100 anaerobes
for every aerobic bacterium.
The most common anaerobic bacteria are
Peptostreptococcus, Veillonella, Actinomyces
and Fusobacterium species.
The most common aerobic bacteria are
Streptococcus, Haemophilus and Neisseria
species.

23. Ear
The most common microorganism
colonizing the outer ear is coagulase-
negative Staphylococcus species.

24. Eye
The surface of the eye is colonized with
coagulase-negative staphylococci as well
as rare numbers of bacteria found in the
nasophyranyx (e.g. Haemophilus sp.,
Neisseria sp. and viridans streptococci).

25. Lower respiratory tract
The larynx, trachea, bronchioles and lower
airways are generally sterile, although
transient colonization with secretions of
the upper respiratory tract may occur after
aspiration.

26. Gastrointestinal tract
The gastrointestinal tract is colonized with
microbes at birth and remains the home for a
diverse population of microorganims
throughout the life of the host.
Although the opportunity for colonization with
new bacteria occurs daily with the ingestion of
food and water, the population remains
relatively constant.
Some factors can lead to change of normal
microflora, e.g. using of antibiotics.

27. Genitourinary tract
In general, the anterior urethra and vagina are the
only anatomic areas of the genitourinary tract
system permanently colonized with microbes.
Although the urinary bladder can be transiently
colonized with bacteria migrating upstream from
the urethra, these should be cleared rapidly by the
bactericidal activity of the uroepithelial cells and
flushing action of voided urine.
The other structures of the urinary system should
be sterile except when disease or an anatomic
abnormality is present.

28. Skin
Although many microorganisms come into contact
with skin surface, this relatively hostile
environment does not support the survival of most
bacteria.
Gram-positive bacteria (e.g. coagulase-negative
staphylococci and, less commonly,
Staphylococcus aureus, corynebacteria and
propionibacteria) are the most common
microorganisms found on the skin surface.
Gram-negative bacteria do not permanently
colonize the skin surface, because the skin is too
dry.

29. Microbial Pathogenesis
Entry into the Host
Must access and adhere to host tissues, penetrate or
evade host defenses, and damage tissue to cause
disease.
Portals of Entry
The three main portals of entry are:
 Mucous membranes
 Skin
 Parenteral

30. Microbial Mechanisms of Pathogenicity:
How Microorganisms Cause Disease

31. I. Mucous Membranes
Epithelial tissue lining the:
Respiratory tract: Easiest and most frequently
used entry site for microbes.
Gastrointestinal tract: Another common entry
site. Enter through water, food, contaminated
fingers and fomites. Must survive stomach HCl,
enzymes, and bile.
Genitourinary tract: Entry site for most sexually
transmitted diseases (STDs).
Conjunctiva: Membrane covering eyes and
eyelids.

32. II. Skin
Unbroken skin is impenetrable by most
microbes.
Some microbes gain access through hair
follicles and sweat glands.
Necator americanus (hookworm) can bore
through intact skin.
Certain fungi (dermatophytes) grow on
skin and produce enzymes that break
down keratin.

33. III. Parenteral Route
Microbes are deposited directly into the
tissues beneath the skin or mucous
membranes.
Examples: Injections, bites, cuts, wounds,
surgery, punctures, and splitting due to swelling
or drying.
Preferred Portal of Entry
Many microbes have a preferred portal of entry
which is a prerequisite to cause disease.
 Example: Streptococcus pneumoniae that are inhaled can
cause pneumonia; if swallowed generally don’t cause
disease.

34. Number of Invading Microbes
Higher number of pathogens increase the
likelihood of developing disease.
LD50: Lethal dose for 50% of hosts.
Number of microbes that will kill 50% of
inoculated test animals.
ID50: Infectious dose for 50% of hosts.
Number of microbes that will cause a
demonstrable infection in 50% of
inoculated test animals.

35. Adherence
 Attachment between of microbe to host tissue requires:
 Adhesins or Ligands: Surface molecules on pathogen
that bind specifically to host cell surface molecules. May
be located on glycocalyx, fimbriae, viral capsid, or other
surface structure.
 Receptors: Surface molecules on host tissues to which
pathogen adhesins bind.
 Cell Wall Components
 M protein: Found on cell surface and fimbriae of
Streptococcus pyogenes. Mediates attachment an
dhelps resist phagocytosis.
 Waxes: In cell wall of Mycobacterium
tuberculosis helps resist digestion after
phagocytosis.

36.  Enzymes
 Extracellular enzymes (exoenzymes) lyse cells, form or dissolve clots, and dissolve materials in tissue.
 . Leukocidins: Destroy white blood cells that are phagocytes. Produced by staphylococci and
streptococci.
 . Hemolysins: Destroy red blood cells. Produced by clostridium perfringens (gangrene) and
streptococci.
 . Coagulases: Produce blots in blood. Clots may protect bacteria from host immune system, by walling
off site of infection. Produced by some staphylococci.
 . Bacterial Kinases: Break down clots produced by body to isolate infection. Made by streptococci and
staphylococci.
 . Hyaluronidase: Breaks down hyaluronic acid which holds cells together in connective tissue. Made by
some streptococci and gangrene causing clostridia.
 . Collagenase: Breaks down collagen which forms connective tissue of muscles, skin, and other organs.
Produced by several clostridia.
 . Necrotizing Factors: Kill body cells.
 . Hypothermic factors: Decrease body temperature.
 . Lecithinase: Destroys plasma membrane of cells.
 . Proteases: Break down proteins in tissue.
 Penetration into Host Cells
 Invasins: Surface proteins that alter actin filaments of host cell cytoskeleton, allowing microbes to enter
cells.
 Examples: Salmonella typhinurium and E. coli.
 Cadherin: A glycoprotein that bridges junctions between cells, allowing microbes to move from one cell
to another.

37. How Bacterial Pathogens Penetrate
Host Defenses
Capsules
 Increase the virulence of many pathogens.
 Examples: Streptococcus pneumoniae, Klebsiella
pneumoniae, Hemophilus influenzae, Bacillus
anthracis, and Yersinia pestis.
 Resist host defenses by impairing phagocytosis.
 Host can produce antibodies to capsule, which
attach to microbe and allow phagocytosis.

38. Cell Wall Components
 M protein: Found on cell surface and fimbriae
of Streptococcus pyogenes. Mediates attachment
and helps resist phagocytosis.
 Waxes: Cell wall of Mycobacterium tuberculosis
helps resist digestion after phagocytosis.

39. Microbial Enzymes
Extracellular enzymes (exoenzymes) lyse cells, form
or dissolve clots, and dissolve materials in tissue.
 Leukocidins: Destroy white blood cells that are
phagocytes. Produced by staphylococci and streptococci.
 Hemolysins: Destroy red blood cells. Produced by
clostridium perfringens (gangrene) and streptococci.
 Coagulases: Produce clots in blood, which may wall off
site of infection from immune response. Produced by some
staphylococci.
 Bacterial Kinases: Break down clots produced by body to
isolate infection. Made by streptococci and staphylococci.
 Hyaluronidase: Breaks down hyaluronic acid which holds
cells together in connective tissue. Made by some
streptococci and gangrene causing clostridia.

40. Severe gangrene caused by Clostridium perfringens.
Source: Tropical Medicine and Parasitology, 1997
Tissue Damage Caused by Microbial
Enzymes of Clostridium perfringens

41. Microbial Enzymes (Continued)
 Collagenase: Breaks down collagen which forms
connective tissue of muscles, skin, and other organs.
Produced by several clostridia.
 Necrotizing Factors: Kill body cells.
 Hypothermic factors: Decrease body temperature.
 Lecithinase: Destroys plasma membrane of cells.
 Proteases: Break down proteins in tissue.

42. Necrotizing fasciitis with blood filled vesicles.
Source: Perspectives in Microbiology, 1995
Tissue Damage Caused by Enzymes of
Flesh-Eating Streptococcus pyogenes

43. Penetration into Host Cells
Invasins: Surface proteins that alter actin
filaments of host cell cytoskeleton, allowing
microbes to enter cells.
 Examples: Salmonella typhinurium and E. coli.
Cadherin: A glycoprotein that bridges
junctions between cells, allowing microbes to
move from one cell to another.

44. How Bacterial Cells Damage Host Cells
Three mechanisms:
Direct Damage
Toxins*
Hypersensitivity Reactions
* Most bacterial damage is carried out by toxins.
1. Direct Damage
 Some bacteria can induce cells to engulf them (E. coli,
Shigella, Salmonella, and Neisseria gonorrhoeae).
 Microbial metabolism and multiplication kills host cells.
 Other microbes enter the cell by excreting enzymes or
through their own motility.

45. 2. Toxin Production
 Toxins: Poisonous substances produced by microbes.
 Frequently toxins are the main pathogenic factor.
 Toxigenicity: Ability of a microbe to produce toxins.
 Toxemia: Presence of toxins in the blood.
 Toxin effects: May include fever, cardiovascular
problems, diarrhea, shock, destruction of red blood cells
and blood vessels, and nervous system disruptions.
 Of 220 known bacterial toxins, 40% damage eucaryotic
cell membranes.
 Two types of toxins:
 Exotoxins
 Endotoxins

46. Exotoxins versus Endotoxins

47. A. Exotoxins
 Proteins: Enzymes that carry out specific reactions.
 Soluble in body fluids, rapidly transported throughout
body in blood or lymph.
 Produced mainly by gram-positive bacteria.
 Most genes for toxins are carried on plasmids or phages.
 Produced inside bacteria and released into host tissue.
 Responsible for disease symptoms and/or death.
 Cytotoxins: Kill or damage host cells.
 Neurotoxins: Interfere with nerve impulses.
 Enterotoxins: Affect lining of gastrointestinal tract.
 Antibodies called antitoxins provide immunity.
 Toxoids: Toxins that have been altered by heat or
chemicals. Used as vaccines for diphtheria and tetanus.

48. Important Exotoxins
 Diphtheria Toxin: Corynebacterium diphtheriae when infected by a
phage carrying tox gene. Cytotoxin inhibits protein synthesis in
eucaryotic cells. Two polypeptides: A (active) and B (binding).
 Erythrogenic Toxins: Streptococcus pyogenes produces three
cytotoxins which damage blood capillaries, causing a red rash.
 Botulinum Toxins: Produced by Clostridium botulinum. Neurotoxin
that inhibits release of neurotransmitter acetylcholine and prevents
transmission of nerve impulses to muscles, causing flaccid paralysis.
Extremely potent toxins.
 Tetanus Toxin: Produced by Clostridium tetani. A neurotoxin that
blocks relaxation of skeletal muscles, causing uncontrollable muscle
spasms (lockjaw) and convulsions.
 Vibrio Enterotoxin: Produced by Vibrio cholerae. Two polypeptides:
A (active) and B (binding). The A subunit of enterotoxin causes
epithelial cells to discharge large amounts of fluids and electrolytes.
 Staphylococcal Enterotoxin: Staphylococcus aureus produces an
enterotoxin similar to cholera toxin. Other enterotoxins cause toxic
shock syndrome.

49. Rash of Scarlet Fever Caused by Erythrogenic
Toxins of Streptococcus pyogenes

50. Neonatal Tetanus (Wrinkled brow and risus sardonicus)
Source: Color Guide to Infectious Diseases, 1992
Muscle Spasms of Tetanus are Caused by
Neurotoxin of Clostridium tetani

51. Rice-water stool of cholera. The A subunit of enterotoxin causes
epithelial cells to discharge large amounts of fluids and electrolytes.
Source: Tropical Medicine and Parasitology, 1995
Vibrio Enterotoxin Causes Profuse Watery Diarrhea

52. Diseases Caused by Staphylococcal Toxins
Scalded Skin Syndrome Toxic Shock Syndrome

53. Endotoxins
 Part of outer membrane surrounding gram-negative
bacteria.
 Endotoxin is lipid portion of lipopolysaccharides (LPS),
called lipid A.
 Effect exerted when gram-negative cells die and cell
walls undergo lysis, liberating endotoxin.
 All produce the same signs and symptoms:
 Chills, fever, weakness, general aches, blood clotting
and tissue death, shock, and even death. Can also
induce miscarriage.
 Fever: Pyrogenic response is caused by endotoxins.

54. Endotoxins (Continued)
Endotoxins do not promote the formation of
effective antibodies.
Organisms that produce endotoxins include:
 Salmonella typhi
 Proteus spp.
 Pseudomonas spp.
 Neisseria spp.
Medical equipment that has been sterilized may
still contain endotoxins.
 Limulus amoebocyte assay (LAL) is a test used to
detect tiny amounts of endotoxin.

55. Events leading to fever:
Gram-negative bacteria are digested by
phagocytes.
LPS is released by digestion in vacuoles, causing
macrophages to release interleukin-1 (IL-1).
IL-1 is carried via blood to hypothalamus, which
controls body temperature.
IL-1 induces hypothalamus to release
prostaglandins, which reset the body’s
thermostat to higher temperature.

56. Endotoxins and the Pyrogenic (Fever) Response

57. Shock: Any life-threatening loss of blood
pressure.
Septic shock: Shock caused by endotoxins
of gram-negative bacteria.
Phagocytosis of bacteria leads to secretion of
tumor necrosis factor (TNF), which alters the
permeability of blood capillaries and causes them
to lose large amounts of fluids.
Low blood pressure affects kidneys, lungs, and
gastrointestinal tract.

58. Plasmids, Lysogeny, and Pathogenicity
Plasmids: Small, circular pieces of DNA that
are not connected to chromosome and are
capable of independent replication.
R (resistance) factors contain antibiotic
resistance genes.
Other plasmids contain genes for toxins and
pathogenic factors: tetanus toxin,
staphylococcal enterotoxin, E. coli enterotoxin
(heat-labile), adhesins, and coagulase.

59. Bacteriophages:
Can incorporate genetic material into
chromosomal DNA and remain latent (lysogeny).
Bacterial cell can change characteristics (lysogenic
conversion) and produce certain toxins or
pathogenic factors:
Diphtheria toxin
Capsules in S. pneumoniae
Botulinum neurotoxin
Staphylococcal enterotoxin
Cholera toxin.

60. Cytopathic Effects (CPE) of Viruses
Viral infection may result in one or several of the
following cytocidal or noncytocidal effects in
infected cells:
1. Inhibit macromolecular synthesis (DNA, RNA,
protein). Some viruses irreversibly stop mitosis
(herpes simplex virus).
2. Release of lysosomal enzymes, resulting in cell
death.
3. Inclusion bodies: Granules in cytoplasm or
nuclei of infected cells. May contain viral parts.
4. Syncytium: Fusion of several adjacent cells to
form a single giant cell.

61. Cytopathic Effects of Viruses (Cont.)
5. Metabolic changes in host without visibly
damaging infected cells. May increase hormone or
protein production by infected cells, which in turn
affects other cells.
6. Interferon production: Interferon produced by
infected cells, protects neighboring cells from
infection.
7. Antigenic changes on cell surface, causing
destruction of infected cells by immune system.
8. Chromosomal changes: Breakage and
incorporation of oncogenes.
9. Transformation: Abnormal cells that have lost
contact inhibition.

62. Microbial Mechanisms of Pathogenicity:
How Microorganisms Cause Disease

63. Initiation of Disease
contact with pathogenic organism:
human to human, animal to human

64. Transmission
• Aerosols to respiratory mucosa
• Fomite to nasopharyngial or conjungtive
mucosa
• Fecal – Oral Route
• Mucosal surface to mucosal surface

65. Transmission
Multiplication
Dissemination
Invasion
Breach of epithelium
Colonization of mucosa
Infectious Disease Cycle
or
Attachment to target cells
to subepithelial or intracellular space
Evasion of
host defense

66. Adherence/Attachment
Specific Adherence Non-specific Adherence
• Receptor-mediated adhesion • Hydrophobic/lipophilic-
mediated adhesion
•Hydrophobic struture on
microbial cell envelope
•Lipophilic area on host cell
membrane

67. Specific Adherence
Bacterial
Viral
Fimbrial
Afimbrial
Microbial adhesin Host cell receptor
Herpes simplex 1 virus Epithelial cells of skin and mucosa
glycoproteins B, C and D heparin sulfate
Measles virus Epithelial, endothelial cells, mononcytes-
macrophages (and others)
hemagglutinin (H) protein CD46
Uropahogenic E coli Epithelial cell
P-pili glycolipid receptor globobiose
fibronectin binding protein
Staphylococcus aureus
fibronectin receptor integrin
Epithelial, endothelial, fibroblastic cells

68. Invasion
bacterial viral
•Transcytosis across superficial
epithelium to subepithilial space
•Induce engulfment by non-
phagocytic host cells
•Local reararrangement of host
cell cytoskeleton
•Phagocytosis
•Utilization of membranous cell
gateway
•Pass through plasma membrane
•Membrane invagination
•Clathrin
•Fusion with host cell plasma
membrane
•HIV gp120/41
•T lymphocyte CD4
•Macrophage CCR5

69. Evasion/Manipulation of Host Defense
• Modulation of innate/inflammatory response
• Resistance to phagocytic killing in subepithelial space
• Serum resistance
• Antigenic variation

70. Modulation of Innate/Inflammatory Response
Adhesin-directed degranulation of mast cells
E. coli bound to mouse mast cell
mast cell
histamine
proteoglycans
cytokines
degranulation

71. Resistance to phagocytic killing in subepithelial space
• Survive within phagocyte
• Inhibit phagocyte mobilization :(chemotaxis, complement activation)
Inhibit chemoattractants: Streptococcus pyogenes degrades C5a
Inhibit chemotaxis: Pertussis toxin causes intracellular rise in cAMP in
neutrophils to impair chemotaxis
• Avoid ingestion
kill phagocytes: Streptolysin O lyses PMNs; Staphylococcus
aureus alpha, beta and gamma toxins and leucocidin lyses
PMNs
capsular protection from opsonization: M proteins,
Streptococcus pyogenes
Bacterial capsules that resemble self: Neisseria meningitidis
(sialic acid); Streptococcus pyogenes (hyaluronic acid)

72. Survival within phagocyte
Escape endosome or phagolysosome:
- Shigella, Listeria monocytogenes
Inhibit phagosome-lysosome fusion
- Legionella pneumophila, Mycobacterium tuberculosis, Salmonella
Survive within phagolysosome (resist enzymatic degration
or neutralize toxic products)
- Inactivate reactive oxygen species: Salmonella, via superoxide
dismutase, catalase, recA
- Resist antimicrobial peptides: Host cationic peptides complexed with
SapA peptide

73. Serum
Resistance
complement
resistance
covalent binding
of activated sialic
acid
LPS galactose
residue
N. gonorrhoeae
changes to
carbohydrate
portion of lipo-
oligosaccharide
prevent insertion
of C9 complex
into outer
membrane
long O-side chains
of LPS
outer membrane
protein Rck
Salmonella
inhibit deposition
of C3
incorporate host
plasma proteins
(decay accelerating
factors) into
membrane
Schistosoma
mansoni
prevent C3
convertase
formation
sialic acid in LPS O
antigen
hydrolyzing
enzymes
intracellular
lifestyle
inhabit blood cells
to avoid exposure
to humoral
factors
(e.g.complement)
PMN cells
lymphocytes
macrophages
red blood cells
Staphylococci
HIV
Mt
Plasmodiumium

74. Antigenic variation
Phase variation Genetic variation
Transmission of genetic information via
mobile genetic elements
Gene recombination
- Pili genes: Neisseria gonorrhoeae
Gene reassortment
- Influenza viruses A, B, C
High mutation rate
- RNA virus: Influenza viruses A, B, C
Recombination of replication products
- DNA virus: terminal redundancy in
linear genome
VSG in Trypanosoma brucei

75. Cell and Tissue Damage
• Induction of apoptosis and necrosis
• Virus-induced cytopathic effect
• Induction of damaging host immune response

76. Induction of apoptosis
Phase variation Genetic variation
Transmission of genetic information via
mobile genetic elements
Gene recombination
- Pili genes: Neisseria gonorrhoeae
Gene reassortment
- Influenza viruses A, B, C
High mutation rate
- RNA virus: Influenza viruses A, B, C
Recombination of replication products
- DNA virus: terminal redundancy in
linear genome
VSG in Trypanosoma brucei

77. Induction of Cell Death
Induction of apoptosis Induction of necrosis
Virus-induced apoptosis:
HIV (CD4+ T cell), EBV, adenoviris
Interfere with cellular regulation of cAMP
-Bordetella pertussis (macrophage)
Activation of caspase-1
Salmonella (macrophages, DC)
SipB binds and activates caspase-1
Sigella flexneri (macrophages)
Invasion Plasmid antigen B (IpaB)
binds and activates host caspase-1
Bacterial toxins:
Diptheria A-B toxin

78. Cell lysis
accumulation of reactive
oxygen intermediates
macrophages
viruses
accumulation of nitrogen
intermediates
accumulation of intracellular
calcium
Rotavirus,
cytomegalovirus, HIV
Syncytia
formation
Paramyxoviruses
(respiratory syncytial
virus, parainfluenza
viruses, measels virus,
herpesvirus, some
retroviruses)
viral-encoded
fusion proteins
Virus-Induced Cytopathic Effect: Part 1

79. production of
eosinophilic or
basophilic
inclusion
bodies
viruses
host cell
transformation
DNA viruses
Burkitt's
lymphoma
(EBV)
inactivation of p53 and Rb,
chromosomal destabilization,
enhancement of foreign DNA
integration and mutagenecity
cervical
carcinoma
(human
papilloma
viruses)
retroviruses
adult T-cell
leukemia
(human T-cell
lymphotropic
virus type 1)
Virus-Induced Cytopathic Effect: Part 2

80. Induction of Damaging Host Immune Response
autoimmune
response
cross-reactivity between self
and mycobacterial heat shock
proteins
cross-reactivity between
components of endocardium
and joint synovial membrane
molecules and antigens in the
streptococcus cell wall
Acute rheumatic
fever after group A
streptococcal
pharyngitis
hypersensitivity
reactions
granuloma
formation
Mycobacterium
tuberculosis
septic
shock/sepsis
bacteria
LPS, peptidoglycan,
lipoteichoic acid,
toxins acting as
superantigens
toxic shock

81. Bacterial virulence factors
Many factors determine the virulence
of bacteria, or their ability to cause
infection and disease.

82. Toxins
Toxins produced by bacteria are
generally classified into two groups:
–exotoxins
–endotoxins

83. Endotoxins of gram-negative
bacteria
The endotoxins of gram-negative bacteria are
derived from bacterial cell walls and are often
liberated when the bacteria lyse.
The substances are heat-stable and can be
extracted (e.g. with phenol-water).

84. Pathophysiological effects of endotoxins
are similar regardless of their bacterial
origin:
–fever
–leukopenia
–hypotension
–impaired organ perfusion and acidosis
–activation of C3 and complement cascade
–disseminated intravascular coagulation
(DIC)
–death

85. Exotoxins
Many gram-positive and gram-negative
bacteria produce exotoxins of considerable
medical importance.
Some of these toxins have had major role in
world history (e.g. toxin of Clostridium tetani).

86. Diphtheria toxin
(toxin of Corynebacterium diphtheriae)
Corynebacterium diphtheriae strains that carry a
temperate bacteriophage with the structural gene
for the toxin are toxigenic and produce diphtheria
toxin.
This native toxin is enzymatically degraded into
two fragments: A and B, linked together by a
disulfide bound. Both fragments are necessary for
toxin activity.

87. Tetanospasmin (toxin of Clostridium tetani)
Clostridium tetani is an anaerobic gram-positive rod
that is widespread in the environment.
Clostridium tetani contaminates wounds, and the
spores germinate in the anaerobic environment of the
devitalized tissue. The vegetative forms of Clostridium
tetani produce toxin tetanospasmin. The released toxin
has two peptides linked by disulfide bounds. Toxin
reaches the central nervous system by retrograde
transport along axons and through the systemic
circulation. The toxin acts by blocking release of an
inhibitory mediator in motor neuron synapses. The
result is initially localized then generalized, muscle
spasms. Extremely small amount of toxin can be lethal
for humans.

88. Botulotoxin (toxin of Clostridium botulinum)
Clostridium botulinum is found in soil or water and may
grow in foods if the environment is appropriately
anaerobic.
An exceedingly potent toxin (the most potent toxin
known) is produced by Clostridium botulinum strains. It
is heat-labile and is destroyed by sufficient heating.
There are eight disctinct serological types of toxin.
Types A, B and E are most commonly associated wih
human disease. Toxin is absorbed from the gut and
carried to motor nerves, where it blocks the release of
acetylcholine at synapses and neuromuscular
junctions. Muscle contraction does not occur, and
paralysis results.

89. Toxins of Clostridium perfringens
Spores of Clostridium perfringens are introduced
into the wounds by contamination with soil or
faeces. In the presence of necrotic tissue (an
anaerobic environment), spores germinate and
vegetative cells produce several different toxins.
Many of these are necrotizing and hemolytic and
favour the spread of gangrene:
– alpha toxin is a lecithinase that damages cell membranes
– theta toxin also has a necrotizing affect
– and other

90. Streptococcal erythrogenic toxin
Some strains of hemolytic lysogenic streptococci
produce a toxin that results in a punctate
maculopapular erythematous rash, as in scarlet
fewer.
Production of erythrogenic toxin is under the
genetic control of temperate bacteriophage. If the
phage is lost, the streptococi cannot produce
toxin.

91. Toxic shock syndrom toxin - 1 (TSST-1)
Some Staphylococcus aureus strains growing on
mucous membranes (e.g. on the vagina in
association with menstruation), or in wounds,
elaborate TSST-1.
Although the toxin has been associated with toxic
shock syndrome, the mechanism of action in
unknown.
The illness is characterized by shock, high fewer, and
a diffuse red rash that later desquamates, multiple
other organs systems are involved as well.

92. Exotoxins associated with
diarrheal diseases
Vibrio cholerae toxin
Staphylococcus aureus enterotoxin
Other enterotoxins - enterotoxins are also
produced by some strains of:
– Yersinia enterocolitica
– Vibrio parahaemolyticus
– Aeromonas species

93. Enzymes
Many species of bacteria produce enzymes that are not
intrinsically toxic but play important role in the infectious
process.
Collagenase:
– degrades collagen, the major protein of fibrous
connective tissue, and promotes spread of infection in
tissue.
Coagulase:
– Staphylococcus aureus produce coagulase, which
works in conjuction with serum factors to coagulate
plasma. Coagulase contributes to the formation of
fibrin walls around staphylococcal lesions, which helps
them persist in tissues.

94. Enzymes
Hyaluronidases:
– enzymes that hydrolyze hyaluronic acid, a constituent of
the ground substance of connective tissue. They are
produced by many bacteria (e.g. staphylococci,
streptococci and anaerobes) and aid in their spread
through tissues.
Streptokinase:
– many hemolytic streptococci produce streptokinase
(fibrinolysin), substance that activates a proteolytic
enzyme of plasma. This enzyme, also called fibrinolysin, is
then able to dissolve coagulated plasma and probably aids
in the spread of streptococci through tissues. Streptokinase
is used in treatment of acute myocardial infarction to
dissolve fibrin clots.

95. Enzymes
Hemolysins and leukocidins:
– Many bacteria produce substances that are
cytolysins - they dissolve red blood cells
(hemolysins) or kill tissue cells or leukocytes
(leukocidins).
– Streptolysin O, for example, is produced by
group A streptococci and is letal for mice and
hemolytic for red blood cells from many animals.

96. Antiphagocytic factors
Many bacterial pathogens are rapidly killed once they
are ingested by polymorphonuclear cells or
macrophages.
Some pathogens evade phagocytosis or leukocyte
microbidical mechanisms by adsorbing normal host
componets to their surfaces.
For example, Staphylococcus aureus has surface
protein A, which binds to the Fc portion of IgG. Other
pathogens have surface factors that impede
phagocytosis e.g. Streptococcus pneumoniae and many
other bacteria have polysaccharide capsules.

97. Adherence factors
Once bacteria enter the body of the host, they
must adhere to cells of a tissue surface. If they do
not adhere, they would be swept away by mucus
and other fluids that bathe the tissue surface.
Adherence (which is only one step in the infectious
process) is followed by development of
microcolonies and subsequent complex steps in
the pathogenesis of infection.

98. Adherence factors
The interactions between bacteria and
tissue cell surfaces in the adhesion process
are complex.
Several factors play important role:
– surface hydrophobicity
– binding molecules on bacteria and host cell
receptor interaction
– and other