BIO 580 Medical Microbiology Unit 2 – Conflicts 1
UNIT TWO – CONFLICTS BETWEEN MICROBES AND HOST
Unit Two – Outline of Topics
I. Entry, Exit, and Transmission
A. Overview
B. Specifics of entry, exit, & transmission
1. Skin
2. Respiratory Tract - nose, trachea, bronchi, lungs
3. Gastrointestinal – Stomach + Intestines
4. Urogenital - Urinary + Genital
5. Oropharynx – mouth; throat
II. Microbial strategies to avoid host nonspecific defenses
A. Avoiding destruction by complement
B. Avoiding interferon
C. Avoiding destruction by phagocytes
III. Microbial Spread and Replication
A. Surface Infections = Local Infections
B. Systemic Infections
1. Spread along lymphatics
2. Spread through the blood
3. Spread from blood to internal tissues
4. Spread from blood to brain
5. Spread along nerves
IV Microbial Strategies to Avoid Specific Defenses
A. Prevent or delay recognition of pathogen antigens
B. Antigenic variation
C. Immunosuppression
D. Persistent infections
V. Pathological Consequences of Infection
A. Pathology caused by the microbe
B. Pathology caused by the immune response to the microbe
1. Pathology resulting from Nonspecific immune defenses
2. Pathology resulting from Specific immune defenses
BIO 580 Medical Microbiology Unit 2 – Conflicts 2
UNIT TWO –Terminology that will be encountered during lecture but not defined
Using a medical dictionary, define:
“acutely ill”
Nuchal rigidity –
Chronic granulomatous disease (CGD) –
Febrile –
Petechiae
Polyarthritis –
Myalgia –
Dyspnea –
Diaphoresis Erythrocyte sedimentation rate (ESR) –
And what is a normal ESR for children? –
Sequela –
Arthralgia
Anorexia
Somnolesence
Rigor
Incubation period –
Pyogenic Pyrogenic –
BIO 580 Medical Microbiology Unit 2 – Conflicts 3
UNIT 2 – CONFLICTS BETWEEN MICROBES AND HOST
Response to Infection – Biologic response gradient
I. ENTRY, EXIT, AND TRANSMISSION
Objectives:
1. know the first line host defenses of each of the 5 systems
2. explain how microbes enter each of the 5 systems
3. what is one of the most important mechanisms for establishment at each site of entry?
4. describe how microbes exit each system
A. OVERVIEW
Some microbes live on body surfaces
Ex. normal skin microbiota like Staphylococcus epidermidis, diphtheroids.
Also some pathogens - Vibrio cholera, Campylobacter jejuni
1. Entry into host
a. Active penetration - invasive
Ex 1. S. epidermidis is not invasive but S. aureus is
Ex 2. Shigella invades epithelial cells of colon - Salmonella invades small intestinal epithelial
cells.
b. Insertion - by biting insect
Exs.
Organism
Plasmodium
Rickettsia typhi
Yersinia pestis
Yellow fever virus
Disease
malaria
typhus
plague
yellow fever
Insect vector
mosquito
rat flea
rat flea
mosquito
c. Break (bite, puncture, burn)
Exs. Pasteurella multocida, rabies virus, Clostridium tetani.
d. Impairment - of surface or systemic defenses
Ex. disorders of phagocytic cells  ↑infections
BIO 580 Medical Microbiology Unit 2 – Conflicts 4
Attachment to target cell - aided by specific receptors
After attaching:
1. remain on outside of cell & multiply on the surface of the cell – Ex. Vibrio
2. enter cell & multiply w/in it – Exs. Shigella, Salmonella, viruses
2. Exit and Transmission
a. Exit body
1) shed - secretions - resp. droplets, saliva, semen, feces
2) sucked out of blood - insects
b. Successful transmission to new host
depends on:
1) number of microbes shed - the more the better
2) stability in the environ. - cysts, spores, naked viruses
3) number of individuals required to infect a new host - varies - Shigella 1-10, Salmonella 106
The most common infections are spread via:
 respiratory route (Exs. colds, influenza)
 fecal-oral route (Ex. diarrheal diseases like Giardia)
 sexual transmission (Ex. gonorrhoea)
 needles - a new mech (Exs. HIV, Ebola, hepatitis B)
BIO 580 Medical Microbiology Unit 2 – Conflicts 5
B. SPECIFICS OF ENTRY, EXIT, AND TRANSMISSION
1. Skin
Rev. of defenses of the skin
Some pathogens can live on non-living layer of skin - Ex. fungi called Dermatophytes
a. Entry across skin barrier
1. break - wound/bite/burn
2. biting insect
3. hair follicles
Ex. S. aureus - lipase, some strains  toxin called exfoliatin - separates layers of dermis
b. Exit & Transmission from skin
Direct contact between infected hosts
viruses: Exs. human papilloma virus (genital warts), herpes, chicken pox
bacteria: Exs. pathogenic staphylococci & streptococci, Treponema pallidum
dermatophytes: athletes foot, ringworm
protozoa: Leishmania
BIO 580 Medical Microbiology Unit 2 – Conflicts 6
2. Respiratory Tract - nose, trachea, bronchi, lungs
a. Entry to RT
Transmission – person to person via respiratory droplets or fomites/fingers
Fate of droplet depends on the size of droplet particle:
Particle diameter
> 10 micrometers
5-10 micrometers
< 5 micrometers
Where it lands
URT: nose, throat
Bronchioles
Alveolar region
Defenses against entry
1. nasal hairs (vibrissae)
2. mucus (containing lysozyme, phagocytes, lactoferrin, maybe antigen specific sIgA)
3. ciliary action
4. cooler temperature (33°C vs 37°C)
Pathogens avoid these defenses
1. attach tightly - Exs. Bordetella pertussis, Neisseria meningitidis, Influenza virus, cold viruses
2. take advantage of dame to muco-ciliary clearance – Streptococcus pneumoniae
3. produce toxin to interfere with ciliary activity - Exs. Bordetella pertussis, Haemophilus
influenzae, Pseudomonas aeruginosa, Mycoplasma pneumoniae
4. inhaled directly into lungs
main defense of lungs - complement, alveolar macrophages, maybe antigen specific sIgA
and IgG
Mycobacterium tuberculosis
b. Exit & Transmission from RT
Cause increase in secretions
inflammation  vas. permeability  fluid  *sneezing
coughing
talking
easily spread because of crowding
dry air impairs mucociliary action (also smoke, alcohol)
from one person’s respiratory tract directly into another's
BIO 580 Medical Microbiology Unit 2 – Conflicts 7
3. Gastrointestinal – Stomach + Intestines
a. Entry to GI
Transmission – fecal-oral route (includes fecal – water/food – oral)
Defenses of GI
1. acid of stomach
2. dense normal microbiota
3. peristalsis, mucus (lysozyme, phagocytes, sIgA)
4. proteolytic enz, bile
5. gut associated lymphoid tissue (GALT)
Pathogens avoid these defenses
1. motility - Exs. V. cholera, Salmonella, some E. coli
2. mucinase - Ex. V. cholera
3. attachment
a. via specific receptors Exs. V. cholerae, rotavirus; Shigella vs. Salmonella
b. mechanical Exs. Giardia lamblia trophozoites, hookworms
4. survive in presence of acid, proteolytic enzymes, bile Exs. Streptococcus faecalis, Salmonella
b. Exit and Transmission from GI
feces
Exs. cysts (Giardia, Cryptosporidium), naked viruses (rotavirus, poliovirus)
BIO 580 Medical Microbiology Unit 2 – Conflicts 8
4. Urogenital - Urinary + Genital
a. Entry to bladder and/or urethra
Transmission – via self-inoculation
Urine in the bladder is normally sterile
Defenses of bladder and lower UT
1. voiding urine
2. phagocytes
3. sIgA
Invaded from the exterior- via the urethra = ascending infection
Pathogens avoid these defenses
1. specialized attachment mechs - fimbriae - Exs. E. coli Neisseria gonorrhoeae, Chlamydia trachomatis
Spread from urethra  bladder - is difficult in males - urethra is 20 cm long
UTI in females are common - 14X greater - 20% get symptomatic UTI - urethra is very short - 5cm
Defenses of female reproductive organs
1. downward flow of mucus (lysozyme, phagocytes)
2. ciliated epithelial cells
3. normal microbiota – esp. lactobacilli, 108/ml in adult female - pH 5
b. Exit and Transmission from Urogenital
transmission via contaminated urine NOT common
Exceptions - leptospira, Lassa virus (rodent urine)
*direct mucosal contact - STI
enhances transmission:
discharge - gonorrhea, chlamydia
sores -syphilis, herpes simplex
BIO 580 Medical Microbiology Unit 2 – Conflicts 9
5. Oropharynx - mouth; throat
a. Entry to oropharynx
Transmission via ingestion, hand-mouth, mouth-mouth
Defenses of oropharynx
1. cleansing mechs - flushing action of saliva
2. lysozyme
3. phagocytes
4. sIgA
5. normal microbiota
Pathogens avoid defenses
1. Attachment - fimbriae
b. Exit and Transmission from oropharynx
1. Saliva - Ex. streptococci
some infection of salivary glands - Exs. EBV (mono) mumps, herpes
SUMMARIZE COMMON THEMES:
What aids in establishment at a site of entry?
What factors encourage transmission of microbes to new hosts?
BIO 580 Medical Microbiology Unit 2 – Conflicts 10
II. MICROBIAL STRATEGIES TO AVOID HOST NONSPECIFIC DEFENSES
Complement, interferon, phagocytosis
Objectives:
1. Understand that successful pathogens have evolved strategies to avoid nonspecific defenses
2. Explain how these pathogen avoidance strategies work.
3. Understand the significance in particular of anti-phagocytic strategies.
A. AVOIDING DESTRUCTION RESULTING FROM ACTIVATION OF COMPLEMENT
Several exs. of strategies to prevent formation of MAC
1. capsules prevent activation of alternate pathway
Ex. S. pneumoniae, Klebsiella
2. coating w/ IgA prevents activation of classical complement
Ex. Campylobacter
3. prevent stabilization of C3 convertase and resulting cascade
Ex. Pathogenic streptococci & Campylobacter
4. degrade C3b & C5b before cell binding
Ex. N. meningitidis, Y. pestis
5. bud off membrane bound C3b & C5b so MAC doesn’t form
6. long chains of polysaccharides prevent MAC formation
Ex. strains of Salmonella
B. AVOIDING INHIBITION BY INTERFERON


poor inducers of interferons – hepatitis B
block action of interferons – hepatitis B, HIV, EBV
BIO 580 Medical Microbiology Unit 2 – Conflicts 11
C. AVOIDING DESTRUCTION BY PHAGOCYTES – very important pathogen strategies!!
1. Inhibit chemotaxis or mobilization of phagocytes
a. toxins that suppress chemotaxis
Ex. Streptococcus, Clostridium perfringens
2. prevent/delay contact with phagocyte
a. capsules
Ex. esp. pathogenic streptococci, Haemophilus influenzae, Klebsiella pneumoniae, many
others
b. fimbriae
Ex. pathogenic neisseria
c. M protein
Ex. S. pyogenes
d. FcR
Ex. Staphylococcus aureus Protein A & S. pyogenes Protein G, herpes group viruses
induce FcR on surface of infected cell
3. Escape from phagosome into cytoplasm
Ex. Shigella, Listeria monocytogenes, Mycobacterium leprae, Trypanosoma cruzi
4. Prevent fusion of lysosome with phagocytic vacuole
Ex. M. tuberculosis, Salmonella typhimurium, Toxoplasma gondii
5. Resist killing and digestion in phagolysosome
Ex. L. monocytogenes, Yersinia pestis, S. typhimurium, reoviruses are actually stimulated
to uncoat by lysosomal enz.
6. Resist oxygen-dependent killing
Ex. M. tuberculosis prevents respiratory burst, M. leprae scavenges ROI
Ex. catalase – staphylococci, L. monocytogenes
7. Kill the phagocyte
Ex. hemolysins of pathogenic streptococci and staphylococci, L. monocytogenes
Ex. Lethal factor of Bacillus anthracis
BIO 580 Medical Microbiology Unit 2 – Conflicts 12
CONCEPT CHECK 5
Neisseria meningitidis (one causative agent of bacterial meningitis) is carried, apparently
harmlessly, in the respiratory tracts of approximately 20% of the population (estimates vary). 1)
Explain how, in general, respiratory tract pathogens are acquired, 2) List the defenses (defenses
against entry and then nonspecific interior defenses) of the respiratory tract that would be
relevant to bacterial infections, and 3) Discuss the strategies that specifically N. meningitidis has
evolved that allows it to avoid the nonspecific defenses of the upper RT.
BIO 580 Medical Microbiology Unit 2 – Conflicts 13
III. REPLICATION AND SPREAD OF MICROBES IN THE HOST
Objectives:
1. Know some of the general differences between local infections and systemic infections
2. Understand the various mechanisms by which microbes can spread from the site of entry to
other systems in the body
There are 2 basic categories of infections - surface infections and systemic infections.
A. SURFACE INFECTIONS = Local Infections




Many microbes multiply at the site of entry and don't invade deeper into tissue or spread
to other systems in the body.
Surface or local infections spread easily on mucosal surfaces (intestinal, respiratory).
Surface infections often result in large scale production and movement of body fluids.
This large scale movement of fluid can spread an infection very quickly (large areas of
the body surface can be involved within a few days).
General Characteristics of Surface Infections:
1. Short incubation times - less than 1 week.
2. Microbes are replicate very rapidly
3. Nonspecific defenses are key to control - the early nonspecific defense mechanisms;
complement activation, interferon, phagocytosis, and NK cells are key to controlling the
infection - no time to wait for specific defenses to activate.
Ex. Common cold, Gastroenteritis, Gonorrhea
B. SYSTEMIC INFECTIONS

Some microbes enter the lymph fluid or blood and then spread through the body
involving more than one system.
General Characteristics of Systemic Infections:
1. Longer incubation times, greater than 1 week. (Ebola virus, 12-21 days incubation;
incubation for HIV is years.)
2. Microbes replicate more slowly
3. Specific defenses (activated Tc, antibodies) are key to control - because of longer
incubation times, there is time for specific defenses to activate and play a role in
controlling infection.
EX. Measles, Typhoid fever, Tuberculosis
BIO 580 Medical Microbiology Unit 2 – Conflicts 14
1. What keeps surface infections from spreading deeper?
a. Temperature - Ex. Rhinovirus- upper respiratory tract is 33°C, lower respiratory tract is
37°C. Rhinovirus don’t replicate well at 37ºC.
b. Mechanism of exiting the infected cell - Ex. Influenza virus spreads through free surface
of epithelial cells but not through the basal surface.
2. Why do some microbes take the risk of spread through the blood and lymph where they will
encounter the full force of the immune system?
Ex. Mumps virus- enters via inhalation but multiplies in salivary glands. Ex. Hepatitis A
virus enters the GI via ingestion, but it replicates in the liver. How would it get from the
intestines to the liver? It needs to travel through the blood.
Systemic Infections often follow a stepwise invasion of different tissues of the body.
1. Spread along the Lymphatics
Many bacteria that spread along the lymphatic route induce significant signs of inflammation.
For example, a minor skin wound followed by red streaking and tender swollen local lymph
nodes are classical signs of inflamed lymphatic vessels.
The bacteria secrete toxins or cause other forms of tissue damage that early on in the course of
infection set off alarm bells to cause acute inflammation and alert the nonspecific interior
defenses. In general, bacterial spread is accompanied by inflammation - bacterial spread is noisy.
In contrast to bacteria, many viruses can invade along the lymphatics without inducing
inflammation, they are silent. Viruses cause little tissue damage early in the course of infection
so inflammatory responses are absent or delayed. EBV- (infectious mono) - may be present for
weeks before any inflammatory responses are activated. And some viruses can infect cells for
long periods of time before they damage them.
BIO 580 Medical Microbiology Unit 2 – Conflicts 15
2. Spread through the Blood
A microbial infection might be arrested at any point during lymphatic spread. But microbes that
can evade phagocytosis or multiply within the lymph nodes will ultimately reach the blood
stream, because movement from one system into the other is easy (see part (a) of picture below).
Small numbers of bacteria can enter the blood without causing damage. Transient bacteremias,
bacteria in the blood, are common.
What happens to microbes moving through the blood is related to:
1. whether they are free in the plasma where they are exposed to phagocytes and antibodies, or
2. whether they are intracellular in circulating cells, like erythrocytes, monocytes, lymphocytes,
where they can escape immune detection – this is a more successful strategy. Exs: EBV and
Listeria are intracellular in monocytes or lymphocytes, malaria in erythrocytes, Salmonella
and Leishmania in macrophages.
Microbes may leave the circulation and enter other body sites as the blood flows through these
tissues/organs.
BIO 580 Medical Microbiology Unit 2 – Conflicts 16
3. Spread from Blood to Internal Tissues
Sometimes free bacteria that enter the blood have the opportunity to colonize internal sites that
are less well protected before being eliminated by phagocytes.
Ex. (add notes)
4. Spread from Blood into Brain
There is a barrier between the blood and the cerebral spinal fluid and between the blood and
brain that is impervious to most microbes (this barrier is called the Blood-Brain Barrier (BBB
But there are some microbes that can cross the
blood-brain barrier and gain access to the CSF
or brain. Often these microbes induce
inflammation that makes the BBB more
permeable. Infections of the CNS are
especially dangerous as the BBB also keeps
out most host immune cells and drugs. – Exs.
Neisseria meningitidis, Haemophilus
influenzae- cause increased permeability of
BBB and cross over into the brain.
BIO 580 Medical Microbiology Unit 2 – Conflicts 17
5. Spread along Nerves
Some microbes can spread along nerve networks. There are few if any host defenses to control,
especially viral, spread once the nerves are infected.
Exs
herpes simplex is never eliminated
varicella-zoster is never eliminated
Rabies is never eliminated and is 100% fatal
Covered in more detail in Unit 3, Diseases of the NS.
BIO 580 Medical Microbiology Unit 2 – Conflicts 18
CONCEPT CHECK 6
Neisseria meningitidis enters the host via the nasopharynx, but invasive strains cause the disease
bacterial meningitis when they infect the meninges of the brain. Discuss how N. meningitidis
moves step-wise through the body from the nasopharynx to the meninges of the brain.
BIO 580 Medical Microbiology Unit 2 – Conflicts 19
IV MICROBIAL STRATEGIES TO AVOID SPECIFIC DEFENSES
Objectives:
1. Understand the significance of pathogen avoidance strategies in relation to replication and
spread, pathology, and transmission.
2. Explain the potential consequences to the host of microbial mimicry.
3. Discuss the significance of antigenic variation.
4. Explain, in detail, the 3 mechanisms that produce antigenic variation
A. PATHOGEN PREVENTS OR DELAYS RECOGNITION OF ITS ANTIGENS
1. Pathogen colonizes “privileged” sites
a. external sites – skin & intestinal lumen
b. internal sites - CNS, joints, testis, and placenta
c. pathogen-created sites – cysts – Ex. Echinococcus
d. integrate in to cell’s DNA – Ex. retroviruses
2. Pathogen is intracellular
a. does not display antigens on cell surface – Ex. herpes
b. puts proteins on an internal membranes – Ex. coronavirus
c. prevents MHC + antigen traffic to cell surface – ex. adenovirus
3. Pathogen’s antigens are very similar to host antigens = mimicry – immune response may
be weak or absent – Ex. scrapie (PrPS is similar to PrPC)
Does NOT always prevent immune detection and pathological consequences.
Example – Association between Streptococcus pyogenes and rheumatic heart disease
(take good notes here)
BIO 580 Medical Microbiology Unit 2 – Conflicts 20
4. Pathogen covers surface with host molecules (camouflage)
a. antibody molecules absorbed via FcR – bacteria and viruses
b. fibrin – coagulase-positive staphylococci
c. host blood group glycoproteins + MHC molecules + antibodies – parasitic worms
5. Pathogen induces a lack of responsiveness to its antigens
a. infection of the fetus – Ex. CMV, rubella
b. produce large quantities of antigen or antigen-antibody complexes and desensitize
immune response– Ex. fungal and protozoan infections
c. exploit gaps in immune response
B. ANTIGENIC VARIATION - change surface Ag presented to host immune



Occurs in the antigens that are recognized by the immune response
More common in long-lived hosts
More common in infections that have short incubation times and pathogen is transmitted
before a secondary response would come to full force.
1. Antigenic variation may occur in a given individual during an infection.
Ex - Trypanosoma, Neisseria, Influenza virus
2. Antigenic variation may occur as the pathogen circulates through the community of hosts
Ex – Poliovirus, Influenza virus
3 main mechanisms that produce antigenic variation:
1. mutation
2. recombination
3. gene switching
BIO 580 Medical Microbiology Unit 2 – Conflicts 21
1. mutation – single base substitutions  subtle changes in surface antigens = antigenic drift.
Exs. rhinovirus, enterovirus, poliovirus, HIV
**Ex. Influenza virus –hemagglutinin and neuraminidase surface proteins
Neuraminidase
Hemagglutinin
entry into cell
RNA genome – 8 segments
Single base mutations in RNA produce slight changes in H that gradually
accumulate year to year = antigenic drift
Seasonal flu epidemics
BIO 580 Medical Microbiology Unit 2 – Conflicts 22
2. recombination of genes  major changes in surface proteins = antigenic shift.
**Ex. influenza A viruses – segments of RNA from human and animal strains recombine
(also known as reassortment)
Human strain
Animal strain
Co-infecting a single host target cell
From the
animal
strain
Recombination leads to a sudden and total change in surface protein = antigenic shift
Pandemic
BIO 580 Medical Microbiology Unit 2 – Conflicts 23
3. gene switching - most dramatic change in antigen
Exs. Trypanosoma - 1000 different genes coding for surface glycoprotein - sequence of
totally unrelated infections.
Neisseria gonorrhoeae – genes coding for pilin and outer membrane proteins.
Time 
BIO 580 Medical Microbiology Unit 2 – Conflicts 24
D. IMMUNOSUPPRESSION
1. Infection of the immune cells  blocking of immune cell function.
Exs.
T cells - HIV, measles virus
B cells – EBV
Macrophages – HIV, CMV, Leishmania
2. Upset coordination of immune regulation
a. polyclonal activation of T or B cells  production of lots of cytokines - upset the
balance. Ex – staphylococci
b. inhibit T cell proliferation. Ex - glycoproteins on the surface of the envelope of HIV.
c. inhibit IL-2 production
d. induce Tregs
3. interfere with local immune defenses.
a. IgA protease. Ex - Neisseria, Streptococcus pneumoniae, Haemophilus influenzae
(remember as Nice STriP of Ham)
E. PERSISTENT INFECTIONS - remain in the host in a persistent state for many years, or
even for the life time of the host.
1. infectious form – hepatitis B in blood
2. low or partial infectivity – adenovirus in tonsils
3. non-infectious form – herpes virus in dorsal root ganglion
Significance of persistence:
1. can be reactivated, usually when host is immunocompromised. Ex – herpes viruses
2. associated with chronic disease of organs like liver. Ex – hepatitis viruses
3. associated with cancer. Exs. – hepatitis, human papilloma virus
BIO 580 Medical Microbiology Unit 2 – Conflicts 25
CONCEPT CHECK 7
The virulence of many viruses is attributable, at least in part, to their ability to evade the body’s
immune defense systems. Viruses exhibit diverse mechanisms for subverting the immune
defenses. Discuss how the human immunodeficiency virus (HIV) evades the host’s specific
immune defenses.
DISCUSSION
Discuss the mechanism of antigenic drift in Influenza viruses.
Discuss the mechanism of antigenic shift in Influenza A viruses.
BIO 580 Medical Microbiology Unit 2 – Conflicts 26
V. PATHOLOGICAL CONSEQUENCES OF INFECTION
Objectives:
1.
2.
3.
4.
5.
6.
7.
Know the various ways that microbes can directly affect the cells/tissues of a host
Contrast exotoxins and endotoxins
List the 4 modes of action of exotoxins and be able to discuss examples of each
Understand the physiological responses of the host to the presence of endotoxin in the body
Recognize the physiological responses to LPS as part of a clinical presentation of a disease
Discuss, in detail, how microbial infections result in fever
Compare and contrast two example lung infections; pneumonia and tuberculosis and the
bacteria that cause them.
A. PATHOLOGY CAUSED BY THE MICROBE
1. metabolic shutdown of infected cell – viruses
2. lysis of infected cell – viruses, intracellular bacteria, protozoa
3. fusion of infected cells – viruses
4. alter antigens that mark host cells, set them up as targets of body’s own defenses –
viruses
5. activate acute inflammatory response – bacteria
6. toxin production – bacteria
BIO 580 Medical Microbiology Unit 2 – Conflicts 27
2 categories of bacterial toxins – exotoxins (secreted) and endotoxins (cell-wall bound)
a. Exotoxins = proteins secreted by Gram positive and Gram negative bacteria (usually
extracellular bacteria)
 are encoded by genes located on plasmids or infecting bacteriophages
 are extremely potent
Exotoxins (see table 17.2) may show one of 4 different modes of action:
1. Aid in survival or spread – very common - many examples of enzymatic toxins (-ase)
a. Hyaluronidase – hydrolyzes hyaluronic acid present in connective tissue
b. Collagenase – disintegrates collagen in connective tissue
c. DNase – degrades DNA
d. Streptokinase – converts plasminogen  plasmin – lysis of fibrin clots
e. Lipases – break lipids
f. Coagulase - splits fibrinogen  fibrin, creating clots
2. Damage or destroy cells – very common - membrane active cytotoxins - lyse RBC (= hemolysins),
phagocytes & lymphocytes (= leukocidins)
a. enzymes like lecithinase, phospholipase
b. pore-forming molecules
3. Superantigens – toxins that over stimulate cytokine release by T cells.
Ex. Staphylococcus aureus TSS strains. Over abundance of IL-2  nausea, vomiting, fever,
rash, falling blood pressure, shock.
TH
secreted by
pathogen
APC
Other exs. avian influenza in humans, SARS
BIO 580 Medical Microbiology Unit 2 – Conflicts 28
4. Interfere with cell metabolism –very common (diphtheria, cholera, anthrax, etc) - share a
common structural arrangement.
2 subunit types – A & B
A subunit is responsible for toxicity
B subunit binds to specific receptors
Example 1 - Diphtheria
Action of diphtheria toxin – prevents protein synthesis & so cell dies.
Enough cells die, organ systems fail  cardiovascular collapse.
Example 2 - Tetanus
Tetanus produces an enzyme called tetanospasmin – can get to the brain by 2 routes:
1. toxin  blood  brain = sudden death
2. toxin  along nerve trunks  peripheral nerves  spinal column  brain = slower death
Action of tetanospasmin - blocks neurotransmitter release of inhibitory neurons – excitatory
transmitter is continuously stimulating  rigid, spastic paralysis
Example 3 – Cholera - will be discussed in Unit 3 (Gastrointestinal)
BIO 580 Medical Microbiology Unit 2 – Conflicts 29
B. PATHOLOGY CAUSED BY THE IMMUNE RESPONSE TO THE MICROBE
1. Pathology resulting from Nonspecific immune defenses
a. Physical impairment of function of organ system
Ex. S. pneumoniae infection of lungs induces acute inflammation (take good notes here)
b. Response to endotoxin = lipopolysaccharide (LPS)
 not secreted, but released when bacterium dies
 toxic only in high doses, mg/kg body weight
LPS triggers a series of physiological responses (Fig. 17.4) in the body that are due to:
1. mast cell degranulation secondary to IgE  large amts of C3a & C5a
2. clotting of blood (via Hageman factor)
3. release of cytokines (esp. TNF, IL1, -IFN)
Physiological responses to endotoxin are numerous, can be mild to very severe and fatal:
1. macrophages release cytokines that stimulate prod. of prostaglandins  fever,
weakness, aches
2. ↓in circulating neutrophils as they aggregate & stick to vessel walls where they release
their toxic granules causing damage to endothelial cells.
3. clotting of blood in peripheral vasculature = disseminated intravascular coagulation
(DIC) – rare - internal hemorrhaging (meningococcemia, Ebola, Dengue)
4. Bradykinin - vasodilation, ↑ vascular permeability
5. hypotension (severe drop in blood volume)  vascular collapse - called endotoxic
shock = septic shock
6. Multiple Organ System Failure (MOSF)
a. lungs - acute respiratory distress syndrome (ARDS)
b. kidneys - kidney failure
c. brain - mental delirium
d. liver - liver failure
BIO 580 Medical Microbiology Unit 2 – Conflicts 30
c. Response to some cytokines = Fever
Fever is a pathological consequence of cytokine production (IL-1 and TNF)
fever = pyrexia Oral
Normal
Fever
What part of the brain regulates body temperature?
Mechanisms that result in fever
1. Stimulating an increase in body temperature – how body “knows” that temperature should be
increased – happens at the chemical/cellular level
Exogenous signals (signal originating from outside the body)
Microbial pyrogens include (best known):
1. Gram negative LPS = endotoxin
2. teichoic acid - GP
3. units of peptidoglycan - GN and GP
4. TSST1 produced by S. aureus
5. erythrogenic toxin prod by Group A strep (S. pyogenes)
6. others yet unknown
Endogenous signals (signals originating from inside the body, produced locally or
systemically) = cytokines (TNF, IL-1)
Drawing
BIO 580 Medical Microbiology Unit 2 – Conflicts 31
Actually raising body temperature – happens at a physiological level
Heat conservation mechanisms:
 behavioral changes
 piloerection - traps an air layer, retains body heat rather than letting it escape
 vasoconstriction - blood is diverted away from body surface where it normally would
be cooled to the body’s interior where it is warmed up.
Heat generation mechanisms:
 shivering – rhythmic contraction of muscles generates heat
Resolution of fever – cooling mechanisms activated so body temperature returns to normal:
 behavioral changes
 vasodilation - increases flow of blood to the body surface where it is cooled

sweating - evaporation from the surface
Symptoms that accompany this cytokine production (in addition to fever):
back pain
generalized myalgia
arthralgia
anorexia
somnolence
chills
What are the potential benefits to the host of experiencing fever?
BIO 580 Medical Microbiology Unit 2 – Conflicts 32
2. Pathology resulting from Specific immune defenses = Hypersensitivities
a. Type I Hypersensitivity – IgE – Anaphylactic
Ex. Typical allergic rxn
What if happens on a large scale? - systemic mast cell degranulation 
 acute fatal anaphylaxis (anaphylactic shock - constriction of smooth muscle,
decrease in blood pressure, vascular collapse, pulmonary edema)
Ex. worm infections, rupture of tapeworm cysts.
b. Type II – IgG – Cytolytic or cytotoxic
Ex - malaria - complement-mediated lysis of the RBC  hemolytic anemia
Also hepatitis B, yellow fever
c. Type III - IgM and IgG- stick to blood vessels or tissues, activating C & neutrophils.
Ex. glomerulonephritis - inflammation of nephrons in kidney
Ex. systemic lupus erythematosus
BIO 580 Medical Microbiology Unit 2 – Conflicts 33
d. Type IV – Delayed Type Hypersensitivity – mediated by T-cells & macrophages = Cellmediated immunity = CMI.
Ex. measles
Ex. Tuberculosis - An ancient disease of humans; chronically-infected macrophages &
persistently stimulated TH
Mycobacterium tuberculosis – obligate aerobe, obligate pathogen. Gram positive that
stains acid-fast due to mycolic acid. Highly resistant to killing by macrophages.
TB is contracted via the respiratory route by inhalation of infectious droplets transmitted by an
infected individual – can remain in the air for hours – inhaled directly into lungs by-passing
muco-ciliary defenses.
Primary Infection – 7 steps
1. M. tuberculosis are inhaled into middle region of lungs
2. M. tb are engulfed by alveolar macrophages (resident in the lungs), but prevent
phagolysosome fusion.
3. Multiply both within macrophages (destroying them) and extracellularly.
4. Lymphocytes and monocytes are attracted. Monocytes differentiate into
macrophages that also phagocytize M. tb.
5. Infected macrophages are carried by lymphatics to regional nodes and also to apices
of lungs.
6. First few weeks, no effective host defense against infection. Ab play no role in
immune defense. M. tb are not opsonized & do not activate classical complement. **
BIO 580 Medical Microbiology Unit 2 – Conflicts 34
7. 2 possible outcomes from primary infection:
1. Control. By 3-8 wks, macs present to and activate TH. TH secrete IL-2 and TNF-
and macs are activated to kill intracellular M. tb. Macs and TH control infection.
The macs and T cells and fibroblasts surround infection and a tubercle (=
granuloma) forms, becomes fibrotic, encapsulated, scars. M. tb are not all killed,
can remain in tubercle for decades, provide continuous boost to CMI.
OR
2. Clinical disease. CMI does not control infection and progressive primary disease
results– children under 5, elderly, advanced AIDS. Bacteria continue to spread in
lungs, macrophage secretion of IL-1 and TNF  clinical symptoms of fever,
weight loss, and profuse night sweats. Lesions fill lungs, interfere with lung
function  death.
Endogenous Reactivation
 Usually within 2 years of a controlled, primary infection, but can occur anytime after
primary infection.
 M. tb are still alive in tubercles. Control and absence of signs of disease results from
precarious balance between presence of M. tb and activity of macrophages and TH.
 Reactivation of disease results from decline in immune competence.


Lesions usually seen first in apex of lungs. Tubercles  necrotic  caseous 
coalesce into larger complexes  centers liquefy  discharge bacteria into bronchial
tree  resume multiplication and spread.
Clinical disease (with symptoms as described above)
Mycobacterium tuberculosis has no direct or toxin-mediated means of causing damage;
in tuberculosis all pathology is caused by the damage induced by the response of
macrophages and T lymphocytes.
BIO 580 Medical Microbiology Unit 2 – Conflicts 35
COMPARE AND CONTRAST
Processes that may result in pathology during viral infections versus processes that may
result in pathology during infection by extracellular bacteria. (Ex. think of the two
genital pathogens herpes virus versus Neisseria gonorrhoeae)
Pneumonia to tuberculosis
Primary progressive tuberculosis with reactivation tuberculosis