Download Bacterial Pathogenesis I

CLASS: 9:00 – 10:00
DATE: October 19, 2010
PROFESSOR: Briles
LECTURE TITLE
Scribe: Adam Baird
Proof:
Page 1 of 5
I. MICROBIAL PATHOGENESIS [S1]
II. MICROBIAL PATHOGENESIS [S2]
a. Whether a pathogen is able to cause symptoms (which is medically known as a disease) is dependent on the
interaction of the pathogen with the host. This interaction is called microbial pathogenesis.
III. MICROBIAL PATHOGENESIS [S3]
a. Microbial pathogenesis can be divided into two parts: innate immunity and antigen-specific adaptive immunity
and microbial virulence mechanisms.
1. Innate immunity and antigen-specific adaptive immunity protects the host from pathogens and
tumors. (Note: We’ll be mainly looking at microbes.)
2. Microbes have to do something unique and special: they have to live in a host that has spent millions
of years (maybe even billions of years) learning to get rid of the pathogen. So, in order to survive, the
microbes must be “clever”, so they possess special mechanisms called microbial virulence
mechanisms. The molecules that are produced by the genes involved in microbial virulence
mechanisms are known virulence factors, which enable the pathogen to combat innate and adaptive
immunity of the host.
b. It’s quite amazing that pathogens haven’t killed all of mankind. We haven’t just gotten rid of all of the
pathogens either. (So there’s a balance between these opposing forces. This balance will be discussed later.)
IV. UNDERSTANDING MICROBIAL PATHOGENESIS LEADS TO… [S4]
a. If we understand that the mechanisms by which microbial pathogenesis works…
1. We are able to develop new antimicrobial drugs and antibiotics.
2. We are able to make new and improved vaccines (because we will be able to identify which
molecules to target).
3. We are able to use cytokines to stimulate innate immunity and protection against microbes (in
cancer, for example).
4. We are able to develop better support therapy, giving patient more of a chance to “fight back” against
the pathogen.
5. We are able to develop new preventive measures (at this time though, this might not be really
conceivable).
V. DISEASE SYMPTOMS [S5]
a. Disease symptoms are usually (but not always) the result of inflammation caused by the host response to get
rid of the pathogen before the pathogen destroys the host.
b. Toxins can cause disease symptoms as well. Some toxins make pathogens to specifically damage the host.
(For example: Cholera causes a toxin that causes severe diarrhea. The toxin causes the diarrhea. The
diarrhea is not caused by the host trying to get rid of the toxin.)
c. Chronic infection (like gum disease, heart disease, certain eye diseases, etc.) can lead to erosion of the host
surfaces, leading to chronic inflammation and other serious problems. The host is trying to protect itself, but
something has gone wrong: the pathogen has managed to survive while the host continues to try to get rid of
it.
VI. ANTIBIOTICS [S6]
a. Antibiotics are originally from natural products (selected in nature from the competition between microbes,
like Penicillin, for example).
b. Antibiotics block essential microbial-specific functions (like DNA replication, protein synthesis, cell wall
synthesis, etc.).
c. Antibiotic resistance comes from mutations in the pathogen. Antibiotic resistance either occurs in a particular
pathogen or in some other pathogen that is then acquired by DNA gene exchange. This leads to new variants
of the original pathogen. These variants can be better than the original, but oftentimes it’s not as good as the
original. In time, these weaker variant pathogens can become more powerful though.
d. Future antibiotics will exploit new targets identified by studies of microbial pathogenesis.
VII. IN VIVO STUDIES OF MICROBIAL PATHOGENESIS ARE CONDUCTED BY… [S7]
a. We can study microbial pathogenesis in vivo by administering drugs, cytokines, antibodies, or gene products
that target bacterial or host processes, blocking host factors, microbial factors, etc.
b. Or, we can make genetic knockout mutants in the host (effectors molecules or receptors) or in the pathogen
(virulence factors). This is much more complex than we actually think though. We can predict what might be
an ideal knockout, but the results may turn out totally different than expected.
VIII. CHART: CLASSIFICATION OF MICROBES [S8]
a. This classification (with respect to human health) is helpful because it helps us understand what the bacteria
are doing.
b. 99.99% of bacteria in the world do not colonize or infect humans – they are free living or in other hosts.
CLASS: 9:00 – 10:00
Scribe: Adam Baird
DATE: October 19, 2010
Proof:
PROFESSOR: Briles
LECTURE TITLE
Page 2 of 5
c. Opportunistic microbes normally don’t infect humans. These microbes can be found in lakes, for example, but
they normally don’t harm humans. From time to time, they can cause trouble though, causing disease in
immune compromised humans (infants, elderly, sick individuals, immune deficient individuals, individuals with
AIDS). Tetanus is a good example of a opportunistic microbe.
d. Normal flora bacteria live in humans. They don’t cause any disease symptoms. Normal flora bacteria exhibit
commensal or symbiotic properties, but don’t harm us. Normal flora bacteria can be found throughout the
human body, in the mouth, eyes, throat, stomach, etc.
e. Disease producing bacteria can be harmful. There are two classifications:
1. Colonized bacteria: Try to behave like normal flora, but have difficulty doing so. They don’t want to
compete with normal flora though, so they can occasionally cause disease. (For example:
Streptococcus pneumoniae)
2. Infectious bacteria: Always cause disease.
IX. NORMAL FLORA [S9]
a. Reside in:
1. Gut (especially the large intestine) – Some normal flora in the gut make enough Vitamin K that our to
supply the whole body. In this case, normal flora is beneficial.
2. Oral cavity
3. Upper airways
4. Genital tract
5. Urinary tract
6. Skin
b. Cause no symptoms
c. Normal flora occupies space where bacteria may reside. Because the normal flora is present, it’s more
difficult for pathogens to be present. This is another benefit that results from having normal flora.
d. Normal flora has spent more time learning how to survive in the body than any other bacteria.
e. Once a normal flora has entered the body, it remains in the body for a long time. (Example: Strep mutans
were found in all humans; the same strains were found in both a mother and her child. The importance: Once
the normal flora is established, it’s usually there for the span of life, unless it’s destroyed.)
f. Antibiotics destroy the normal flora, though, especially in the gut. Normal flora does grow back over time, but
with chaos. The normal flora is re-established with influence from environment, other people, etc.
X. NORMAL FLORA [S10]
XI. ATTRIBUTES OF A PATHOGENIC MICROBE [S11]
a. Characteristics of a pathogenic microbe (potential exam question):
1. Pathogenic microbes are acquired from a host (like someone else).
2. Pathogenic microbes have a specific environment that it resides, called a niche.
3. Pathogenic microbes must be able to evade host defenses. If pathogenic microbes can’t evade the
host defenses, they don’t cause any disease or symptoms, and it dies off.
4. Pathogenic microbes must be able to grow and multiply in the host. If pathogenic microbes can grow
or multiply in the host, they don’t cause any disease or symptoms, and it dies off.
5. Pathogenic microbes must produce disease symptoms
6. Pathogenic microbes must be able to be transferred to others.
XII. NO TITLE [S12]
a. The evolutionary success of a pathogen is measured by its ability to infect or colonize not only the initial host,
but other hosts as well (transmission).
b. The evolutionary success of a pathogen is not measured by its ability to kill. (The pathogen is not concerned
with this; it simply wants to grow, reproduce, and be transferred to more hosts.)
XIII. NO TITLE [S13]
a. All pathogens have developed way to be transferred to others.
b. Most pathogens have evolved to keep its host alive for a long enough time to grow, reproduce, and be
passed on to more hosts.
c. Example: Syphilis. In the 1400’s, syphilis developed and spread rapidly, and those who were infected soon
died. The organism got smarter and more clever though, to the point that those who were infected by syphilis
may have not even be aware of it for a long time. Syphilis learned how to keep it’s host alive so that it could
grow, reproduce, and then be passed on to more hosts.
XIV. NO TITLE [S14]
a. Example: HIV/AIDS took a similar strategy that syphilis did. It developed a long incubation period, oftentimes
without showing any serious symptoms (other than occasionally feeling sick). This gave the pathogen time to
grow and develop without the host even being aware.
XV. NO TITLE [S15]
CLASS: 9:00 – 10:00
Scribe: Adam Baird
DATE: October 19, 2010
Proof:
PROFESSOR: Briles
LECTURE TITLE
Page 3 of 5
a. There are other pathogens that don’t mind killing the host.
1. Example: Vibrio cholera tries to get transmitted as live bacteria from a human’s gut (excreted in
watery diarrhea), into the environment, and into a new host (usually by drink). It wants to be
transmitted in large numbers so that it effectively infects the new host.
2. Example: Anthrax infects the host (a species on the African savanna, for instance), killing it as
quickly as possible. As the host dies, spores are excreted into the ground. A new host (another
species on the African savanna, for instance) walks over the ground, inhaling the spores. Once the
spores are in the new host, the cycle repeats.
b. There aren’t many pathogens that benefit from killing the host though.
XVI. FROM THE PERSPECTIVE OF THE HOST: HOST DEFENSE MECHANISMS [S16]
XVII. MAJOR HOST DEFENSES [S17]
XVIII. MAJOR HOST DEFENSES [S18]
a. Mechanical Barriers
1. Skin – First line of defense
2. Epithelial Cells – Tight junctions provide another line of defense
3. Mucus – Another line of defense; produced in the upper airways; sticky, highly-charged material that
traps bacteria
4. Cilia – Remove the mucus, pushing it towards the throat and into the stomach
5. Stomach Acid
6. Proteases
b. Phagocytes – Defensive patrol of mucosal surfaces in the gut, upper airways, tissues, spleen, liver, etc.
1. Macrophage – Phagocytes found in the spleen
2. Kuffer Cell – Phagocytes found in the liver
3. Granulocytes
c. Pattern Recognition Receptors
1. Toll-Like Receptors (TLR) – Recognize particular bacterial molecules
2. C-Reactive Protein – Molecule related to complement that recognizes particular bacterial molecules
3. Mannose-Binding Lectin – Humans don’t make mannose, so Mannose-Binding Lectin recognizes
when mannose is present, tags it, and gets rid of it.
d. Complement – Series of proteins that can be activated in a variety of ways. They are activated when a
pathogen is present. Complements either tag the pathogen for planned phagocytosis or they can drill a hole
in the pathogen membrane, causing lysis.
e. Cytokines – Hundred of molecules that are produced by human cells when inflammation is detected.
Cytokines signal other cells for defensive help. Some cytokines bring in additional cells to help, some
cytokines activate other cells, or mature other cells, or even signal for the whole system to shut down.
1. Inteferon α, β, γ
2. TNF – α, β
3. IL-1, IL-2, IL-4, IL-6, IL-17, etc
f. Antibodies
1. IgM, IgA, IgG, IgE
g. T-Cells
1. CD4, CD8
h. NK-Cells
XIX. RELATIVE CONCENTRATION OF SELECTED IMMUNE MEDIATORS [S19]
a. Chart explaining concentration of immune mediators needed for defense.
b. The more antibodies available, the better chance there is to make an interaction between the antibodies and
the pathogen, the better chance there is to protect host against harm.
c. There are about 5 million polys mononuclear cells, which can turn into macrophages in the presence of an
infection.
d. There are fewer T Cells (and even fewer antigen specific T Cells. T Cell responses take a while to develop.
XX. PHAGOCYTES (PMN & MACROPHAGES) [S20]
a. Polymorphonuclear leukocytes (PMN) are also known as granulocytes
b. Ingest and destroy microbes
c. Can find microbes by roaming and then finding one, or they can find microbes by chemotaxis.
1. Bacterial breakdown of products (N-formyl methionine)
2. Complement fragments (C5a)
3. Leukotriene from stimulated lymphocytes
d. Can recognize microbes by molecules on the surface of the microbes.
1. May be deposited complement (c3b)
CLASS: 9:00 – 10:00
Scribe: Adam Baird
DATE: October 19, 2010
Proof:
PROFESSOR: Briles
LECTURE TITLE
Page 4 of 5
2. May be Antibody Fc. (Note: The binding sites are on one end, the Antibody Fc sites are on the other
end. The macrophages have a receptor that can recognize Fc receptors. If too many receptors get
loaded up in an particular area, the whole area will be tagged for digestion.)
3. Repeating structures on microbe surfaces (manose-binding lectin).
XXI. PROTECTIVE ACTION OF ANTIBODY [S21]
a. Antibodies alone
1. Antibodies can block adherence. In order for a pathogen to be kept from being swept away by the
mucus, it must attach or “hold” onto something. So, when the pathogen can’t attach or “hold” onto
something, it’s swept away by the mucus.
2. Antibodies can block toxin activity. If the toxin can’t bind itself to the host, further activity breaks
down.
3. Antibodies block enzyme activity.
b. Antibodies in conjunction with complement
1. Aggregates and opsonizes toxins and microbes to be phagocytized and destroyed
2. Blocks enzyme activity
3. Lyses host cells bearing bacterial or viral antigens (containing bacteria or viruses)
4. Lyses Gram-negative bacteria
XXII. COMPLEMENT’S ROLE IN OPSONOPHAGOCYTOSIS [S22]
a. C3 is activated through:
1. The alternative pathway (factor B) by many microbial surfaces. (Extracellular pathogens generally
inhibit this pathway.)
2. The classical pathway (C1q) by IgG and IgM antibody bond to pathogen surfaces.
3. The mannose pathway, where mannose is exposed on the bacterial surface.
b. C3 activation and surface deposition mediates:
1. Chemotaxis (C5a)
2. Opsonization (iC3b)
3. Lysis (membrane attack complex – C5b, C6, C6, C8, C9)
XXIII. NK CELLS [S23]
a. Natural Killer (NK) cells lyse host cells identified by:
1. IgG (ADCC) – Kills cells infected with virus and bacteria
2. Tumor Antigens – Tumor surveillance
b. NK cells are just like the antibody causing the complement to lyse the cell, giving the immune system two
different ways to defend against pathogens. So if the pathogen manages to work its way past one of these
mechanisms, the immune system has another mechanism to use, like a back-up defense. This is why the
immune system is so good, and really why humans are still alive. We have multiple defenses, even if one
layer fails.)
c. NK cells are significant producers of γ-interferon
1. Cell mediated immunity – Intracellular bacteria and viruses
XXIV. CYTOKINES [S24]
a. Provide communication between immune cells.
b. Activate/inactivate immune cells
c. Can stimulate protection against microbial infections
d. Can restore tissue to a non-inflammatory state as an infection subsides
e. Mediate many of the inflammatory symptoms of infectious disease.
XXV. INTERFERONS [S25]
a. A type of cytokine.
b. Interfere with viral replication and are also coordinating signal responses against pathogens.
c. Enhance innate and cell mediated immunity by activating monocytes and lymphocytes
XXVI. INTERFERONS [S26]
a. Two basic families of interferons
1. γ interferons are produced by immune T cells
2. α and β interferons are produced by infected cells
XXVII. RECOGNITION OF PATHOGENS IS FACILITATED BY PRRs WHICH RECOGNIZE PAMPs [S27]
a. Innate immunity = infection recognized immediately and acted upon accordingly by the immune system.
Innate immunity in humans is constantly working.
b. Adaptive immunity = antibodies and T cells.
c. It’s important for the immune system to respond quickly.
d. PRR = Pattern Recognition Receptors (On the host)
1. Family of TLRs (Toll-Like Receptors)
CLASS: 9:00 – 10:00
Scribe: Adam Baird
DATE: October 19, 2010
Proof:
PROFESSOR: Briles
LECTURE TITLE
Page 5 of 5
2. C-Reactive Protein
3. Mannose-Binding Lectin
e. PAMP = Pathogen-Associated Molecular Patterns (On the microbe)
1. Cell walls of bacteria
2. Lipopolysaccharide (LPS) of bacteria
3. Flagella of bacteria
XXVIII. HELPER (CD4) T CELLS [S28]
a. Helper (CD4) T Cells
1. Activate and help B cells in making antibodies
2. Mediate cell-mediated immunity by enhancing the production of cytotoxic T cells and activate
macrophages to kill intracellular bacteria, destroying the infected host tissue.
XXIX. INFLAMMATION [S29]
a. Inflammation enhances microbial killing, often at the expense of the host tissue though.
XXX. INFLAMMATION IS MEDIATED BY… [S30]
a. Inflammation is mediated by
1. Microbial products (lipopolysaccharide, cell wall, some toxins)
2. Antibody and complement
3. Cell mediated immunity (Example: Small pox vaccination causing a “dent” in skin)
XXXI. THE HOST SEQUESTERS FREE IRON TO PROTECT AGAINST TISSUE DAMAGE… [S31]
a. The host sequesters free iron to protect against tissue damage by free radicals and against extracellular
growth of bacteria.
b. The host sequesters free iron by:
1. Transferrin – Transports and sequesters iron for host use
2. Lactoferrin – Sequesters iron from pathogens and hosts
3. Fever – decreases availability of iron for bacteria during infection
XXXII. TWO TYPES OF PATHOGENIC BACTERIA [S32]
a. Extracellular – Replicate outside of cells and must therefore avoid being killed by phagocytes or complement.
b. Intracellular – Replicate inside cells and must therefore avoid being killed inside phagocytes by the
antibacterial properties.
XXXIII. [End 51:50 mins]