Transcript No Slide Title

INNATE HOST DEFENSES
CHAPTER 16
Patient suffering from
advanced Leprosy
Copyright © 2012 John Wiley &
Sons, Inc. All rights reserved.
If you have an infection you essentially always have a disease
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E.coli kills two girls in U.S. Pacific Northwest, boy hospitalized SEATTLE (Reuters) - Two young
girls have died and a boy was hospitalized in critical condition in the Pacific Northwest on
Wednesday after becoming infected with E.coli in two separate incidents, health officials said.
Investigations have been launched into the source and strain of the bacteria that killed a 3-yearold girl in Lynden, Washington, and a 4-year-old girl, Serena Profitt, in Otis, Oregon.
A third child, Bradley Sutton, 5, has also tested positive for E.coli and was being treated at Mary
Bridge Children's Hospital in Tacoma, Washington, a hospital spokeswoman said. Possible
sources of the E. coli infection include high-risk foods such as undercooked meat, unpasteurized
milk or juices, restaurants at which cases have eaten, exposure to live animals and recreational
water. Most of the multiple strains of E. coli are harmless or cause relatively brief illness but a
few, including O157:H7, can cause severe illness and can lead to HUS, the Mayo Clinic said.
H-7
O157 protein on cell wall
The Trials of Stem Cell Therapy Edgar Irastorza was just 31 when his heart stopped
beating in October 2008. He survived the heart attack, but the scar tissue that resulted
cut his heart’s pumping ability by a third. He couldn’t pick up his children. He couldn’t
dance. He fell asleep every night wondering if he would wake up in the morning.
Desperation motivated Mr. Irastorza to volunteer for a highly unusual medical
research trial: getting stem cells injected directly into his heart. Edgar Irastorza, who
had stem cells injected into his heart after a major heart attack, was break-dancing
again a few years after the procedure. As many as 4,500 clinical trials involving stem
cells are underway in the United States to treat patients with heart disease, blindness,
Parkinson’s, H.I.V., diabetes, blood cancers and spinal cord injuries, among other
conditions. Initial studies suggest that stem cell therapy can be delivered safely, said
Dr. Ellen Feigal, senior vice president of research and development at the California
Institute of Regenerative Medicine, the state stem cell agency, which has awarded
more than $2 billion toward stem cell research since 2006 and is enrolling patients in
10 clinical trials this year. Stem cells harvested from an embryo can turn into any of
the body’s 200 cell types and, theoretically, live as long as the body does, unlike most
cells. The basic idea of therapies using stem cells is simple: Inject them, for example,
into a brain whose cells are dying, and replacement cells could presumably grow. The
same would hold true for muscles, blood, organs and bone. In theory, stem cells can
make repairs, lead to new growth and replace missing pieces.
CHAPTER 16 INNATE HOST DEFENSES
Innate host defenses- act against any type of invading organisms (as compared to
specific host defenses which act against specific agents (antigens). Typically,
nonspecific host defenses perform their function before specific body defense
mechanisms are activated and include the following:
1. Physical barriers, such as skin and mucous membrane and the chemicals that they
secrete
2. Chemical barriers, including antimicrobial substances in body fluids such as saliva,
mucus, gastric juices and iron limiting mechanisms
3. Cellular defenses, consisting of certain cells that engulf (phagocytize) invading
microorganisms
4. Inflammation, the reddening, swelling, and temperature increases in tissues at sites
of infection
5. Fever, the elevation of body temperature to kill invading agents and/or inactivate
their toxic products.
6. Molecular defenses, such as interferon and complement, that destroy or impede
invading microbes.
Adaptive host defenses will be covered in Chapter 17- specific host defenses
Physical barriers- The skin and mucous
membranes protect your body and
internal organs from injury and infectious
agents.
Chemical Barriers
Sweat glands
High salt content of sweat
Sweat and sebum produced by sebaceous gland produce
secretions with a low pH
Acid pH of the stomach
Lysozyme in tears, saliva and mucus
Transferrin- a protein in the blood plasma, binds free iron that
is present in the blood. Bacteria require iron as a cofactor for some
enzymes. The binding of iron by transferrin inhibits the growth of
bacteria in the bloodstream.
Defensins in mucus are a group of molecules that can kill
pathogens by forming pores in their membranes or inhibit growth by
other mechanisms
Defensins are small proteins found in both vertebrates and invertebrates. They are active against bacteria, fungi and
enveloped viruses. Cells of the immune system contain these peptides to assist in killing phagocytosed bacteria, for
example in neutral granulocytes and almost all epithelial cells. Most defensins function by penetrating
the cell membrane by way of electrical attraction, and once embedded, forming a pore
in the membrane which allows efflux.
Cellular DefensesDefensive Cells- Blood consists of
about 60 percent liquid called plasma
and 40 percent formed elements (cells
and cell fragments- (i.e., platelets).
Boxed in area includes cell
types involved in innate host
defense mechanisms
Lymphoid system mostly associated with specific
defense mechanisms-in the next chapter
Blood consists of about
60% liquid called
plasma and 40 percent
formed elements (cells
and cell fragments)
Fig. 16.1 Formed (cellular) elements of the blood
Phagocytes- Phagocytes engulf foreign materials.
Neutrophils- represent 50-70 percent of total leukocyts (also known as
polymorphonuclear leukocytes or PMNL's) are released from the bone marrow continuously to
maintain a stable circulating population. They last 1 to 3 days after activation. Contain oxidative
chemicals to kill internalized microbes and are phagocytic.
Eosinophils- 1-5% of the total leukocytes. Release defensive chemicals to
damage parasites (worms): phagocytic. They contain granules which in turn contain chemical
mediators of inflammation (e.g., histamine, major basic protein, lipases, Rnase, Dnases, peroxidase)
which are toxic to both parasites and host tissues. Eosinophils are thought to be a major player in
asthma.
Basophils – 0.1% of total leukocytes. Release histamine and other chemicals
(heparin, proteolytic enzymes, lipid mediators, e.g., leukotrienes and several cytokines, during –
inflammation: responsible for allergic symptoms. Histamine and proteoglycans are pre-stored in the
cell’s granules and are important source of the cytokine, interleukin-4, considered one of the critical
cytokines in the development of allergies and the production of IgE (will discuss IgE in detail in the
next chapter).
Monocytes (macrophages)- 2-10% of white blood cells -migrate from the bone marrow into the
blood. When these cells move from blood into tissues, they go through a series of cellular changes,
maturing into macrophages. Macrophages are “big eater: that destroy not only microorganisms but also
larger particles, such as debris left from neutrophils that have died after ingesting bacteria. Although
macrophages take longer than neutrophils to reach an infection site, they arise in larger numbers than
neutrophils.
Macrophages are either fixed or wandering. Fixed macrophages remain
stationary in tissues , e.g., lung, liver, bone, spleen and connective tissue and are given different names,
depending on the tissue in which they reside. Wandering macrophages circulate in the blood.
The process of phagocytosis. The
phagocyte must i) find, ii) adhere to, iii) ingest
and iv) digest the microorganism.
Chemotaxis phagocytes first must find the invading microorganisms. Both the infectious
agent and the damaged tissues release specific chemical substances to which phagocytes are
attracted. In addition, basophils and mast cells release histamine, and phagocytes already at the
infection site release chemicals called cytokines which among other things attract additional
phagocytic cells.
What you need to know about the chemotactic process is that the specific chemical
agent (damaged tissue “stuff” for example) activate the polymerization of
cytoskeletal actin fibers to move the macrophage (or PMN) in a concentrationdependent manner to the site of attack or injury.
Neutrophil chemotaxis
http://www.youtube.com/watch?v=EpC6G_DGqkI
Adherence and ingestion-The ability of the
phagocyte cell membrane to bind to specific
molecules on the surface of the microbe is called
adherence. A very important virulence factor is the
capsule or surface anti-phagocytic proteins (M
protein of S. pyogenes). In a previous chapter we
described adherens which are important proteins in
the adherence process.
Digestion (following slide).
Monocytes are part of the family of white blood cells called
granulocytes
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Biogen Reports Its Alzheimer’s Drug Sharply Slowed Cognitive Decline An
experimental drug for Alzheimer’s disease sharply slowed the decline in
mental function in a small clinical trial, researchers reported Friday, reviving
hopes for an approach to therapy that until now has experienced repeated
failures. The drug, called aducanumab, met and in some cases greatly
exceeded Wall Street expectations in terms of how much the highest dose
slowed cognitive decline. However, there was a high incidence of a particular
side effect that might make it difficult to use the highest dose. Aducanumab,
which until now has been called BIIB037, is designed to get rid of amyloid
plaque in the brain, which is widely believed to be a cause of the dementia in
Alzheimer’s disease. However, other drugs designed to prevent or eliminate
plaque have failed in large clinical trials, raising questions about what role the
plaque really plays. Johnson & Johnson and Pfizer abandoned a drug they were
jointly developing after it showed virtually no effect in large trials. Eli Lilly and
Roche are continuing to test their respective drugs despite initial failures.
Experts say there is some suggestion the drugs might work if used early
enough, when the disease is still mild
Results announced from Phase 1 single ascending dose study of PRX002, a monoclonal
antibody for the potential treatment of Parkinson's disease Prothena Corporation plc, a latestage clinical biotechnology company focused on the discovery, development and
commercialization of novel protein immunotherapy programs, has announced positive results
from a Phase 1 single ascending dose study of PRX002, a monoclonal antibody for the potential
treatment of Parkinson's disease and other related synucleinopathies. PRX002 is the focus of a
worldwide collaboration between Prothena and Roche. PRX002 was safe and well-tolerated,
meeting the primary objective of the study. Further, results from this study showed that
administration of PRX002 leads to mean reduction of free serum alpha-synuclein levels of up to
96%. These overall results were highly statistically significant (p<0.00001). Reduction of free
serum alpha-synuclein, a protein potentially involved in the onset and progression of
Parkinson's disease and the target of PRX002, was shown to be robust, rapid and dosedependent after just a single dose. There is genetic and pathological evidence that supports a
causal role of alpha-synuclein in Parkinson's disease," said Todd Sherer, PhD, CEO of the
Michael J. Fox Foundation for Parkinson's Research. "The Phase 1 double-blind, placebocontrolled, single ascending dose study enrolled 40 healthy volunteers. All volunteers enrolled
were randomized 3:1 into five escalating dose cohorts (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10
mg/kg or 30 mg/kg) to receive either PRX002 or placebo. No hypersensitivity reactions or
drug-related serious adverse events were reported. PRX002 demonstrated favorable
pharmacokinetic properties, supporting the current dosing frequency in the on-going Phase 1
multiple ascending dose study in patients with Parkinson's disease. There were no treatment
emergent adverse events (TEAEs) in greater than 10% of subjects. The only TEAEs in greater
than 5% of subjects were vessel puncture site pain, headache and viral infection. All PRX002related adverse events were mild and no dose limiting toxicities were observed.
Fig. 16.3 Phagocytosis of two bacterial cells by a neutrophil
Digestion: Phagocytic cells have several mechanisms for digesting
and destroying ingested microbes.
1. Lysosomes found in the phagocytes cytoplasm. These
organelles, which contain digestive enzymes and small proteins
called defensins (Defensins promote fusion and lysis of negatively charged
membranes), fuse with the phagosome forming phagolysosomes.
2. Macrophages can also use other metabolic products to kill
ingested microbes. These phagocytic cells use oxygen to form
hydrogen peroxide (H2O2), nitric oxide free-radical (ONOO-),
superoxide ions (O2-) and hypocholorite ions (ClO-)(ingredient of
household bleach).
The products, indicated above, produced by macrophages to kill
ingested microbes are likely important players in most inflammatory
responses which can be harmful to the host.
Some microbes have developed mechanisms to prevent their destruction
within a phagolysosome.
1. Some bacteria (S. pneumoniae, Y. pestis) produce capsules which
either prevent them from being engulfed or from being destroyed if
engulfed.
2. Some bacteria- leprosy or tuberculosis organisms can resist digestion
by phagocytes.
3. Some bacteria- produce toxins that kill phagocytes by causing the
release of the phagocytes own lysosomal enzymes into its cytoplasm,
e.g., leukocidin (both staph and strept), and streptolysin released by
streptococci.
As indicated in the recent article about MRSA- leukocidin is an
important player in pneumonial death: Severity (of MRSA) is often due
to leukocidan termed Panton-Valentine leukocidin.
Extracellular killing- The leukocytes
responsible for killing intracellular viruses
are natural killer (NK) cells.
Natural killer cells (or NK cells) are a type of cytotoxic
lymphocyte that constitute a major component of the
innate immune system. NK cells play a major role in
the rejection of tumors and cells infected by viruses.
They kill cells by releasing small cytoplasmic granules
of proteins called perforin and granzyme that cause the
target cell to die by apoptosis (programmed cell death).
The Lymphatic System
The lymphatic system which is closely associated
with cardiovascular system, consists of a network
of vessels, nodes and other lymphatic tissues, and
the fluid lymph. It has three major functions:
1) collect excess fluid from the spaces between
body cells,
2) transport digested fats to the cardiovascular
system and
3) provide many of the nonspecific and specific
defense mechanisms against infection and
disease.
Inflammation- is a body’s defense response
to tissue damage from microbial infection. It
is also a response to mechanical injury (cuts
and abrasions), burns, sunburn, chemicals
(e.g., phenol), and allergies.
Cardinal signs or symptoms of
inflammation: 1) increase in temperature 2)
redness 3) swelling and 4) pain in the
infected or injured site.
Fig. 16.6 Steps in the process of
inflammation and subsequent healing
Molecular defenses- involve
the actions of interferon and
complement
Chronic inflammation- When an inflammation is not destroyed, host
defenses attempt to limit or confine the agent so that it cannot spread to
surrounding tissue. For example, granulomatous inflammation results
in granulomas. A granuloma is a pocket of tissue that surrounds and
wall off the inflammatory agent (gummas of syphilis, lepromas of
Hansens bacillus, and tubercles of tuberculosis)
Fever- a rise in temperature in infected or injured tissue is one sign of a
local inflammatory reaction. Fever, a systemic increase in body
temperature, often accompanies inflammation. Body temperature is
maintained by the hypothalamus and is most often increased by
pyrogens. Fever can 1) increase body temperature above the optimum
of the infecting agent or its toxins, 2) increase the level of immune
responses by increasing the rate of chemical reactions in the body.
IFNs belong to the large class of
glycoproteins known as cytokines.
Interferons are named after their ability to
"interfere" with viral replication within
host cells. IFNs have other functions: they
activate immune cells, such as natural killer
cells and macrophages; they increase
recognition of infection or tumor cells by
up-regulating antigen presentation to T
lymphocytes; and they increase the ability
of uninfected host cells to resist new
infection by virus.
Certain host symptoms, such as aching
muscles and fever, are related to the
production of IFNs during infection.
Both beta-interferon and gamma interferon can also function to modulate the immune system by
stimulating the production of cytokines (proteins involved in host defense among other functions).
Interferon alpha and beta activate antiviral proteins in neighboring cells- they do not enter the cell
they are going to protect- instead they bind to a surface receptor and trigger a G-protein activated
cascade which in turn activates antiviral proteins.
Fig. 16.7 The mechanism by which interferons a and b act.
The binding of IFN to its receptor results in the transcription of a
group of genes that code for antiviral proteins involved in
preventing viral replication in that cell. As a consequence the cell
will be protected from infection with a virus until the antiviral
proteins are degraded, a process which takes several days. The
antiviral state in IFN-treated cells results from the synthesis of two
enzymes that result in the inhibition of protein synthesis. One
protein indirectly affects protein synthesis by breaking down
viral mRNA the other directly affects protein synthesis by
inhibiting elongation
Complement- refers to a set or more than 20 large regulatory
proteins that play a key role in host defense. They are
produced by the liver and circulate in plasma in an inactive form.
These proteins account for about 10 percent of all plasma
proteins.
General function:
1) enhance phagocytosis by phagocytes,
2) lyse microorganisms, bacteria and
enveloped viruses directly and
3) generate peptide fragments that
regulate inflammation and immune responses.
inflammation and phagocyte chemotaxis.
Opsonization- the complement system can counteract the capsule/M-protein type
defenses of the organism by binding to opsonins (antibodies) which are in turn
used to uptake bacteria into phagocytic cells. This process is called opsonization
or immune adherence
Membrane attack complexes
Fig. 16.8 The complement system
Holes in a red blood cell caused by the
complement attack complex
Membrane attack complexes
Side view of a membrane attack complex
Fig. 16.9 Complement lesions in cell membrane
physical barriers
phagocytosis
extracellular killing-NK cells
Inflammatory response
fever
interferons
complement Fig. 16.10 A summary
Of the body’s nonSpecific defenses