Transcript Questions: How does the body: fight a viral infection? a

Questions:
How does the body defend against a:
bacterial infection?
viral infection?
cancer?
What is an autoimmune disease?
What is a monoclonal antibody?
Pathogens
The human contains about 1013 human cells and also about 1014 bacterial,
fungal and protozoan cells which represent thousands of microbial species.
These microbes call the “normal flora” are usually limited to certain areas
of the body including skin, mouth, large intestine and the vagina.
In addition, humans are always infected with viruses, most of which rarely,
if ever, become symptomatic.
Alberts Molec. Biol. Cell. 4th ed. 2002
.
Pathogens are usually distinct from normal flora that only cause trouble if
our immune systems are weakened or gain access to a normally sterile part
of our body (for example bowel perforation enables the gut flora to enter
the peritoneal cavity).
Pathogens must:
1) colonize the host.
2) find a nutritional niche in the body.
3) avoid host innate and adaptive immune responses.
4) replicate using host resources.
5) exit and spread to a new host.
Alberts Molec. Biol. Cell. 2002
Our immune system is divided into two parts:
the innate or non-specific immune system and the
adaptive or specific immune system.
The innate immune system, present in invertebrates as well as
vertebrates, is an existing response to invading pathogens. The innate
systems relies on protective barriers, toxic molecules and phagocytic cells
that ingest and then destroy invading organisms.
The adaptive immune system is an induced response to a particular
pathogen; it can provide long lasting protection.
Innate or “non-specific” defense.
This is a general defense against bacteria or viruses rather than a particular
bacteria or particular virus.
Mechanisms of innate immunity:
I. Materials, defensins, produced mucus layers kill bacteria, fungi
(including yeast) and parasites (including protozoa and nematodes).
Defensins are usually small peptides with a positive charge and a
hydrophobic domain.
The killing probably involves making holes in membranes that do not
contain cholesterol. Once inside the bacteria, defensins can bind to the
DNA.
Defensins are new focus of biotech firms that propose these reagents as a
means of fighting infections by bacteria resistant to antibiotic drugs.
II. Mechanisms of innate immunity: White blood cells
There are several different kinds of white blood cells.
They are often characterized as
granulocytes: neutrophils, eosinophils and basophils.
Monocytes which differentiate into macrophages
Lymphocytes
Platelets (really only pieces of cells)
Eosinophil upper left, basophil lower left, four neutrophils
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Lymphocyte, monocyte, neutrophil (left to right) and platelets (small).
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Neutrophils and monocytes/ macrophages defend against bacterial infection.
Neutrophils make up 70% of the white blood cells in human blood, are
produced in the bone marrow and when mature enter the blood stream and
circulate throughout the body.
At a site of injury or infection, they are first to the site. They are stimulated
to migrate out of the blood stream and into the tissue. One in the tissue, they
hunt down the bacteria by a process of chemotaxis,
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When a neutrophil (or a monocyte) contacts a bacteriium, it ingests it by a
process called phagocytosis.
How do neutrophil kill the bacteria?
1. The phagosome containing the bacteria fuses with a lysosome which
contains digestive enzymes able to digest sugars, proteins, fats and nucleic
acids.
2. The lyososome of neutrophils also contains defensins.
3. Enzymes in the membranes of the phagosome produce H2O2 that helps kill
the bacteria.
4. Pathogens binding to the cell surface also turn on production of more antifungal proteins, more defensins and various cytokines.
Cytokines are secreted molecules that can activate many processes including:
a) attract inflammatory cells, b) trigger fever (most bacteria and viruses grow
better at lower temperature whereas adaptive immune responses are more
potent at higher temperatures).
Slightly after the neutrophils, monocytes move into the area. They also ingest
and kill bacteria.
In addition, they clean up the debris left from the neutrophils that only live
about 48 hours and then die in the tissue.
Monocytes also carry some of the foreign material from the bacteria or other
pathogen to lymph nodes where they display it to the lymphocytes to initiate a
specific immune response.
III Mechanisms of innate immune response: complement.
The bacteria surface “activates complement” Complement is a cascade
of 20 interacting soluble proteins that after activation serve to:
1. call in the neutrophils, by creating chemoattractants.
2. mark the bacteria as targets for ingestion by neutrophils and
monocytes.
3. make holes in the bacterial or target cell membranes, contributing to
cell death.
Alberts Molec. Biol. Cell. 2002
How do some pathogens avoid being killed by the leukocytes?
Some (gram-positive bacteria) coat themselves with a thick polysaccharide coat
or capsule that is not recognized by complement system or leukocyte receptors
and thus not ingested.
Others, such as mycobacterium tuberculosis prevents maturation of the
phagosome, i.e. various toxic reagents are not secreted into the vacuole.
Others escape from the phagosome and survive in the cytoplasm.
Alberts Molec. Biol. Cell. 2002
Defense against viral infection.
We have several lines of defense against viruses.
1. Cells can recognize double stranded RNA (this is not a feature of normal
cells). The cells first degrade this double-stranded RNA into short
segments (21-25 nucleotide pairs long). These then bind to any single
stranded RNA with the same sequence leading to the destruction of the
single stranded RNA.
2. dsRNA also turns of production and secretion of two proteins called
interferon a and interferon b. The interferons bind to surface receptors of
the infected cell and its neighbors and through a signal transduction process
activate latent RNAase which nonspecifically degrades ssRNA.
Interferons also turn on specific kinases that can inhibit initiation of protein
synthesis. These defenses prevent the virus from replicating. However,
often the infected cell itself will die.
Alberts Molec. Biol. Cell. 2002
Natural killer cells induce virus-infected cells to kill themselves.
Natural killer cells are a kind of lymphocyte that can destroy virusinfected cells by inducing the infected cell to kill itself (undergo
apoptosis).
Natural killer cells tend to kill cells with low levels of particular surface
proteins called Class 1 MHC proteins (MHC= major histocompatibility
complex).
Many viruses have developed mechanisms to inhibit the expression of
Class I MHC molecules (in order to avoid a different kind of lymphocyte,
a cytotoxic T-cells). For the same reason, some cancers also have low
levels of Class I MHC.
Interferon stimulates killing by natural killer cells and stimulates Class I
MHC production by uninfected cells, thereby protecting them from being
targets of the natural killer cells.
Interferons enhance expression of certain cell surface proteins called class
I MHC proteins in un-infected cells. These proteins present viral antigens
to cytotoxic T- lymphocytes (we’ll discuss this more later).
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Blood with neutrophil and platelets
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Lymphocyte in blood
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Monocyte, normal blood
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