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L4 – How to destroy a Microorganism?
Phagocytic cells are key to getting rid of microorganisms living outside the
cells
...
Eosinophils are also weakly
phagocytic
...

• Monocytes, macrophages and dendritic cells are referred to as
mononuclear phagocytes
...
The cytoplasm of neutrophils and eosinoplhis contains
granules that stain differently with dyes such as eosin (eosinophil
granules do stain but neutrophil granules remain unstained)
• Neutrophils are the most abundant type of leukocyte (70% of our white
blood cells are neutrophils) in the circulation
...
They quickly leave the
blood and enter the tissues and are attracted to the site of infection by
chemotaxis
...
Precoating (opsonising) microorganisms with
antibodies can help facilitate phagocytosis
...
primary azurophil granules –contains myeloperoxidase,
defensins and cathepsin G
b
...

• Eosinophils, while they are able to carry out phagocytosis, carry out
extracellular killing by releasing toxic molecules, by a process of
exocytosis, on the surface of parasites that are too large to be engulfed
by phagocytosis
...
In this case, it will by
binding the eosinophil to the parasite (ADCC)
...
Macrophages cannot
only phagocytose and kill microorganisms, they can also show bits of
microorganisms to helper T-cells of the adaptive immune response
(antigen presentation)
...
These are known as cells of the mononuclear
phagocyte lineage
...

• Macrophages can fuse together to form a granuloma
...
In this case, Th-cells secrete IFN-γ,
activating the macrophage and enhancing its microbicidal activity,
enabling them to kill the bacteria
...
Chlamydia, Mycobacteria and Listeria are all
intracellular pathogens
...
In response to infection
and recognising PAMPs, the cells move from tissues and migrate to
local secondary lymphoid tissues, like the lymph nodes
...


Phagocyte migration from blood circulation into tissues
•
•

•

•

The blood is a transit system to get the cells of the immune system to
where they are supposed to be
...

The phagocytic cell adheres to the surface of the blood vessel
endothelium and this is mediated by a number of different molecules
that are both present on the surface of the phagocytic cell and on the
surface of the endothelium cells
...
Adhesion molecules on the
phagocytes are always expressed
...

They then squeeze through the blood vessel endothelium cells and are
attracted to the site of infection by chemotaxis, which usually involves a
concentration gradient of substances that are going to be highest at the
site of the infection (these substances are produced by infectious
agents as well as our own tissue in response to infection) and the
phagocytic cells will migrate in the direction of that concentration
gradient to the site of infection
...
This process
informs the phagocyte that something potentially dangerous has been
encountered
...

Specialised structures in the cytosol of the phagocyte, lysosomes,
contain granules packed with anti-microbial substances
...

The killing mechanisms of the phagocytic cells include molecules based upon
molecular oxygen, such as superoxide, hydroxyl radical, hydrogen peroxide
and nitric oxide and oxygen independent mechanisms such as proteases,
lysozyme and lactoferrin, a molecule which removes the essential nutrient iron
from the surroundings of the engulfed bacteria
...

• Once phagocytosis is initiated there is a large increase in the hexose
monophosphate shunt, generating reduced NADPH
...
cytochrome b558 has a
very low redox potential (-245mV) hence allowing it to reduce
molecular oxygen directly to superoxide anion
...

• The superoxide anion under the influence of superoxide dismutase can
be converted to hydrogen peroxide, which with ferrous ions can be
converted to hydroxyl radicals or in the presence of chloride ions and
myeloperoxidase can form hypochlorite and chloramines
...

• Furthermore, the combination of hydrogen peroxide, myeloperoxidase
and halide ions constitutes a potent halogenating system capable of
killing both bacteria and viruses
...

It is increasingly recognised that one of the many activities of nitric oxide is to
act as a microbicidal agent
...
This enzyme can be inhibited by the arginine
analogue, N-monomethyl-L-arginine (L-NMMA), which can be used to
delineate the role of nitric oxide in any particular physiological action
...

• The action of superoxide dismutase by consuming hydrogen ions
raises the pH of the vacuole gently, allowing a family of cationic
proteins and peptides to function optimally as antibiotics
...

Further damage is inflicted on the bacterial membrane by the neutral
proteinase cathepsin G and via direct transfer to the microbial surface
of a protein, which increases bacterial permeability
...

Lactoferrin, by complexing with iron, denies the growing bacteria an
essential nutrient
...

The pH of the vacuole eventually drops and a variety of proteolytic and
other hydrolytic enzymes digest the killed organisms
...

Antibody and complement help phagocytosis
The phagocytosis of microorganisms by cells of the innate immune response
can be greatly aided if the organism becomes coated or opsonised with
antibody, produced by B-cells of adaptive immune response
...

Many bacteria have a capsule on their surface
...
Thus in the presence of only the innate immune
system, such bacteria can survive relatively well
...

The binding of a single antibody molecule to a phagocytic cell leads to only a
low affinity interaction
...
The bacterium coated with the many antibody molecules will form
a high avidity multiple bond with the phagocytic cell
...

In addition, when antibody binds to antigen, complement is activated and is
able to opsonize microorganisms, further facilitating phagocytosis
...

 



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