Summary
Summary Immunology of Tropical Infectious Diseases (16/20)
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This is a summary of the course that is given in the master Infectious and Tropical Diseases.
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Immunology and host pathogen interaction1. The innate immunity of the invertebrate host
In the transmission of a pathogen there is sometimes an arthropod needed. This means that the
pathogen also has to survive in the arthropods and thus has to have ways to either evade or combat
the immune system of the arthropods. There are many different arthropods that can transfer many
different pathogens. Sometimes the invertebrate host is more than just a vector for the pathogen.
Insects also have microbiomes that can make it difficult for pathogens to survive in the insect. The
parasite life cycle will depend on specific interactions with the vector, these can be seen in the
following figure.
Seeing that most of these arthropods are blood feeders makes it that the pathogen will come in the
gut. This means the pathogen has to overcome the environment of the midgut and to pass through
the wall of the midgut. So the pathogen will go from the lumen of the midgut to the hemocoel and
eventually will reach the saliva glands. The gut of the insect can be a trigger for the pathogen to start
differentiate into another form. The anterior and the hind part of the gut are protected by cuticule.
The crop before the gut is needed to dehydrate the blood meal. This process is ATP dependent and
makes that the insect needs to rest after a bloodmeal. The midgut will do the digestion and the
uptake of nutrients. The midgut has a high pH (9-10), a highly proteolytic activity
(trypsin/chymotrypsin) and there is continue competition between the gut microbiome and the
pathogen. This is then also the place where the pathogen has to move out of the digestion system.
The pH is needed to neutralize the enzymes of the human that get activated in an acidic pH. The
proventriculus will regulate the amount of blood that goes to the midgut. Furthermore it will
produce the peritrophic matrix (PM) which represents as a mechanical barrier and will protects the
midgut barrier from degradation by enzymes. This contains chitin and proteoglycans. Between the
PM and the endothelium there is a small gap, the ectoperitrophic space. When the pathogen is able
to cross the PM it comes in the ectoperitrophic space. From there it can directly contact the
endothelium and invade the tissue. So it is a physiological barrier and a physical barrier.
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,The insects also have an immune system, this immune system is only an innate immune system. They
don’t have something like an adaptive immune system or something that looks like the adaptive
immune system. The immune system cells are called hemocytes. The cells are produced during larval
development in a lymphoid organ that is located in the thorax. The adult stage will lose this organ and
thus cannot make any hemocytes. The hemocytes that where once produced can be proliferated in
adult insects but not differentiated anymore. Hemocytes can be divided into three different types,
these are:
- Plasmatocytes: Plasmatocytes will phagocyte pathogens, but they are small and need to
phagocyte sometimes larger pathogens then their own cell size. In order to do this they
encapsulate the pathogen by surround the pathogen with immune cells. The cells that are most
capable of doing this are the lamellocytes, because of their shape. The plasmatocytes are also a
big source of AMPs.
- Lamellocytes: these cells will do encapsulation and melanization. Melanin is a molecule derived
from kerosine, it is highly water insoluble, it is black coloured and it is used in insect to encapsulate
and intoxicate pathogens. So melanization will result in a black colour sedimentation of melanin
around the pathogen.
- Crystal cells/oenocytoids: these will form proteins at a high concentration that will crystalize
intracellularly, this protein is a pro-phenol oxidase which will also lead to melanisation.
You have circulating hemocytes, that are constantly patrolling in the body and you have sessile
hemocytes, that are located somewhere in the insect but are not motile. The fat body is also very
important for the immune system. It is a lipid stall that is important in triggering the immune system,
because it is a source of anti-microbial peptides (AMP). The hemolymph is the functional blood of the
insect and will contain the 3 types of hemocytes (plasmatocytes, lamellocytes and crystal cells or
oenocytoids).
The circulation is accomplished by a primitive heart tube. This
is a tube that can contract and push out the hemolymph with
the hemocytes on both the anterior and the posterior side of
the tube. The tube has 7 openings which are called ostia.
Immune cells will gather around these ostia and will make
contact with an infection that will migrate to the heart.
The hemolymph will 3 time go in the “antegrade” direction and
then 2 times in the “retrograde” direction.
2
,These are three major immunity pathways which are controlled by negative regulators.
1) Toll pathway against fungi and gram-positive bacteria
The toll pathway will recognize a molecule which is known
as a spätzle, this is a molecule like a cytokine that gets
activated by the presents of a pathogen. So it doesn’t
recognize the pathogen directly but it recognizes a cytokine
that is activated in response to infection. This spätlze will
bind a Toll receptor. The Toll receptor will activate a signal
pathway in which a dMyD88 will be formed. dMyD88 will
activate Rel1, this is a transcription factor that has more or
less the same function as NF-κB (nuclear factor kappa beta).
This transcription factor will promote the transcription of
effector genes, an example is AMP. This pathway is
regulated by cactus, this will inhibit Rel1. Rel1 stands for
relish 1.
2) Imd pathway against gram negative bacteria and protozoa
The Imd (immunodeficiency) pathway will use a PGRP-LC (peptidoglycan recognition protein) receptor
which will eventually activate Rel2 (NF-κB like transcription factor). This pathway can be activated by
the pathogen peptidoglycan layer directly. This pathway can be inhibited by caspar. This means caspar
is the regulatory protein of this pathway. An overexpression of Rel2 can give resistance against the
plasmodium parasite. This means that the vector will not transmit plasmodium anymore. The
overexpression can be done by inducing of the Rel2 genes.
3) Jak/Stat pathway against viruses
This is a pathway that will be triggered by cytokines. The cytokine is either a upd or vago molecule.
Upd stands for unpaired. These molecules can bind dome which will activate the Hop proteins. The
Hop proteins will then activate Stat. Stat is a transcription factor which will promote the transcription
of the effector genes. This pathway can be regulated by Socs and Pias. These two are inhibitors for Hop
and Stat respectively.
The arthropod immune system has an anti-viral
immunity. This system works with RNA interference.
An example is the protection against flaviviruses. A
flavivirus has a positive RNA genome. This has to
change to a negative RNA strand. The positive and
negative strand will then form a viral dsRNA complex.
This complex is recognised by the R2D2-Dicer2
complex. Dicer2 can cleave the dsRNA complex which
forms then small interference RNA (siRNA). Dicer2 will
also promotes the transcription of the vago genes that
will activate Jak/Stat pathway. The siRNA can go to the
Pre-RISC complex to form the RISC complex. In the RISC
complex the sense strand will always be removed and
the antisense strand will stay in the RISC complex. By
leaving the antisense strand in the RISC complex it can
recognise the viral sense strand in the infected cells and destroys them. Making it that the viral RNA
will be destroyed and thus the virus gets destroyed.
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, The immune pathways are activated by upstream immune signalling molecules. Toll 7 can directly
recognise viral particles and will induce autophagy against set particle. The upstream signalling
pathways are proteolytic cascades, these pathways can be triggered by the full pathogen or by parts
of the pathogens. Gram negative binding proteins (GNBPs) get activated by binding molecules from
fungi or bacteria. They will gain a serine protease activity (proteolytic cascade) that will activate spätzle
that is circulating in the hemolymph and will migrate to the toll receptor.
Lipopolysacharide from gram negative bacteria are very harmful. You only can inject 0,5ng/kg LPS in
the human body, to prevent endotoxic shock or endotoxic reactions. LPS in a sample is measured with
the LAL (limulus amebocyte lysate test) assay. The amoebocytes are the hemocytes but they behave
like an amoeba. These test is based on limulus and they collect hemolymph. They make a lysate that
contains all the pathways. They use a synthetic peptide that is a chromogenic substrate. The enzyme
will cut the peptide and you will see a colored product. The more LPS you have the more color you see.
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