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Title: Discuss the central role of inflammation in infectious diseases
Description: My UCL infection and immunity masters essay titled 'Discuss the central role of inflammation in infectious diseases' for module at Institute of Child Health. Has original hand-drawn diagrams by me and referenced throughout. Remember this work will be on turnitin so don't just copy cause you'll get caught! Take ideas and references though if desired.

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Discuss the central role of inflammation
in infectious diseases
Candidate number: KFZW7

Lay abstract word count: 195
Scientific abstract word count: 186
Paper word count: 2, 986

1

Lay Abstract
Pathogens are biological agents that can cause disease in a host, such as
viruses, bacteria, fungi and parasites
...
The first challenge for pathogens is to cross the
physical barrier of the skin in order to gain entry
...
Inflammation is the
body’s response to damage/infection, and is the next big challenge for any
pathogen to overcome
...
And, like in any war collateral damage occurs, which in this
case is in the form of host vascular and tissue damage
...
This two pronged approach of inflammation is crucial in
protecting the host from infectious diseases; however prolonged inflammation
can help to escalate the damage caused by these diseases, potentially
threatening the life of the host
...
Although intrinsically protective,
inflammation is at the core of pathogenesis and a fine balance is required to keep
inflammatory processes beneficial
...
They are also important sources of immune-regulatory cytokines
...
However, due to inflammatory induced damage,
platelets can also have a role in causing serious cerebral malaria
...
In Japanese encephalitis virus infection, devastating encephalitis has
been linked to destructive host inflammatory processes increasing the
permeability of the blood brain barrier
...


2

Introduction
Inflammation is the host’s response to danger signals, whether in the form of
damage or infection
...
This makes
inflammation crucial in protecting us from infectious agents
...
This is
owing to barrier protection and intrinsic host defences, which are inherited and
exquisitely adapted for protection
...
It is at this point that inflammation plays a key role in our
survival by trapping the pathogen and attracting immune cells to destroy it before
there is a chance of dissemination
...
, 2013)
...
I will
also discuss in more depth, research into the inflammatory roles of platelets and
how they are a necessary part of the acute inflammatory response, along with
being implicated in aiding disease progression
...
There appears to be a
fine balance between inflammation being helpful and being destructive
...

The objective of this essay is to link both the beneficial effects of inflammation
and the potentially destructive effects
...


Inflammation is an essential part of the immune response
Inflammation involves many different processes, culminating together and
resulting in the distinctive characteristics of heat, redness, swelling and pain
...
It is the failure
of homeostasis resulting in chronic inflammation that tips the balance from
beneficial to damaging
...

There are three key components to an effective immune response; recognition,
regulatory and effector mechanisms (Medzhitov, 2007)
...


Recognition
mechanisms
Inflammation
facilitates innate and
adaptive cell
recruitment
enhancing further
recognition

Figure 1 – Schematic showing
the central role of inflammation
within the immune response
...
There are sentinel immune cells in the skin, e
...
mast cells
and macrophages, which are ideally placed for fast detection of danger (Urb and
Sheppard, 2012)
...
This is the first
trigger, leading to inflammation and the initiation of the rest of the immune
response
...
These inflammatory molecules,
e
...
cytokines and chemokines, all aim to amplify the immune response via
4

changing the nature of the endothelium, causing vasodilation and attracting
immune cells
...
The ability of immune cells to be able to travel to the
site of infection in the circulation and then squeeze across the endothelium is
crucial, as without this protection cannot occur (Muller, 2013)
...
Hence, this mechanism is desired only locally at the site of
infection, and nowhere else in order to confine pathogenesis to specific locations
...
Complement has powerful
antimicrobial effects required to effectively eliminate many pathogens, e
...

Pseudomonas aeruginosa (Zhang et al
...
Acute inflammation is crucial in
pathogen clearance; conversely chronic or misplaced inflammation can cause
immunopathogenesis which can be worse than the damage caused by the
invading pathogen
...
As mentioned, there are sentinel
cells in the skin, but platelets are the sentinel cells of circulation
...
, 2014)
...
Therefore, although they are small their sheer numbers along
with the fact they can directly interact with infectious agents, other immune cells
and vascular endothelium, enables them to exert diverse and large scale
inflammatory effects (figure 2)
...
,
2014)
...
, 2007)
...
Lysosomal granules contain digestive enzymes
including those with antimicrobial properties, but these enzymes can
unfortunately also facilitate vascular damage, often aiding in the pathogenesis of
infectious diseases
...


5

Figure 2 – Schematic summarising some of the main inflammatory effects shaped by

platelets, with examples given in blue
...
Indeed,
platelets are crucial as a first line of defence due to their ability to quickly detect
and respond to invasion/damage (Fujimi et al
...
Once activated, granules
are exocytosed to release their contents, causing an activated platelet to have an
increased surface area of 2-4 times their original size (White and Clawson, 1980)
...
Some of these receptors include Toll-like receptors1/2/4/6/8 and 9 (TLRs) (Cognasse et al
...
Therefore platelets can directly
act as immune cells, propagating an inflammatory response due to the presence
of an invading pathogen, in an attempt to quickly contain and eliminate
...
During
inflammation, platelets have the ability to recruit both innate and adaptive
immune cells to the site of infection, which is an important part of controlling
infectious disease and acquiring memory
...
Activated T-cells recruited to the site of
infection can directly bind to CD40 expressing platelets via T-cell CD40L
...
, 2004)
...


Figure 3 – Diagram depicting some key platelet interactions and the affects these
interactions have on other immune cells
...
Platelets ubiquitously express P-selectin glycoprotein ligand-1
(PSGL-1) on their cell surface, and once activated they also express P-selectin
(released from granules), as do stimulated endothelial cells
...
Therefore once activated, platelets have the ability
to bind to both endothelium and immune cells at once, promoting aggregation
and rolling adhesion (figure 3) (Frenette et al
...
, 2001)
...

As discussed later, this can also lead to increased pathogenesis e
...
in malaria
infection
...
PF4 has many functions
including the recruitment of neutrophils and fibroblasts (Deuel et al
...

Neutrophils can protect the host from invading pathogens via degranulation and
phagocytosis
...
PF4 also
helps to maintain an inflammatory response by stimulating basophils to realise
histamine, which is a potent pro-inflammatory molecule causing vasodilation
(Brindley et al
...

A study showed, via the creation of a platelet-deficient mouse model, that
excessive thrombocytopenia resulted in significantly increased mortality (~40%)
following burn injury (Fujimi et al
...
They showed that in normal mice, post
burning, the immune-regulatory cytokine TGFβ1 levels spiked and remained
elevated for ~12hrs
...
Platelet-derived TGFβ1 normally regulates
these cytokines, showing that platelets are required to regulate the inflammatory
response to injury (Fujimi et al
...
This implies that not only are platelets
required to induce inflammation but they are also required for a controlled
inflammatory response
...
Burn trauma also results in the disruption of the intestinal epithelium
increasing permeability (Sir, 2000)
...
This further damage induces more inflammation, which needs to
be quickly resolved and the epithelium restored before severe harm and organ
failure can ensue (Samonte, 2004)
...
This is evident
in studies of severe malaria versus uncomplicated malaria infection where
platelets can contribute both positively and negatively to disease outcome
...
As shown in figure 4, PF4 is released from activated
platelets where it then enters infected erythrocytes to directly kill the parasite
within (McMorran et al
...
This is an important protective role of platelets,
and indeed platelet-deficient mice are more susceptible to high levels of
parasitemia and increased disease severity (McMorran et al
...

8

Platelet
exposure to
parasite
infected
erythrocytes via
CD36/PfEMP1
interaction

Platelet
activation

Release
of high
levels of
PF4

PF4 binds to
infected cells
via erythrocyte
antigen
receptor,
DARC

Figure 4 – Schematic depicting the platelet-derived PF4 plasmocidal
mechanism of action against malaria parasites during their blood stage of the
life cycle (McMorran et al
...
, 2012)
...
CD36 is a platelet scavenger receptor protein, and parasite protein
PfEMP1 is expressed on infected red blood cells
...
, 2010)
...
At no point do they directly infect
cells of the brain
...
Many studies have shown that inflammatory
processes are to blame for this, involving the upregulation of adhesion molecules
and the imbalance of the pro-inflammatory cytokine, TNFα
...
, 2008)
...
TNFα is
normally produced at a controlled level in the brain where is has many crucial
neurophysiological roles; however high levels cause side effects such as
seizures
...
Therefore it is possible to see how systemic inflammation,
as a result of malaria infection, could lead to cerebral malaria (figure 5)
...
g
...
Circulating infected erythrocytes
expressing PfEMP1 can bind to ICAM-1 on the stimulated, yet uninfected
endothelium
...
, 2010)
...


Blood
stage
malaria

Prolonged
systemic
inflammation

Induced
TNFα
increase
in the CNS

Stimulated
endothelial
cells in the
CNS

Formation
of
aggregates
in microvascular

Cerebral
malaria

Figure 5 – Schematic depicting the influence of systemic inflammation on the central
nervous system leading to cerebral malaria
...
This highlights the fine
balance between inflammation being good and being bad, and has led me to
wonder, when is inflammation of the brain ever good?

Infectious encephalitis
Encephalitis is essentially inflammation of the brain which is associated with
neurological dysfunction (Venkatesan et al
...
Although encephalitis is a
relatively rare event, all types of infectious agents from viruses to helminths have
been implicated
...
It is therefore important to determine in each specific infectious disease
which causes the most devastation, virus or host, and to use this information for
treatment
...
, 2015)
...
, 2007; Li et al
...
JEV can infect a number of different cell
types including macrophages and DCs (Aleyas et al
...
, 2008)
...


10

Protection
JEV
propagates
through
CNS
neurones

Devastating
encephalitis

Increase in
CNS
inflammatory
cytokines

Damage to
neurones

More
inflammation

BBB
disruption

More
inflammation

Figure 6 – Schematic showing the effects of CNS neuronal infection by Japanese
encephalitis virus
...


The infection of neurones by many neurotropic viruses, e
...
α-herpesviruses,
leads to the dramatic increase of the pro-inflammatory cytokine, CXCL10, from
the neurones soon after infection (Steain et al
...
Microglial cells are the
resident immune cells of the CNS and they can respond very quickly to neuronal
infection, also releasing a number of pro-inflammatory cytokines (Ghoshal et al
...
These include IL-1, TNFα, INFγ and IL-6, with various studies showing
that their effects can be both protective and detrimental
...
g
...
, 1991)
...
, 2013)
...
So, despite protective effects, these cytokines do result in a cycle of
damage followed by more inflammation (figure 6)
...
Is this a regular downfall of the
inflammatory response, or has the virus somehow hijacked regulatory
mechanisms to induce this? At the peak of cytokine/chemokine levels, BBB
permeability increases due to a reduced expression of tight junction proteins in
the microvasculature endothelium, ~4 days after infection (Li et al
...
This
convincingly shows that BBB compromise is a consequence of infection and not
needed by the virus for CNS entry
...
Even
though JEV can infect some immune cells, there is no conclusive evidence to
suggest this is a mechanism promoting further CNS entry
...
, 1995)
...
Promising
treatments like these further leads to the problem of getting therapies to infiltrate
through the BBB to infer protection
...
If successful this research could be used
to deliver antibodies against host factors, such as pro-inflammatory cytokines
...
Chronic inflammation on the other hand can be devastating
and in the era of many effective antimicrobial drugs, often unnecessary
...
Indeed I would further
contend that since inflammation is involved in first line defence, that the priming
and recruitment of adaptive immunity, although important in forming memory,
only becomes necessary because inflammation’s failure as a first line of defence
...

A benefit of understanding immunopathogenesis is that we have the ability to
target inflammation within therapies, without the fear of causing resistant
mutations in infectious agents
...


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PLoS Pathogen, 5(1)
Title: Discuss the central role of inflammation in infectious diseases
Description: My UCL infection and immunity masters essay titled 'Discuss the central role of inflammation in infectious diseases' for module at Institute of Child Health. Has original hand-drawn diagrams by me and referenced throughout. Remember this work will be on turnitin so don't just copy cause you'll get caught! Take ideas and references though if desired.