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“…once a pathological process has started ‘one damn thing leads to another’ ” (Spector,
W.G. 1989). Discuss this statement with reference to named examples.
Introduction
This essay will, on the whole, provide support for Spector’s theory; once a pathological
process has begun, one thing inevitably leads to another. With such a wide variety of
potential areas for discussion, this essay will focus on pathological processes that are caused
by viral infection. This will enable an effective analysis of Spector’s statement with regards
to viruses, as well as a coherent and in depth discussion and comparison between each of
the viruses selected. Four viruses have been selected: herpes simplex virus (HSV) 1, human
immunodeficiency virus (HIV), rubella and the rabies virus (RABV). Each virus will be briefly
introduced, followed by a closer examination of its pathological process. This examination
will be employed to assess Spector’s statement in a comprehensive manner.
Herpes
The HSV is one of the most prevalent viruses in the world. HSV-1 is the most common
subtype, with 68% of Americans over 12 years of age being seropositive for the virus (Smith
and Robinson, 2002). The overall seroprevalence for HSV-1 is 30-100%, compared to 20-60%
for HSV-2, depending on socioeconomic status. While primary infection is often
asymptomatic, it can cause unsightly and painful lesions on the mouth and face. In these
cases the infection is more extreme than the recurrent forms. A major clinical feature of
HSV-1 is its recurrence, which can persist throughout an infected individual’s life (Colledge,
et al., 2010).
Complications arising from the pathological process involved in HSV-1 include sporadic viral
encephalitis and herpes simplex keratitis (HSK). HSK is of interest to this discussion as it is
not usually present upon primary infection, but is a later, more serious progression. The
primary infection site is predominantly located within the mouth (Kaye and Choudhary,
2006). At first glance this development appears to support Spector’s statement, as the initial
infection has progressed to elicit HSK in the eyes. Once the virus has been shed by an
inoculated individual, and transferred to another via their mucosal surface (for example the
mouth), the virus enters the surrounding epithelial cells and replicates. This can cause
herpes labialis (lesions), commonly known as ‘cold sores’ (Colledge, et al., 2010). The
appearance of these lesions again supports Spector’s statement; once infection has
occurred, the virus replicates and infects host cells, causing observable skin lesions.
HSV-1 establishes latency in the sensory ganglia, via infection of sensory neurons that
innervate the infected area. HSV-1 glycoprotein (GP) C and GPB are essential for attachment
to the host cells, as the virus binds to heparan sulphate proteoglycan in order to invade the
neuron (Conrady et al., 2010). This invasion of the neuron is beneficial to the virus in many
ways. It can use the cells own protein biosynthesis pathways to create viral proteins, such as
ICP0. Neurons also enable HSV-1 to evade the immune system. This is attributed to the
general decreased expression of major histocompatibility complex (MHC) 1 molecules, and a
suppression of cytotoxic T lymphocyte killing (Lampson, 1995). ICPO further aids the virus in
evading the immune response as it inhibits the Stat-1 pathway, therefore suppressing
interferon production (Conrady et al., 2010). These processes allow the virus to replicate,
and infect increasing numbers of cells, enabling progression of the infection.
Once the virus has entered the neuron it is transported up the axon, via the neurons axonal
retrograde transport, to the cell body. As these are sensory neurons the cell bodies are
situated in ganglia, such as the trigeminal ganglia (Rowe et al., 2013). This can occur at a
rate of 48-66mm/day (Maratou et al, 1998). Once in the cell body the virus inserts its DNA
into the cell nucleus via the nuclear pores. At this point divergence between latency and
progression to the lytic cycle occurs. While the mechanisms that control the choice between
these two pathways are yet to be fully understood, ICP0 is known to contribute in
determining the balance between HSV-1 latency and lytic cycles (Smith, et al., 2011). The
latency cycle has the potential to continue indefinitely (Colledge et al., 2010). This
eventuality would contradict Spector’s view on pathological processes, as here there is no
progression of the infection. However, in the majority of cases recurrence of the infection is
likely (Rowe et al, 2013).From its dormant state in the ganglia, HSV-1 can reoccur to infect
the primary infection site, causing conditions like herpes labialis or gingivostomitis. It is
therefore hypothesised that due to its neuronal location, HSV-1 can infect other areas of the
body, for example HSK in the eyes (Rowe et al, 2013). 26% of cases with the most common
form of HSK undergo spontaneously cure. However, the other 74% would require treatment
in order to halt the progression of the disease (Kaye and Choudhary, 2006). The overall
implications of this, with regards to Spector’s statement, are that one thing has led to the
next in the progression of this disease. While the latent cycle initially appears to contradict
this, it could be argued that it is a necessary step towards reinfection and ultimately the
progression of the virus.
HIV
In 2013, 34 million people were estimated to be living with HIV by the Joint United Nations
Programme on HIV/AIDS (UNAIDS, 2013). There are two subtypes of HIV; HIV1 is prominent
worldwide, while HIV2 is largely restricted to Western Africa (Colledge, et al., 2010). Due to
its worldwide prevalence only HIV1 will be in discussed. Any future reference to HIV will be
in relation to HIV1.
Mucosal exposure to the virus is the most common form of transmission. This exposure
leads to dendritic cells (DC), CD4+ T lymphocytes or Langerhans cells transporting the virus
to the lymph nodes. HIV gains access to cells via the CD4 receptor, and therefore CD4+
monocyte-macrophages, follicular dendritic cells, and microglial are all susceptible to
infection. As the virus comes into contact with CD4+ cells, GP120 binds to CD4, causing a
conformational change in GP120 (Chad and Kim, 1998). This conformational allows
interaction with one of two cytokine receptors (CXCR4 or CCR5). The two membranes fuse,
and the viral RNA and enzymes are able to enter the cell. This process is facilitated by GP41
(Wyatt and Sodroski, 1998).
HIV infection can be classified into four stages. The first stage is 3-4 week latency. In this
stage there are no symptoms, and no clinical signs of disease. This is followed by 3-4 weeks
of influenza-like symptoms, coupled with a huge spike in viral load. Once the adaptive
immune system initiates its response, this viral load is greatly decreased. However, this is
the process that is responsible for the development of AIDS, as cytotoxic T lymphocytes
(CTL) eliminate infected CD4+ T cells in order to halt viral replication (Iwami et al., 2009).
While in early infections the reduction of the viral load can lead to an asymptomatic latency,
with viral loads reduced to clinically undetectable levels, it is still very much in support of
Spector’s statement (Huang et al, 2012). This is because once the infection of HIV has been
established, the mechanism that at first gives rise to latency is also the mechanism that
eventually leads to AIDS. The latency can last for a matter of weeks or up to 20 years
(Colledge et al., 2010). The final stage, discussed in more detail later, is acquired
immunodeficiency syndrome (AIDS). From initial examination, the pathological process of
HIV appears to follow Spector’s theory of disease progression. As each outcome can be
predicted and monitored clinically, demonstrating its cascade-like progression.
Both HIV and HSV-1 exhibit latency. However, with regards to HIV this is not a cyclic process
and the vast majority of cases show an increased impairment of the immune system. This is
caused by the destruction of CD4+ T cells, which eventually leads to AIDS and finally death
(Zolopa et al., 2009). It is proposed that a switch between the aforementioned chemokine
receptors (from CCR5 to CXCR4) could cause an increased rate of viral replication (Iwami et
al., 2009). This causes disruption to the balance between viral load and CTL killing, which is
keeping the viral load constant. As the immune system is already under strain, with steadily
decreasing numbers of CD4+ T cells, this increased viral replication rate exceeds the
immunodeficiency threshold (<200cells/µL) causing AIDS (WHO, 2007). While the patient
does not die of AIDS, the reduction of CD4+ cells leaves them at a greatly increased risk of
opportunistic infections (Colledge et al., 2010). A non-CD4+ T cell deficient immune system
would rapidly clear these infections. However, AIDS patients cannot. Therefore in the
absence of treatment for these infections, they will die. The progression from HIV to AIDS
and ultimately death is in strong support of Spector’s statement. As the pathological
processes discussed above show, each step directly leads on to the following one, from the
initial infection to death by opportunistic infection as a result of immunodeficiency.
Rubella
The rubella virus (also known as German measles) is a single stranded RNA virus with
worldwide prevalence. In non-vaccinated countries 80-85% of young adults have evidence
for prior infection (Colledge et al., 2010). It is spread via secretary droplets, and therefore
the primary site of infection is often the respiratory epithelium. From here it is transported
to the lymph nodes by antigen presenting cells (APC), which is generally followed by
dissemination (Kudesia and Wreghitt, 2009). While 50-80% of primary infections are
asymptomatic, symptoms can include the characteristic manicupapular rash, a mild but
constant fever, joint pain or arthritis (seen less often in children) and post auricular
lymphadenopathy. Lymphadenopathy can be used as a diagnostic, as it is present in all cases
(Kudesia and Wreghitt, 2009). It is very rarely problematic, and it has been known for
parents to knowingly subject their infants to infection at ‘measles parties’ (Richard and
Masserey Spicher, 2007). Rubella therefore seems to oppose Spector’s statement, as if one
thing were to lead to another there would certainly be more serious consequences.
Congenital rubella syndrome (CRS) is a complication arising from rubella infection in a
pregnant woman. CRS can cause some devastating birth defects, and even induce
spontaneous abortion (Duszak, 2009). The earlier the infection, the more severe the
congenital defects are. If the infection occurs between the first and second months of
gestation there is a 65-80% chance that the foetus will develop congenital defects. These
are usually very serious, and often multiple defects are present. After three months the
chance of illness decreases to 30-35%, and usually only one defect is present. Nevertheless
these congenital defects have the potential to be very serious. The most frequent defect is
deafness; however glaucoma, mental retardation, congenital heart disease and pulmonary
stenosis are all possible (Colledge, et al., 2010). After four months there is only 10% chance
of illness, with deafness again being the most common defect. This can develop later in life,
along with other diseases they are at increased risks to, such as diabetes mellitus. Therefore
long term check backs are recommended. CRS appears to support Spector’s theory of
pathological processes, as once the foetus has become infected the end stage developments
that occur are very severe.
Rubella is able to disseminate throughout the body, via the bloodstream, before the
maternal immune system has initiated an adequate response. It can therefore infect many
tissues, including the placenta. Placental damage then permits the virus access across the
placenta, and into the foetus (Duszak, 2009). This infection occurs through the chorion, from
the shedding of maternal epithelium and endothelium, gaining access to foetal circulation
and organs (Banatvala and Brown, 2004). Due to the foetus being unable to produce
interferon (IFN) the virus can replicate freely, where it would be repressed in an adult
(Ygberg and Nilsson, 2012). The foetus must therefore rely on maternal immunoglobulin (Ig)
G antibodies. However, unfortunately in early gestation these are only found at levels of 510% of maternal serum, which cannot contain the virus (Webster, 1998). Although rubella is
able to induce apoptosis, via the caspase dependent pathway, generally this does not occur
as the rubella virus is normally noncytolytic (Hofmann et al., 1999). The infection does
however inhibit normal cell growth and mitotic division, which can disturb organogenesis
and lead to many of the observed congenital defects (Duszak, 2009; Best, 2007). This action
of rubella is in support of Spector’s statement, as from the initial infection of the mother the
stages of infection follow a cascade of events, which can lead to spontaneous abortion or
severe birth defects.
Rabies
The rabies virus (RABV) exhibits near worldwide prevalence, with only Australia, Antarctica
and Western Europe are considered to be virus free. Nevertheless these countries do still
experience rare, isolated cases (Jackson and Wunner, 2007). There are around 55,000
deaths worldwide caused by RABV (Jackson and Wunner, 2007; Chopy et al., 2011a). RABV
is most commonly transmitted through saliva, usually via a bite, into the subcutaneous
tissue or muscle (Jackson and Wunner, 2007). From within the muscle RABV is able to infect
motor end plates, through nicotinic acetylcholine receptors. Incubation generally occurs
within the muscle, possibly caused by endogenous RNA silencing mechanisms. This
incubation period is generally considered to last for 1-2 months. However, if the initial bite
caused nerve damage this incubation period can be severely decreased (Hemachudha et al,
2013). It is proposed that viral glycoprotein is responsible for all of the viral action described
above, uptake and transport, and is also responsible for the synaptic transfer that follows
the incubation period (Jackson, 2002). Unlike in the previous examples of HIV and herpes ,
RABV does not have a latent stage. Therefore the initial infection is always seen to support
Spector’s statement, with each event triggering the next.
During the incubation period there is very little immune response, due to the
ineffectiveness of the local antigen presenting cell activation (Li et al., 2008). Following
incubation RABV propagates, using the neuronal network in which it is already established.
This propagation occurs in two forms, centripetal and centrifugal. Centripetal propagation
occurs quickly once replication has begun, transcending a synapse every 12 hours
(Hemachudha et al., 2013). RABV utilises retrograde transneural transfer within motor and
interneurons in order to distribute to the brainstem, spinal cord and higher order central
nervous system (CNS). Centrifugal propagation is a slower process that culminates in
infection of the dorsal and ventral roots. RABV can subsequently spread, via sensory
neurons, to the visceral organs and skin (Hemachudha et al., 2013). RABV continues to
support Spector’s statement, infecting and disseminating throughout the body.
Immunosuppressive proteins, inhibiting immune cell proliferation and cytokine production
enable RABV to evade the adaptive immune response (Chopy et al., 2011b). RABV is assisted
in this evasion by its situation in the neurons, comparable to herpes (Hemachudha et al.,
2013). However, the innate immune response is initiated to by the surrounding glial cells, as
well as the neurons themselves. The JAK/STAT pathway is instigated with the aim of
producing type 1 IFN, which under normal circumstances induces apoptosis. While this does
cause an inflammatory response it has been proposed that RABV actually utilises this
process, increasing its infection of neurons (Chopy et al., 2011b). RABV does however
produce cytoplasmic Negri bodies, containing toll-like receptor (TLR) 3. TLR3 usually binds
IFN, inducing apoptoses, however as it is contained within these Nigre bodies it cannot.
Therefore the neurons, and the RABV, survive (Hemachudha et al., 2013). While there is
some cell death, most of the neuronal changes occur due to altered cell behaviour. This
includes defective ion channels, and abnormalities in neurotransmitter release (Jackson,
2002). The formation of Nigre bodies substantiates Spector’s statement, as the invasion into
the neurons induces their formation, and their formation in turn allows the advancement of
infection within the surrounding areas.
80% of people infected with RABV develop encephalitis, termed classical or furious rabies.
This presents with episodes of hyper excitability, seizures, agitation, aggression,
hallucinations and confusion, separated by periods of lucidity. These symptoms stem from
the widespread RABV infection of the CNS, when compared to paralytic rabies
(Hemachudha et al., 2013). A high fever (42°C) is common, and is often seen with sweating
and hypersalivation. 50-80% of these cases present with hydrophobia, which is likely caused
by the infection of neurons within the nucleus ambiguus that regulate motor neuron
controlled inspiration. These are also thought to play a role in the progression to severe
paralysis, coma with multiple organ failure and ultimately death (Jackson and Wunner,
2013). This is the strongest piece of supporting evidence for Spector’s statement. The fact
that death is caused by a direct result of the initial infection, unlike that of HIV/AIDS,
presents irrefutable evidence for one thing leading to another. This has occurred to such an
extent that, without intervention, the virus eventually leads to death.
The remaining 20% of RABV infections cause paralytic rabies. This presents with flaccid
muscle weakness, which is apparent early on in the infection. Progression results in the
patient being mute, due to laryngeal muscle weakness. Respiratory muscle weakness
eventually leads to death (Jackson and Wunner, 2013). Generally with rabies once the
symptoms are present, the viral progression is too advanced and no means of treatment will
stop death (Mader et al., 2012). Once again Spector’s statement is strongly supported by
the final outcome of RABV progression.
Conclusion
Herpes, HIV, rubella and RABV have been discussed, and contrasting arguments evaluated.
Although these contradictory arguments have been explored, the overall outcome of this
discussion is that Spector is correct. However on the whole the pathological processes of
these viral infections are more complex than Spector’s statement allows. Herpes and HIV
both demonstrate that a simple cascade effect is possibly not the best way to describe their
pathogenesis and pathophysiology. However, both can still be described to fit Spector’s
statement, because each progressive phase occurs as a result of the previous phase. While
in adults rubella is self-limiting, its pathogenesis in CRS can cause very serious complications
for the foetus. The processes involved in CRS agree with Spector’s statement. Therefore,
rubella provides evidence both in support of, and in contrast to, Spector’s statement. RABV
provides the strongest supporting evidence, with a progression that ultimately leads to the
death of the infected individual. The final conclusion is therefore that, on the whole,
Spector’s statement can be used to describe the pathological process of these viruses.
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