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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. References Banatvala, J.E. and Brown, D.W.G. (2004) Rubella. Lancet.363, pp. 1127-1137 Best, J.M. (2007) Rubella. Seminars in Fetal & Neonatal Medicine. 12, pp. 182-192 Chan, D. and Kim, P. (1998) HIV entry and its inhibition. Cell. 93(5), pp. 681-684 Chopy, D., Detje, C.N., Lafage, M., Kalinke, U. and Lafon, M. (2011a) The type I interferon response bridles rabies virus infection and reduces pathogenicity. Journal of Neurovirology. 17, pp. 353-367 Chopy, D., Pothlichet, J., Lafage, M., Mégret, F., Fiette, L., Si-Tahar, M. and Lafon, M. (2011b) Ambivalent role of the innate immune response in rabies virus pathogenesis. Journal of virology. 85(13), pp. 6657-6668. Colledge, N.R., Walker, B.R. and Ralston, S.H. (2010) Davidson’s Principles & Practice of Medicine. Edinburgh: Churchill Livingstone, Elsevier. Conrady, C.D., Drevets, D.A. and Carr, D.J.J. (2010) Herpes simplex type I (HSV-1) infection of the nervous system: Is an immune response a good thing? Journal of Neuroimmunology. 220, pp. 1-9 Duszak, R.S. (2009) Congenital rubella syndrome – major review. Optometry. 80, pp. 36-43 Hemachudha, T., Ugolini, G., Wacharapluesadee, S., Sungkarat, W., Shuangshoti, S. and Laothamatas, J. (2013) Human rabies: neuropathogenesis, diagnosis, and management. The Lancet Neurology. 12(5),pp. 498-513. Hofmann, J., Pletz, M. W., and Liebert, U. G. (1999) Rubella virus-induced cytopathic effect in vitro is caused by apoptosis. Journal of general virology. 80(7), pp. 1657-1664. Huang, G. Takeuchi, Y. and Korobeinikov, A. (2012) HIV evolution and progression of the infection to AIDS. Journal of Theoretical Biology. 307, pp. 149-159 Iwami, S., Nakaoka, S., Takeuchi, Y., Miura, Y., and Miura, T. (2009) Immune impairment thresholds in HIV infection. Immunology letters. 123(2), pp. 149-154. Jackson, A.C. (2002) Rabies Pathogenesis. Journal of Viralneurology. 8, pp. 267-269 Jackson, A.C. and Wunner, W.H. (2007) Rabies. 2nd ed. London: Elsevier Joint United Nations Programme on HIV/AIDS (UNAIDS), (2013) Global Report: UNAIDS Report on the Global Aids Epidemic 2013. : World Health Organisation (Who) Kaye, S. and Choudhary, A. (2006) Herpes Simplex Keratitis. Progress in Retinal and Eye Research. 25, pp. 354-380 Kudesia, G. and Wreghitt, T. (2009) Clinical and Diagnostic Virology. Cambridge: Cambridge University Press. Lampson, L. A. (1995) Interpreting MHC class I expression and class I/class II reciprocity in the CNS: reconciling divergent findings. Microscopy research and technique. 32(4), pp. 267285 Li, J., McGettigan, J. P., Faber, M., Schnell, M. J., and Dietzschold, B. (2008) Infection of monocytes or immature dendritic cells (DCs) with an attenuated rabies virus results in DC maturation and a strong activation of the NFκB signaling pathway. Vaccine. 26(3), pp. 419426. Mader Jr, E. C., Maury, J. S., Santana-Gould, L., Craver, R. D., El-Abassi, R., Segura-Palacios, E. and Sumner, A. J. (2012) Human rabies with initial manifestations that mimic acute brachial neuritis and Guillain-Barré syndrome.Clinical medicine insights. Case reports. 5, pp. 49-55. Maratou, E., Theophilidis, G. and Arsenakis, M. (1998) Axonal transport of herpes simplex virus-1 in an in vitro model based on the isolated sciatic nerve of the frog Rana ridibunda. Journal of Neuroscience Methods. 79, pp. 75-78 Richard, J. L., and Masserey Spicher, V. (2007) Ongoing measles outbreak in Switzerland: results from November 2006 to July 2007. Euro Surveillance. 12(7-9), pp. 273-274. Rowe, A.M, St Leger, A.J., Jeon, S., Dhaliwal, D.K., Knickelbein, J.E. and Hendricks, R.L. (2013) Herpes Keratitis. Progress in Retinal and Eye Research. 32, pp. 88-101 Smith, M.C., Boutell, C. and Davido, D.J. (2011) HSV-1 ICPO: Paving the way for viral replication. Future Virology. 6(4), pp. 421-429 Smith, J.S. and Robinson, N.J. (2002) Age-Specific Prevalence of Infection with Herpes Simplex Virus Types 2 and 1: A Global Review. The Journal of Infectious Diseases. 186, pp. S3-S28 Webster, W. S. (1998) Teratogen update: congenital rubella. Teratology. 58(1), pp. 13-23. Wyatt, R. and Sodroski, J. (1998) The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science. 280(5371), pp. 1884–1888. World Health Organisation (WHO) (2007) WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. France: WHO Ygberg, S. and Nilsson, A. (2012) The developing immune system – from foetus to toddler. Acta Pædiatrica. 101, pp. 120–127 Zolopa, A. R., Andersen, J., Komarow, L., Sanne, I., Sanchez, A., Hogg, E., Suckow, C. and Powderly, W. (2009) Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLOS one. 4(5), e5575.