By Stephen J Gamble
ABSTRACT
COVID-19 is a worldwide pandemic caused by the SARS-CoV-2 Corona virus. Following the acute phase of the infection, a number of people exhibit post infection symptoms that may last for a number of months. Evidence is presented that some other viral infections may cause effects which present a number of years after the initial infection either as re-activation of dormant virus or as delayed effects on other systems. There is a growing body of evidence that SARS-CoV-2 may also cause some of these long delayed effects. As this infection has only existed for just over one year, the full extent of these long delayed effects cannot yet be fully evaluated.
- INTRODUCTION
This paper is part of an ongoing larger study by the author concerning the roles and interactions of dopamine and mitochondria in disease, including how other factors (e.g. viruses) might affect these.
In late 2019 and through the whole of 2020 the COVID-19 pandemic, caused by the SARS-CoV-2 virus, has spread around the world. This looks as if it will continue at least for most of 2021. If similar Corona virus epidemics like SARS and MERS can act as a model there may be smaller outbreaks around the world for a further two or three years until it is finally subdued.
The SARS-Cov-2 virus is a member of the Corona virus family. Diseases in bats, chickens and other animals known about since the mid-1930s are now identified as being caused by Corona viruses. The family of Corona viruses seems to have around 47 members (ICTV, 2019). It was not until 1965 that human Corona viruses were isolated and grown by David Tyrrell at the MRC Common Cold Unit (Tyrrell and Bynoe 1965). In 1967 they were first visualised by electron microscopy showing the now familiar crown of spike proteins (Almeida and Tyrrell 1967). There appear to be at a minimum seven pathogenic human Corona viruses, four (229E, OC43, NL63, HKU1) cause mild disease (the Common Cold) and three that cause serious disease, SARS-CoV-1 (causes SARS), MERS-CoV (MERS) and SARS-CoV-2 (COVID-19). In the early 2000s new viruses called NL and HCoV-NH were discovered (Kahn and McIntosh, 2005) but are so closely related to NL63 that they appear to be variants. Corona viruses are responsible for only about 15% of common cold infections, the vast majority of colds being caused by Rhinoviruses.
- LONG COVID AND OTHER IMMEDIATE COMPLICATIONS
Whilst some people who contract the virus may not show symptoms, most people who have the virus symptoms recover after 10 to 14 days. There are a range of symptoms, which vary from person to person, but the common features are a respiratory tract infection with some similar symptoms to an extremely severe form of influenza. A small percentage of people do not recover after 14 days and their condition deteriorates to the point that many need hospitalisation, and in a smaller percentage (but still a significant number) the condition is fatal.
When people recover from COVID-19 (the virus cannot be detected in their body and they are not releasing virus into the environment) they typically have post viral effects like fatigue and slight confusion. In most people these issues quickly resolve, but some still suffer from these and other effects several months later. This extended condition has been termed Long COVID.
Taquet (2021) describes the complications of long COVID as including anxiety, depression, intercranial haemorrhage, stroke, psychosis and insomnia. He reports that after six months 33.6% of patients still report one or more of these conditions.
- LONG TERM EFFECTS OF OTHER VIRUSES
Is there evidence of longer term effects after other viral infections? The classic example of longer term viral effects is measles which when encountered early in life remains dormant in the body then sometimes becomes reactivated as shingles many years later. Another example of a longer term virus effect is cold sores, which are caused by a herpes virus which remains dormant until re-activated during another cold.
Following the Spanish ‘flu pandemic from 1918 to 1920 there seems to have been an increase in reported cases of schizophrenia. Karl Menninger (1926) studied 200 patients presenting with post viral psychosis at a hospital in Boston, USA. About one third were diagnosed as having Dementia Praecox (the old name for schizophrenia). About five years later he was able to follow up fifty of these patients and found two thirds had completely recovered. This is not unexpected as many people only ever have only one bout of psychosis and then recover.
Fuller Torrey et al (1991) question that if the influenza virus can occasionally cause psychosis could it also infect the newborn or the foetus then cause similar psychosis after a delay of 15 to 20 years. They then go on to say that this model could be supported by the work of Ravenholt and Foege that suggests the influenza virus can cause Parkinson’s after being latent for a number of years.
Working with Tim Crow of the MRC Division of Psychiatry, David Tyrrell (1979) investigated the cerebrospinal fluid (CSF) of patients with a range of psychiatric and neurological conditions for the presence of potentially causative viruses. They found samples from a number of patients, across a range of conditions, contained something which killed cells in culture. They attributed this cytopathogenic effect to the presence of a Virus Like Antigen (VLA).
Taylor et al (1985a) attempted to further characterise this VLA. Spinning down CSF in ultracentrifuge produced a small pellet but no identifiable virus. The VLA effect was not destroyed by strong UV light. Taylor et al (1985b) measured levels of different forms of the enzyme enolase in the CSF and there was a correlation between increased enolase levels and samples with the VLA agent. As enolase is found in cells any increase in CSF might indicate cell damage in the CNS. There was a small, non significant, increase in gamma enolase and a significant increase in alpha enolase in VLA positive samples. Interestingly gamma enolase is found more in neurons and alpha enolase is found more in glial and other support cells.
Mered et al (1983) tried to isolate the VLA agent from their own set of CSFs but without success.
- POTENTIAL INVOLVEMENT OF MITOCHONDRIA
In cell culture SARS-CoV-2 has been shown to preferentially bind to neural cells. Many viruses have also been shown to interact with mitochondria (Ohta and Nishiyama, 2011). Mitochondria have roles in the immune response, ageing and some diseases such as Parkinson’s and some dementias. There is a growing body of evidence (Singh et all (2020), Ganji and Reddy (2021)) that SARS-CoV-2 highjacks and reproduces in mitochondria. Given that mitochondria evolved from free living bacteria, it is as if the SARS-CoV-2 virus in attacking mitochondria is acting as some form of bacteriophage. If there are COVID-19 virus interactions with mitochondria, is it possible this will result in much longer term effects of COVID-19?
A common symptom of both Parkinson’s disease, where there is destruction of dopamine neurones in the substantia nigra in the brainstem, and COVID-19 is loss of the sense of taste and smell. There are also dopamine neurons in the olfactory system. Although, rather than the neurons themselves, in the olfactory system the virus seems more likely to attack the glial (support) cells. Interestingly glial cells were also those found by Taylor et al (1985b) to be damaged by their VLA.
Hu et al (2020) identified eight gene variants in the UK BioBank samples which lead to increased risk of death from COVID-19 infection. These included TOMM7 which is related to mitochondrial dysfunction and WSB1 which relates to the immune system.
- POTENTIAL VERY LONG TERM EFFECTS OF COVID-19
Brudin et al (2020) discuss three recent papers which each describe the early onset of Parkinson’s like symptoms in a single patient following on from infection with SARS-CoV-2. In one case the patient recovered spontaneously and the others responded to dopaminergic medication. Whilst this could suggest that COVID-19 could trigger Parkinson’s caution needs to be exercised. Firstly, these are only a very small number of cases within a very large population of patients that have had COVID-19, so this could be a result that has arisen purely by chance. There is the possibility that these three patients already had Parkinson’s symptoms that had not been noticed but were detected because the patients were under observation during their COVID-19 episode. Brudin goes on to discuss a number of post mortem studies of the brains of people who died with COVID-19 but not Parkinson’s. In one particular study they report patients had inflammatory changes in the brainstem which are typical of those seen in Parkinson’s disease.
Pavel et al (2020) state that dopaminergic neurons are highly susceptible to infection by the virus. Because they tend to be large cells with a high energy requirement they need to be closely related to large numbers of mitochondria. If mitochondria are impaired and there is insufficient energy available the cells may fall into oxidative stress and that could be enough to kill the neurones and start neuro-degeneration.
De Erausquin et al (2020) report that SARS-CoV-2 RNA has been found in the CSF of infected people. They also state that olfactory deficits are common with a range of viral infections and note that these are also characteristic of neurodegenerative disease. They say that there is growing evidence that the long term effects on the central nervous system may lead in later years to increases in cognitive decline, Alzheimer’s and other dementias. Taquat also warns that there may be large numbers of patients with neurological or psychiatric conditions triggered by SARS-CoV-2 who will need support for many years to come.
- CONCLUSIONS
We have only known about SAR-CoV-2 for just over a year so it is difficult to know accurately what, if any, the long term effects there will be. Fortunately vaccines and improved treatments are now becoming available that will give us control over the spread and seriousness of COVID-19.
There is evidence, limited at the moment, that in some people the virus might promote or bring forward Parkinson’s disease. There is also early evidence that SARS-CoV-2 might damage other parts of the central nervous system that could lead long term to cognitive decline and potentially Alzheimer’s or other dementias.
If these effects are seen within the first year, they might be an indication of what may follow on a wider scale in the longer term. Given the interactions of this virus with neurons and mitochondria longer term surveillance will be necessary to monitor any increase in neurodegenerative or mitochondrial disease.
REFERENCES
Almeida JD and Tyrrell DAJ (1967) The Morphology of Three Previously Uncharacterised Respiratory Viruses that Grow in Organ Culture, Journal of General Virology 1967, 1, pp 175-178.
Brudin P, Nath A and Beckham JD (2020) Is COVID-19 a Perfect Storm for Parkinson’s Disease? Trends in Neurosciences, December 2020, 43, No 12, pp 931-933.
De Erausquin GA, Snyder H, Carrillo M, Hosseini AA, Brugha TS, Seshadri S and the CNS SARS-CoV-2 Consortium. (2021) The Chronic Neuropsychiatric Sequelae of COVID-19: The Need for a Prospective Study of Viral Impact on Brain Functioning. Alzheimer’s and Dementia, 2021, 1-9.
Ganji R and Reddy PH (2021) Impact of COVID-19 on Mitochondrial-Based Immunity in Aging and Age-Related Diseases. Frontiers in Aging Neuroscience, 12, 614650.
Hu J, Li C, Wang S, Li T and Zhang H (2021) Genetic Variants are Identified to Increase Risk of COVID-19 Related Mortality From UK BioBank Data. Human Genetics 15, 10 https://doi.org/10.1186/s40246-021-00306-7
ICTV – International Committee on Taxonomy of Viruses (2019) ICTV (ictvonline.org) Accessed online 23 March 2021.
Mered B, Albrecht P, Torrey EF, Weinberger DR, Potkin SG and Winfrey CJ (1983) Failure to Isolate Virus from CSF of Schizophrenics. Lancet 1983, ii, 919.
Ohta A and Nishiyama Y (2011) Mitochondria and Viruses. Mitochondrion 11, pp1-12.
Pavel A, Murray DK and Stoessl AJ (2020) COVID-19 and Selective Vulnerability to Parkinsons’s Disease. Lancet Neurology 19, pp719.
Singh KK, Chaubey G, Chen JY and Suravajhala (2020) Decoding SARS-CoV-2 Hijacking of Host Mitochonria in COVID-19. Am J Physiol Cell Physiol, 319, pp C258-C267.
Taquet M (2021) Neurological Reverberations. The Biomedical Scientist, March 2021, pp16-17.
Taylor GR, Crow TJ, Carter GI and Gamble SJ (1985a) Cytopathogenic Cerebrospinal Fluid from Neurological and Psychiatric Patients. Experimental and Molecular Pathology, 42, pp271-277.
Taylor GR, Roberts GW, Crow TJ, Royds JA, Gamble SJ, Taylor CB, Carter GI and Timperley WR (1985b) The Cytopathogenic Agent in CSF: Evidence for a Relationship with Enolase Levels. Journal of Neurology, Neurosurgery and Psychiatry, 48, p281.
Torrey EF, Bowler AE and Rawlings R (1991) An Influenza Epidemic and the Seasonality of Schizophrenic Births. Chapter 7 in Psychiatry and Biological Factors (Ed: E Kurstak) Wiley, Boston.
Tyrrell DAJ and Byone ML (1965) Cultivation of a Novel Type of Common-cold Virus in Organ Cultures. British Medical Journal 1965, 1, pp 1467-1470.
Tyrrell DAJ, Crow TJ, Parry RP, Johnstone EC and Ferrier IN (1979) Possible Virus in Schizophrenia and Some Neurological Disorders. Lancet, 1, pp839-841.
Author
Stephen J Gamble MIScT, FIBMS
Stephen has recently retired from a major research institute in the Cambridge area as a Research Assistant working on the molecular biology of cancers and ageing. As well as being a professional biologist, he has long standing interests in astronomy, astronautics and planetary science.