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Pandemic Journal

Dr Robert Hess: Long Covid risk factors

Dr Robert HEss

Dr Robert Hess – 02/15/2022

Dr Robert Hess: Long Covid risk factors now identified.

According to the latest figures, between 10 and 30 percent of all persons who test positive for SARS-CoV-2 go on to develop long-term symptoms that can last for weeks, months or potentially even years. These can vary greatly depending on the severity of the disease, the age of the patient and his or her medical history. When – or indeed whether – those who suffer so‑called “Long Covid” can expect their symptoms to clear up is unclear, and there is as is as yet no treatment for the condition that does more than just alleviate symptoms. A U.S.-based research group has now identified four factors that significantly increase the risk of Long Covid.

 

In order to derive a more complete picture of Long Covid and to better define the term, an international team of researchers has analyzed data from a large-scale survey of covid-specific symptoms, involving 16 studies conducted in different countries around the world. The researchers found that there were no fewer than 55 long-term effects associated with COVID-19. Most of these effects are classic clinical symptoms such as fatigue, headaches, joint pain, anosmia (olfactory disturbance), ageusia (lost sense of taste), muscle weakness, depression and cognitive impairment (i.e. concentration and memory problems). However, long-term effects such as respiratory problems and hair loss, as well as diseases such as myocarditis, the onset of diabetes mellitus and thromboembolism, have also been observed.
In some cases, these long-term effects also overlap with vaccination side-effects. It is therefore is important to take into account the point in time when the symptoms first manifested themselves. Some patients infected with SARS CoV 2 are at greater risk of developing Long Covid than others. Triggers for the syndrome have previously included advanced age, severe obesity and underlying pulmonary/coronary conditions. Gender also appears to play a role: the research concludes that women are disproportionately affected by fatigue syndrome as a long-term consequence of infection.

Recent studies suggest that people who have been hospitalized for COVID-19 are significantly more likely to suffer from long-term sequelae. In this group, no fewer than 76 percent of patients were still suffering from Long Covid symptoms six months after discharge.

A team of researchers led by Yapeng Su at the Institute for Systems Biology in Seattle has now identified four additional risk factors for Long Covid. For the purposes of their research, the team followed almost 300 patients from their initial COVID-19 diagnosis through convalescence (two to three months after diagnosis) in an in-depth multimicroscopic longitudinal study. The subjects, whose age ranged from 18 to 89 years, had contracted COVID-19 in 2020 and early 2021. Consequently, the results cannot be extrapolated to the Omicron variant.

The patients were quizzed about more than 20 symptoms considered typical of Long Covid, such as persistent fatigue, shortness of breath or cognitive impairment (see above). Of those who reported three or more symptoms, 95 percent had one or more of the four risk factors identified in the study:

1) a high viral load in the blood at the onset of infection, as evidenced by high levels of viral RNA;

2) the presence of certain autoantibodies which are directed against the patient’s own immune system, have the capacity to aggravate an infection and also occur in rheumatoid arthritis or other autoimmune diseases (COVID-19 sufferers can form a large quantity of such antibodies, which are detectable up to six months after the acute illness and are evidently involved in the development of Long Covid syndrome);

3) reactivation of the Epstein-Barr virus (EBV) which is responsible for triggering glandular fever, a disease that many people become infected with at a young age (EBV can lie dormant in the body for very many years and become active again during systemic illness, in much the same way as the herpes virus);

4) the presence of diabetes mellitus (Type 2).


More than 60 percent of those examined in the study exhibited two or more of the typical symptoms. Autoantibodies were found in two-thirds of them, and no other factor played such a significant role. Diabetes, high viral load and EBV were each identified in one third of the sample. Typically, however, more than one factor was present at the same time, and the combined effect therefore proved decisive. These findings could now open up new approaches to the treatment of Long Covid.

Preliminary data from Israel indicates that vaccination against SARS-CoV-2 inhibits the development of Long Covid syndrome. In the specific case of Israel, the vaccine administered was exclusively of the mRNA variety. This was found to not only reduce the risk of severe disease but also to make long-term sequelae following vaccine breakthrough less likely. Data from individuals who contracted SARS-CoV-2 relatively early in the pandemic suggests that vaccination could also reduce the risk of Long Covid: persons who became infected after previously receiving the BioNTech/Pfizer vaccine were significantly less likely to report typical long-term symptoms (e.g. fatigue and persistent exhaustion) than those who were unvaccinated at the time of infection. In fact, vaccinated people were no more likely to complain of certain symptoms than people who had never contracted SARS-CoV-2. The results of the study are preliminary, however, and the peer review process has yet to be carried out.


As mentioned in our last Keynote, we will now be incorporating these risk factors into our prophylactic program and updating it with regard to Long Covid symptomatology in addition to vaccination side-effects. Thanks to our C-19 saliva testing and antibody monitoring last year, we have already managed to collect all specific data in this regard for our Premium clients, which puts us one step ahead. We will be shortening the intervals between tests for clients with a higher risk profile and introducing even more targeted diagnostic methods.

Pandemic Journal

Dr Robert Hess: How do viruses interfere with the p53 pathway?

Dr Robert HEss

Dr Robert Hess – 12/06/2021

Dr Robert Hess: How do viruses – and more particularly SARS-CoV-2 – interfere with the p53 pathway?

We look at the strategies employed by viruses against this tumor suppressor gene.

Since the onset of the pandemic, research has been conducted into the extent to which SARS-Cov-2 affects the p53 tumor suppressor gene and its pathway. Two widely published studies from 2020 and 2021 have provided interesting insights into this, revealing the molecular strategies by means of which viruses such as SARS-CoV-2 target the p53 function. It is also interesting to compare the combat strategies of other viruses with those of SARS-CoV-2, and we will also briefly discuss this below.

Virtually all viruses have evolved strategies and molecular tools to disable and/or control cell regulatory mechanisms in their hosts that might otherwise impede replication, dissemination or persistence. To this end, viruses have evolved specific proteins to target cell decision centers that regulate cell proliferation and survival as well as the innate immune response mechanisms used by cells to defend against viral infections, for example interferon-gamma-mediated antiviral responses.

Among these decision centers and mechanisms, the p53 tumor suppressor protein plays an important role. This stress-inducible factor can directly and indirectly command a variety of signaling pathways that control DNA replication and repair, cell proliferation, programmed cell death, metabolism and innate immune responses. This broad spectrum of suppressive effects makes p53 a highly “legitimate” target for many different cancers which seek to inactivate it by mutation, deletion or other mechanisms.

The p53 protein was originally discovered as a cellular target of the large T antigen (LT) of the oncogenic Simian Virus 40 (SV40). Over the years, a number of studies have identified an astonishing variety of molecular devices employed by each known viral family to hijack, control or impair the functionality of p53. In persistent oncogenic viruses, such as the human high-risk papillomaviruses (HPV 16, 18, 31, 45), these devices are so specific and powerful that they permanently inactivate p53 functionality and produce an oncogenic effect. Non-oncogenic viruses also produce proteins that interact with p53 or p53 regulators, thereby confirming that control of p53 is an essential mechanism to support efficient viral replication, propagation and in some cases persistence.


In this article, we briefly summarize the current state of knowledge regarding the mechanisms by which viruses interfere with the p53 pathway and the consequences that flow from this. We then discuss the evidence to date on how SARS-CoV-2 attacks the p53 pathway and look at the potential functional impact of this disruption on replication, pathogenesis and the potential long-term consequences of infection.


VIRAL STRATEGIES FOR THE CIRCUMVENTION OF P53
Seen from the perspective of a virus, the presence of an active p53 in the host cell represents a threat that must be neutralized or circumvented in order for the virus to go about its business of replication and propagation. The most immediate challenges posed by p53 are stress-induced programmed death of the host cell and induction of innate or adaptive immune responses of the antiviral kind. Programmed cell death – primarily through apoptosis – is a radical protective response at cellular level that effectively destroys the viral host cell. The p53 protein acts as a stress-activated switch for many pro-apoptotic pathways, so by seizing command of this switch, the virus ensures that it can control the survival and lifespan of its host cell.

The mechanisms chosen by individual viruses to the detriment of p53 depend on cell tropism, propagation cycle, and modalities of latency or persistence. In the next section, we give examples of three strategies that viruses use to target the p53 pathway: Hit and Run, Hide and Seek, Kidnap and Exploit. The name given to each of these strategies describes how the virus exploits the host cell for its own replication and propagation purposes and reveals the perfect adaptation of the virus to a particular ecological niche.

Hit and Run
Exemplifying the Hit and Run strategy is the influenza virus (IAV), a member of the Orthomyxoviridae family of RNA viruses and one of the most common agents of human respiratory infections. Speed is of the essence for IAV, as the time available to it for the cycle of infection, replication, and reproduction is very short. This cytolytic virus triggers host cell apoptosis to promote the release of virions from infected cells. It therefore employs the unusual strategy of attacking p53 to activate its ability to trigger programmed cell death.

Hide and Seek
This viral strategy comprises two sequential phases: first, the attenuation of p53 functions (hide) and second, the positive mobilization of p53 (seek) to support the virus at different stages of its life cycle. A typical example of such a hide-and-seek strategy is HIV-1, a lentivirus that latently infects CD4 lymphocytes and causes a loss of T-helper functions that in turn leads to AIDS. HIV-1 has evolved several proteins that target p53 either early or late in the viral life cycle.

Kidnap and Exploit
This strategy is a somewhat more sophisticated form of Hide and Seek in which the virus manipulates p53 with a whole range of molecular tools, not only to attenuate the antiviral effects mediated by p53, but also to exploit p53 as a factor that controls and facilitates viral replication. Examples of this strategy include members of the Herpesviridae family, such as herpes simplex virus 1 (HSV-1) and Epstein-Barr virus (EBV). Infection with HSV-1 is often asymptomatic: it manifests itself mainly as benign herpetic skin and mucosal lesions, but due to its persistence in neurons, the virus can also cause latent, recurrent infections.


HOW DO SARS-COV VIRUSES INTERFERE WITH THE p53 PATHWAY?
Information on how SARS-CoV-2 targets and manipulates the p53 pathway is still sparse and limited. However, the information we have for SARS-CoV-1 is more detailed. Given that the two viruses are approximately 89% genomically homologous and share many similarities in their infection and pathogenesis mechanisms, it is reasonable to speculate that both viruses use similar molecular mechanisms to target and circumvent p53.

The observations summarized above underscore the fact that SARS-CoV viruses, like most other virus families, have evolved and developed molecular tools that are well adapted to targeting p53 and its signaling pathway. The strategy followed by these viruses shares similarities with the kidnap-and-exploit strategy described above for EBV and HSV1. The distinguishing feature of this strategy is the hijacking of p53 by viral antigens that initiate alternative pathways for the degradation of p53, thereby not only impairing the suppressor functions of p53 but also protecting it from regulation under stress conditions. This mechanism shifts p53 from its normal cell response pathway to a viral response pathway, allowing the virus to bypass components of the p53-controlled pathways or even use them to its own advantage. How this mechanism affects the pathogenesis of SARS-CoV infections and, in particular, the progression of Covid-19 remains a matter for conjecture for now. Two scenarios can be considered:

1) p53 could serve as an antiviral factor that limits SARS-CoV virus replication and reproduction. Consequently, the rate and extent of virus replication might depend on how efficient it is in causing p53 degradation.

2) In parallel with the impairment of p53, SARS-CoV viruses also set in motion molecular programs that lead to oxidative cell and DNA damage and have the potential to hyperactivate p53, resulting in rapid and massive apoptosis. This mechanism could be a contributory factor in the severe lung inflammation and respiratory distress seen in severe forms of Covid-19. Again, p53 could act as a regulator, with the extent of cell and tissue damage depending on the intensity of the p53-mediated responses.


Placing these two scenarios in sequence, one can speculate that SARS-CoV tools (e.g. nsp3 or RCHY1) rapidly switch off p53 function upon infection, thus protecting the virus from innate immune responses and allowing replication. As replication and virus production begin to decline, p53 again becomes available for activation by DNA damage and other stress response pathways of the cell. At this point, the host cell has accumulated considerable oxidative damage, causing p53 to enter a hyperactive state. This, in turn, may contribute to setting in motion a sequence of events that leads to severe inflammation and tissue damage.


Further investigation is needed to determine whether restoring and normalizing p53 activity could be an accessible and affordable objective for Covid-19 therapy. To us, this seems to be a promising target, and we endorse the focus on p53 and its pathway. Further studies are already underway, and we continue to stay on top of the latest developments. The methylation of p53 genes is already central to the epigenetic monitoring of our Premium clients, with review and analysis taking place every three months. The current direction taken by pandemic with regard to SARS-CoV-2 and its impact on p53 further increases the need for monitoring. My traditional focus is on cancer prevention, and since the beginning of the pandemic, we have also become deeply involved in immunology. We are therefore following the fusion of these two areas of research with great interest.