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Krooniset bakteeri-infektiot (Luettu 311137 kertaa)
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Re: Krooniset bakteeri-infektiot
Vastaus #390 - 15.05.2021 - 00:34:33
 
Cooperation between Epstein-Barr Virus Immune Evasion Proteins Spreads Protection from CD8+ T Cell Recognition across All Three Phases of the Lytic Cycle

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004322

Published: August 21, 2014

Introduction

Members of the human herpes family of viruses have co-evolved with their hosts to persist as largely asymptomatic, latent infections. However, under conditions of immune T cell impairment as seen for example in immunosuppressed transplant recipients, herpesviruses may reactivate, often with clinical symptoms [1]–[4]. This reflects the vital role of T cell-mediated immune responses in controlling, albeit not eliminating, persistent herpesvirus infections [5]–[8]. The ability of these viruses to persist and be transmitted by the immune host is achieved through two strategies: firstly, the establishment of a latent infection with minimal if any viral antigen expression in long lived cell types, and secondly, the synthesis of viral proteins that interfere with antigen processing pathways in the infected cell during the virus-productive phase of replication. Multiple immune evasion proteins have been identified within herpesviruses of the α and β families (e.g., herpes simplex virus, HSV, and cytomegalovirus, CMV, respectively) and these proteins have been shown to cooperate with each other during lytic cycle replication of the individual viruses. Whether the γ-herpesvirus immune evasion mechanisms similarly cooperate with each other is unknown.

The prototypic human γ-herpesvirus, Epstein-Barr virus (EBV), establishes latency in the memory B lymphocyte pool [9]. Studies of infectious mononucleosis patients suggest that during primary infection, EBV seeds this compartment as a reservoir of infected cells by inducing a growth-transforming infection of B lymphocytes through the coordinated expression of 8 transformation-associated proteins [9]. Upon establishment of virus persistence, such growth-transformed cells are well controlled by latent antigen-specific CD8+ T cells, and the virus is maintained in a latent and immunologically silent state in resting B cells. Periodically the virus reactivates into its lytic or virus productive phase of replication to allow infection of new cells and transmission to other hosts. Lytic replication is characterized by the sequential expression of two immediate-early (IE) genes (BZLF1 and BRLF1), around 30 early (E) genes followed by around 30 late (L) genes. This provides a potentially diverse repertoire of antigens for immune targeting and strong responses are made to epitopes drawn from the immediate early and some early expressed antigens. A testament to the efficacy of the lytic and latent epitope-specific CD8+ T cell responses is that although 90% of adults worldwide are infected with EBV, infection remains largely asymptomatic [10]. However, high levels of viral particles have been proposed to be synthesised and shed in such immune hosts [11]. Additionally in vitro models show that in the absence of immune effectors, B cells reactivating from latency in to lytic cycle can remain viable and go on producing virus for several days [12]. In vivo therefore, T cell recognition within this extended window of replication has the potential to limit virus production, and evading recognition would clearly be of an advantage to the virus in increasing its chances of transmission from the virus-carrying host.

Following the observation that HLA-class I expression at the cell surface of EBV-infected cells was decreased upon entry into lytic cycle [13], it was also demonstrated that there was increasing evasion of CD8+ T cell recognition by cells replicating EBV as they progressed through lytic cycle [14]. Thus EBV-specific CD8+ T cells which targeted antigens expressed in the IE wave of expression recognised their target epitopes relatively well, while CD8+ T cells specific for E expressed proteins recognised their target epitopes at an intermediate level, and L epitope-specific effectors were relatively poor at recognising their targets.

Subsequently, three EBV lytic cycle genes were shown by ectopic expression in EBV-negative cell models to encode proteins that interfere with the HLA class I antigen processing pathway [15]–[18]. These proteins are: BNLF2a, which associates with the Transporter associated with Antigen Processing (TAP) to block translocation of peptide fragments from the cytosol to the endoplasmic reticulum, thus preventing their access to HLA class I molecules [15], [19]–[21]; BGLF5, which encodes an exonuclease that degrades mRNA and thus reduces global levels of host cell transcripts, including those for HLA and TAP [17], [22], [23]; and BILF1, which binds to HLA class I/peptide complexes and both interferes with their transport to the cell surface and increases the turnover of pre-existing cell-surface HLA class I/peptide complexes, targeting them for lysosomal degradation [16], [24], [25].

Although the individual EBV evasion genes have been well-studied in model systems, little is known about their contributions to evasion in the context of natural EBV lytic cycle. The limited information available suggests that BNLF2a may only be effective during the IE- and E-phases of lytic cycle [19], and yet cells in the L-phase show greatest resistance to EBV-specific CD8+ T cells. To better understand why L-phase viral antigens are less immunogenic, we have knocked-down BNLF2a, BGLF5 and BILF1 expression in spontaneously lytic LCLs and examined the efficiency of recognition of these cells by IE, E and L antigen-specific CD8+ T cell clones. The data show that of these three gene products, BNLF2a and BILF1 are the major effectors of evasion and they cooperate to provide immune protection across all three phases of the lytic cycle.


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Re: Krooniset bakteeri-infektiot
Vastaus #391 - 15.05.2021 - 00:46:34
 
Lyme borreliosis and multiple sclerosis: any connection? A seroepidemic study.

http://www.aaem.pl/Lyme-borreliosis-and-multiple-sclerosis-any-connection-A-sero...

year 2000

ABSTRACT
A total of 769 adult neurological patients hospitalised in clinics and hospitals situated in the Lublin region (eastern Poland) were examined during the years 1997-2000 with ELISA test for the presence of anti-Borrelia burgdorferi sensu lato antibodies. A statististically significant (p=0.0422) relationship was found between the clinically confirmed diagnosis of multiple sclerosis and the positive serologic reaction with Borrelia antigen. Ten out 26 patients with multiple sclerosis (38.5%) showed positive serologic reaction to Borrelia, whereas among the total number of examined neurological patients the frequency of positive findings was twice as low (19.4%). The result suggests that multiple sclerosis may be often associated with Borrelia infection
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Re: Krooniset bakteeri-infektiot
Vastaus #392 - 08.06.2021 - 20:29:18
 
Australian EBV Progressive MS trial: Three years on

https://msra.org.au/news/ebv-progressive-ms-trial-three-years-on/

18 May, 2021

 - A treatment called ‘adoptive T cell immunotherapy’ – which targets the Epstein Barr virus (EBV) – was shown to be safe in a group of 10 people with progressive MS in a small phase I (safety) trial back in 2018.
  - The treatment takes the person’s T cells from the immune system and boosts their capacity to recognise and kill EBV-infected cells.
  - EBV has long been implicated in the development of MS.
  - The scientists now report on the participants’ clinical outcomes three years after they received the treatment.

In 2018 MS Research Australia announced the outcomes of a novel, cutting-edge clinical trial. This trial, funded by MS Research Australia and MS QLD, aimed to test a new treatment option for people with progressive MS. The treatment was a new method called ‘adoptive T cell immunotherapy’ – which targets the Epstein Barr virus (EBV). This trial was an early-stage trial designed to test this treatment option’s safety, an essential step of earlier trials.

The procedure involves taking blood from participants and extracting T cells, which are immune cells that recognize and kill specific cells, such as virus-infected or cancer cells. From this T cell mix, cells that target EBV are specifically expanded to create a powerful “immune arsenal” against EBV. The cells are then reintroduced to the person’s body and target the EBV hiding in the body.

Initial clinical trial

Initially, the trial was carried out by Professor Michael Pender from The University of Queensland and Professor Rajiv Khanna AO from QIMR Berghofer Medical Research Institute. MS Research Australia is proud to have contributed to the funding of this project and significantly supported Professor Pender’s EBV research over the last decade. You can read more on this research and the original trial here.

Professor Pender and his team have now followed up on the original participants in the trial, and their findings have just been published in the journal Frontiers in Neurology.

Three years on

Following the trial, the researchers collected data at the two year mark from 10 participants who had received the treatment and then again at the three year mark from 9 participants. No serious treatment-related adverse events were observed. Four participants had at least some sustained clinical improvement at year two, including reduced fatigue in three participants and reduced disability in two participants. Three participants experienced a sustained improvement in at least some symptoms at year three. More sustained clinical improvement was associated with better EBV-targeting power of the reinfused cells (ie higher percentage of T cells specifically recognizing EBV).

They conclude from this follow-up study that this treatment is well-tolerated and can provide some degree of clinical improvement, sustained for up to three years after treatment. Once again, this is based on small numbers of participants and the trial was designed mainly to test the safety of this treatment option.
Future directions for adoptive T cell immunotherapy

The next steps of this research are underway, and a further clinical trial has started. It is important to note that there are slight differences between the follow-up trial and the original trial. In the original trial, the process involved taking cells from a person with MS, boosting their EBV-killing capacity, and then reintroducing those cells to the same person. In the next iteration, the researchers are using EBV-targeted cells, but this time collected from a healthy unrelated donor instead of the person themselves. This iteration aims to be more scalable, allowing the researchers to treat more participants more efficiently and ensure highly efficient targeting of EBV, and early indications from clinical study have provided encouraging results. These studies have now been extended to a Randomized, Placebo-Controlled Phase 2 Study.

This is an important study as it is a novel way to treat MS, and is also targeting progressive MS, a form of MS for which, unfortunately, we have very few treatment options. We look forward to bringing you the results of the next stage of these trials.
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Re: Krooniset bakteeri-infektiot
Vastaus #393 - 08.06.2021 - 20:33:15
 
EBV infection and MS risk genes work together to facilitate MS

https://msra.org.au/news/ebv-infection-and-ms-risk-genes/

22 May, 2019

  - Infection with Epstein-Barr Virus (EBV) is one of the known risk factors of developing MS but how EBV relates to MS risk is still an open question.
  - New research by Australian researchers has looked at the effect of EBV infection on genetic activity in immune cells.
  - Findings showed that EBV controls some MS risk genes.

What is Epstein Barr Virus (EBV)?

EBV (the virus that causes glandular fever) is a virus that belongs to the herpes virus family and it infects a type of immune cell in the blood known as a B cell. Once a person has been infected with EBV they carry the virus in their B cells for life, meaning their body has to continually control the EBV infection for the rest of their lifetime.

What do we already know about the link between EBV and MS?

Infection with EBV has long been known to be associated with the development of MS. However, while the majority of the population has been infected with the virus (only a small percent will develop recognisable symptoms), 100% of those with MS are thought to be infected.

This shows that while EBV plays a huge role in MS an EBV infection is not sufficient by itself to cause MS. So why do some people who contract EBV develop MS yet others never do? Part of the answer may lie in our genetics.

Previous research funded by MS Research Australia by Professor Michael Pender has shown that people with MS inadequately control these EBV hijacked immune cells and now Australian scientists might have uncovered an interesting interplay between the MS genetic risk factors and EBV.

A new link discovered between EBV and MS risk genes

In a new study, researchers at the Westmead Institute of Medical Research have investigated the way that EBV infection changes which genes the B cells are using and hence changes the way these cells act. Published in Genome Medicine, the researchers compared the gene activity of B cells that were infected with EBV and grown in the laboratory, and cells that had not been infected. They were particularly interested to see whether there would be any changes in the 200+ genetic elements that have already been identified as risk factors for the development of MS.

The research findings explained…

The research showed that a significant proportion of these MS risk genes were influenced by the presence of EBV. This means that:

  - The infected cells used the MS risk genes differently in the presence of EBV.
  -Some of these genes, in turn, controlled other genes in the cell, meaning there was a domino effect resulting in a number of changes within the cell.
  - Further experiments showed that EBV may drive some of these changes at a cellular level through the binding of a molecule called EBNA2. When EBV is hijacking a cell it might try and use a number of cellular genes, and a portion of those are already known as MS risk genes.

This study indicates that the MS risk genes may be working together with EBV infection to facilitate the development of MS and that this interaction may be one way genetic changes act at a biological level to increase the risk of MS.

What do these new findings mean for the future?

A better understanding of the way that EBV infection relates to MS development is important to drive new therapeutic approaches for this disease. Professor Michael Pender’s work has led to the development of a new treatment strategy, currently in clinical trials, based on the idea that boosting a person with MS’s ability to control ongoing EBV infection could help treat MS.
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Re: Krooniset bakteeri-infektiot
Vastaus #394 - 30.07.2021 - 15:31:53
 
Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation

https://www.mdpi.com/2076-0817/10/6/763

Published: 17 June 2021

Abstract
Coronavirus disease 2019 (COVID-19) patients sometimes experience long-term symptoms following resolution of acute disease, including fatigue, brain fog, and rashes. Collectively these have become known as long COVID. Our aim was to first determine long COVID prevalence in 185 randomly surveyed COVID-19 patients and, subsequently, to determine if there was an association between occurrence of long COVID symptoms and reactivation of Epstein–Barr virus (EBV) in 68 COVID-19 patients recruited from those surveyed. We found the prevalence of long COVID symptoms to be 30.3% (56/185), which included 4 initially asymptomatic COVID-19 patients who later developed long COVID symptoms. Next, we found that 66.7% (20/30) of long COVID subjects versus 10% (2/20) of control subjects in our primary study group were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM. The difference was significant (p < 0.001, Fisher’s exact test). A similar ratio was observed in a secondary group of 18 subjects 21–90 days after testing positive for COVID-19, indicating reactivation may occur soon after or concurrently with COVID-19 infection. These findings suggest that many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation.


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Re: Krooniset bakteeri-infektiot
Vastaus #395 - 17.10.2021 - 15:29:39
 
https://ectrims2021.abstractserver.com/program/#/details/presentations/505

P638 - Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis



M.P Pender1, S.J Hodgkinson2,3, S. Broadley4, JW. Lindsey5, Z.A Ioannides1, B. Bagert6, L. Gamelin7, E. Liu7, W. Ye7, J. Willmer7, A. Bar-Or8

Introduction: Mounting evidence suggests Epstein-Barr virus (EBV) is a necessary risk factor for development of multiple sclerosis (MS) [Abrahamyan et al. JNNP 2020]. Early experience with autologous EBV-specific T-cell therapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018; Ioannides ZA et al. Front Neurol 2021].

Objectives/aims: Evaluate the safety and potential efficacy of ATA188 in adults with progressive MS in an ongoing open-label extension (OLE) study, including an imaging biomarker: magnetization transfer ratio (MTR).
Methods: In part 1 of this 2-part Phase I/II study, 4 cohorts received escalating doses of ATA188. Patients (pts) were followed for 1 year and could participate in a 4-year OLE. Sustained disability improvement (SDI; including expanded disability status scale [EDSS] and timed 25-foot walk), as well as safety, were measured [Pender MP et al. EAN 2020]. As a biomarker of improvement, change from baseline in MTR, an exploratory endpoint, was assessed.

Results: 25 pts received ≥1 dose of ATA188 and were followed for up to 33 mos (m). No grade >3 adverse events (AE), dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion-related reactions were observed. 2 treatment-emergent serious AEs were previously reported (muscle spasticity [grade 2; not treatment related]; MS relapse [grade 3; possibly treatment related]) and, as of April 2021, 1 was reported in the OLE (fall; grade 2; not treatment related). Efficacy was evaluated in 24 pts in the initial 12m period and, as of April 2021, in 18 pts in the OLE followed for up to 33m. 9 pts met SDI criteria either in the initial 12m period (n=7) or in the OLE (n=2); of these, 7 had sustained EDSS improvement. Of the 8 pts that achieved SDI and entered the OLE, 7 maintained SDI at all subsequent timepoints. Pts with sustained EDSS improvement (vs those without) had greater increases in MTR signal (in unenhancing T2 lesions and normal-appearing brain tissue) at 12m.

Conclusions: Preliminary data indicate ATA188 is well tolerated. Sustained EDSS improvement drove SDI in most pts, and in all but 1 pt, SDI was maintained at all subsequent timepoints. As a biomarker associated with disability, pts with sustained EDSS improvement (vs those without) showed greater increases in MTR signal at 12m, which may be suggestive of remyelination. The Phase 2 portion of this study, EMBOLD (NCT03283826), is ongoing and currently enrolling.
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