Infection Epstein-Barr (EBB), [Mono], Cancer & Covid

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TB2K Girls with Guns
Mods, I didn't know what kind of prefix to use, but since EBB can rear it's ungly head at any time in your life, I went with infection. If you think a better prefix is on the list, please feel free to change.

Hat-tip to Nomifyle for the video find.

This gal has some (I think) viable theories and great questions based on her digging.

What made me listen was that I had mono back in 6th grade, and then was diagnosed with Epstein-Barr (EBB) in the mid 90's, so I was interested in what she had to say.

I did NOT know that 95% of the world's population have had EBB!!! (IF ONLY we could figure out how to eradicate EBB from our systems!)

R/T 32:31

Epstein-Barr, Cancer, and Covid Connections



So then I started to dig and came across this 2020 article.....


STUDY COULD SUGGEST A NEW WAY TO CONTROL EPSTEIN-BARR VIRUS

A team of researchers at University of Utah Health have shown the Epstein-Barr virus — which causes mononucleosis and is linked to development of several cancers — uses a novel strategy to survive. The virus takes the reins of its host’s cellular machinery to make copies of itself and to prioritize the production of its own proteins over those of the host cell. The researchers say the work is in the early stages but one day they hope to exploit this knowledge to develop a new kind of treatment for infection by the Epstein-Barr virus.

Epstein–Barr virus (EBV) is a human herpesvirus found in 95% of the human population. Like other herpesviruses, EBV can be spread from person to person. However, the virus generally remains latent—that is, it lingers inside of cells without actively replicating—for the lifetime of the host and rarely causes disease beyond the initial infection. In some cases, though, environmental triggers, including stress or coincident infections and immune suppression, create conditions in which the virus can thrive, occasionally sparking a rare type of lymphoma or other cancer.

Four years ago, the U of U Health research team found that spironolactone, a medicine routinely used to treat heart failure, has an unexpected antiviral activity against EBV. They discovered the drug targets an EBV protein, called SM, that the Swaminathan lab and others previously showed is essential for EBV replication.

“We were puzzled as to how spironolactone, a drug thought to work on a completely unrelated pathway involving sodium flux in the kidney, would have an effect on the virus or on SM function,” says senior author Sankar Swaminathan, M.D., division chief of infectious disease at U of U Health and professor of internal medicine.

Now, they’ve figured out more about how it works and have published their findings in the Proceedings of the National Academy of Sciences.

Several years ago, a group of French researchers found that spironolactone degrades a host protein called XPB, which plays an important role in cellular transcription — one of the first steps in gene expression. Following up on this lead, Swaminathan and his colleague Dinesh Verma conducted a series of experiments to explore the potential link between the two proteins that the drug interacts with, XPB and SM.

The researchers first used a molecular biology technique to specifically lower the amount of XPB in host cells. The result was that the virus failed to reactivate and acted as if it no longer had functional SM. Next, the research team showed that SM ferries the XPB protein directly to viral DNA.

Finally, the researchers used a technique that involved chemically tagging uridine, one of the four building blocks of the RNA alphabet, to study replication of the virus. Using this technique, they demonstrated that knocking down XPB resulted in lower levels of messenger RNAs for 15 specific viral proteins whose production SM facilitated, while expression of other EBV genes was not affected.

“We showed that SM surprisingly plays a role in activating transcription and co-opts this one cellular protein to do this,” says Dinesh Verma, Ph.D., research assistant professor of internal medicine.

According to Swaminathan, these 15 proteins perform functions that allow the virus to replicate in healthy people. “The virus has evolved to make these proteins at just the right time to keep the infected cells from getting killed just long enough to make some copies of the virus and maybe infect a couple more cells before the immune system kicks in and takes care of it,” Swaminathan says. “As is often the case with viruses, this solution is both very specific and highly clever.”

In patients whose immune systems are compromised, these very same properties—keeping the infected cells alive and helping them evade the immune system—can lead to unchecked proliferation, a common characteristic of cancer.

The researchers are now trying to find new drugs that target XPB to prevent reactivation of EBV and other human herpesviruses in transplant patients, HIV patients, and other immunocompromised patients.

“The long-term idea is that we would be able to develop drugs that would keep the virus completely latent and that this would help decrease the risk of the development of cancers related to EBV,” Swaminathan says.

# # #

“Epstein–Barr virus co-opts TFIIH component XPB to specifically activate essential viral lytic promoters” by Dinesh Verma, Trenton Mel Church and Sankar Swaminathan has been published online in PNAS.

The research was supported by the National Cancer Institute.
 

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This next link is a (very long) 2021 peer-reviewed research paper, so I'll only be bringing over the "ABSTRACT, AUTHOR SUMMARY," and "DISCUSSION"


NK cells eliminate Epstein-Barr virus bound to B cells through a specific antibody-mediated uptake

Abstract
Epstein Barr virus (EBV) causes a highly prevalent and lifelong infection contributing to the development of some malignancies. In addition to the key role played by T cells in controlling this pathogen, NK cells mediate cytotoxicity and IFNγ production in response to EBV-infected B cells in lytic cycle, both directly and through antibody (Ab)-dependent activation. We recently described that EBV-specific Ab-dependent NK cell interaction with viral particles (VP) bound to B cells triggered degranulation and TNFα secretion but not B cell lysis nor IFNγ production. In this report we show that NK cell activation under these conditions reduced B cell transformation by EBV. NK cells eliminated VP from the surface of B cells through a specific and active process which required tyrosine kinase activation, actin polymerization and Ca2+, being independent of proteolysis and perforin. VP were displayed at the NK cell surface before being internalized and partially shuttled to early endosomes and lysosomes. VP transfer was encompassed by a trogocytosis process including the EBV receptor CD21, together with CD19 and CD20. Our study reveals a novel facet of the antibody-dependent NK cell mediated response to this viral infection.

Author summary
Epstein-Barr virus (EBV) is a member of the herpesvirus family which causes a frequent and lifelong infection. The immune system is unable to fully eliminate the virus, which remains dormant in infected B lymphocytes. EBV reactivation leads to the production of new infective particles, spreading to other cells and favoring its transmission. EBV infection goes generally unnoticed in healthy individuals, though it may occasionally cause a disease termed Infectious Mononucleosis, as well as severe disorders in patients with a defective immune response. Remarkably, EBV has oncogenic potential contributing to the development of some tumors, and has been associated to autoimmune diseases. T lymphocytes and Natural Killer (NK) cells play an essential role in the defense against EBV, killing infected cells when the virus reactivates. Antiviral NK cell functions may be also triggered by antibodies (Ab) recognizing infected cells. In this report we provide the first evidence supporting that NK cells in combination with anti-EBV Ab are able to eliminate the virus attached to the surface of B cells, reducing their infection without killing them.

Discussion
In the present study we provide evidence of a novel antibody-dependent mechanism whereby NK cells can actively remove B cell-bound EBV particles, independently of protease and perforin activities. NK cell uptake of VP was followed by their internalization and, moreover, was associated to trogocytosis of B cell membrane molecules. NK cell incubation with VP-bound B cells in the presence of EBV S+ reduced B cell transformation, compared to that noticed with EBV S-. These observations indirectly supported that antibody-dependent NK cell elimination of B cell-bound EBV might partially prevent viral entry. As previously reported, NK cell activation in the same experimental system induced degranulation and TNFα secretion, in the absence of cytotoxicity and IFNγ production which play a key role in NK cell response to EBV-infected cells in lytic cycle. We previously hypothesized that NK cell activation under these conditions might transiently reduce their cytolytic granule content which, together with CD16 shedding, would transiently hamper their response to EBV-infected cells. Moreover, TNFα activation of the NFκB pathway might potentially enhance infection progression [36,37]. Consistent with previous observations in cytotoxicity assays, video microscopy analysis showed that B cells remained viable following their interaction with NK cells. These results indirectly supported that NK cell activation by IgG bound to VP on the B cell surface did not engage adhesion molecules (i.e. LFA-1 and CD2), which are key for synapse stabilization, polarized degranulation and optimal perforin insertion on the target cell plasma membrane [38]. Altogether these observations suggest that the same process might have opposite effects at different stages of EBV infection, preventing initial viral internalization in B cells but, on the other hand, potentially reducing the Ab-dependent NK cell response to EBV-infected cells. Dynamics of individual NK cell interactions with B cells bound to several VP indicated that the efficiency of this mechanism is limited, suggesting that its ability to reduce EBV B cell infection in vivo would ultimately depend on the relative proportions of NK cells interacting with B cell-bound VP in tissues. It is plausible that a similar process might also operate against other viral infections. Yet, in every case, the putative effectiveness to prevent infection would be predictably conditioned by different factors, particularly the specific mechanism and kinetics of VP internalization. In addition, the likelihood of NK and VP-bound B cells interactions in different tissues is important. In this regard the lymphoepithelial layer of tonsils and adenoids constitutes the main site of initial EBV replication [6,3941] and of infection of naïve B cells. These migrate from high endothelial venules to the area beneath the crypt epithelium [6,41], where NK cells are found [42] and CD16 expression may be induced upon IL-2 activation [43]. On the other hand, other cell types expressing FcγR (e.g. CD16+ T cells, monocytes, dendritic cells, neutrophils) might also contribute to IgG-mediated elimination of B cell-bound VP. Actually, our preliminary data indicate that a similar effect may be mediated by monocytes. Further studies are required to explore the underlying mechanisms and specific functional implications for this lineage, including the role of different FcγR (i.e. CD16A, CD32 and CD64).

Following their uptake by NK cells VP were, at least partially, internalized and shuttled to early endosomes and lysosomes. HLA class II molecules are expressed by human activated NK cells, being detectable in a subset of circulating adaptive NK cells. We previously reported that activation by HCMV in the presence of specific antibodies promoted HLA class II expression in NK cells, which stimulated memory CD4+ T cells from HCMV+ donors in a HLA-II-dependent manner [44]. Thus, it is plausible that EBV uptake by NK cells might also promote specific Ag presentation to CD4+ T cells.

Uptake of B cell-bound VP by NK cells was encompassed by transfer of CD21 and other membrane molecules. This process was reminiscent of trogocytosis, defined as an active receptor-induced and contact-dependent intercellular transfer of membrane patches, containing the driving ligand(s) together with additional molecules [3234]. NK cell-mediated trogocytosis has been observed upon direct formation of an activating immune synapse with target cells [45]. A similar process has been reported following the interaction of IgG bound to target cell surface antigens with FcγR-bearing effector cells (i.e. monocytes, macrophages, neutrophils and NK cells) [46]. In our experimental system, detection on NK cells of CD21 and CD19 suggested that the pull out was primarily mediated through B cell-bound VP, indirectly dragging other plasma membrane molecules (e.g. CD20). The transfer of B cell membrane molecules was limited as compared to that induced by Rituximab suggesting that the mechanical forces exerted indirectly through VP-IgG are weaker than those directly acting on the cell membrane.

Functional implications of trogocytosis have been reported depending on the cell types and molecules involved [47]; yet, information on this process in the context of viral infections is scarce. In this regard, antibody-dependent uptake of HIV bound to target cells mediated by a monocytic cell line was described [48]. In addition, NK cells were reported to acquire CD21 expression upon interaction with HLA-I defective B cell lines [45], potentially allowing NK cell infection by EBV. Our preliminary data indirectly suggest that CD21 acquired by NK cells through trogocytosis might bind EBV VP, further exposing them to a direct interaction with the pathogen.

In this regard, the possibility that EBV may infect NK cells is supported by the identification of rare EBV+ NK cell lymphoproliferative disorders [49], together with a report on in vitro EBV infection of NK cells [50], in which expression of three EBV genes (BZLF1, BALF2 and EBNA1) was detected in exposed NK cell lines. Based on this approach we addressed whether CD16-dependent internalization of trogocytosed EBV VP by NK cells might promote their infection. However, no expression of the mentioned EBV genes nor of EBNA2 was detected in NK cells from co-cultures with VP coated B cells and EBV S+, in contrast to control EBV-exposed B cells. These results do not support that the Ab-induced EBV uptake may facilitate NK cell infection by EBV, but do not rule out that this might exceptionally occur in vivo.

A relevant role of CD16A in the control of EBV infection is supported by chronic viral replication observed in the first reported complete deficiency of this receptor, which impaired ADCC [14]. Another CD16A mutation, leading to deficient CD2 expression and natural cytotoxicity but unaltered ADCC, was associated to different viral infections, including EBV in some patients [51], in line with the role of direct NK cell recognition in viral infection control.

Our results suggest that NK cell-mediated elimination of B cell-bound VP might contribute to immune defense against EBV, complementing the role of CD16A-triggered ADCC and IFNγ production against infected cells in lytic cycle.
 

Signwatcher

Has No Life - Lives on TB
All I know is Epstein-Barr Virus or Chronic Mono, whichever you prefer to call it, has been a huge life altering burden for me for 40 years now.

I take a bunch 'o herbs and vitamins every day (about 26), just to have tolerable days.

I believe they make a difference. I've read studies have shown that if you believe vitamins and herbs make a difference, they do. LOL!

In any case, since I was debilitated by it at the age of 23, it's all been uphill since then.
 

abby normal

insert appropriate adjective here
Interesting! I had mono in 6th grade also. I have felt for decades that I could have some type of undiagnosed immune disorder... I seem to catch every kind of crud going around despite my strong supplement game.

Will have to dig deeper into this when I'm not so exhausted. Thank you for the thread!
 
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