B cell development following EBV infection


This one is hard core science that is way above my pay-grade so it will take time for me to ascertain what it all means, but if there are science geeks out there you may find this of interest.

SoRelle ED, Dai J, Reinoso-Vizcaino NM, Barry AP, Chan C, Luftig MA. Time-resolved transcriptomes reveal diverse B cell fate trajectories in the early response to Epstein-Barr virus infection. Cell Rep. 2022 Aug 30;40(9):111286. doi: 10.1016/j.celrep.2022.111286. Epstein-Barr virus infection of B lymphocytes elicits diverse host responses via well-adapted transcriptional control dynamics. Consequently, this host-pathogen interaction provides a powerful system to explore fundamental processes leading to consensus fate decisions. Here, we use single-cell transcriptomics to construct a genome-wide multistate model of B cell fates upon EBV infection. Additional single-cell data from human tonsils reveal correspondence of model states to analogous in vivo phenotypes within secondary lymphoid tissue, including an EBV+ analog of multipotent activated precursors that can yield early memory B cells. These resources yield exquisitely detailed perspectives of the transforming cellular landscape during an viral infection that simulates antigen-induced B cell activation and differentiation.

This element is taken and adapted from the introduction of the paper which you can read if interested as it is open access.

Epstein-Barr virus (EBV) is an gammaherpesvirus present in >90% of adults (associated with susceptibility to MS. We have suggested that one way it does that is that it generates memory B cells, which could be the trigger for autoimmunity

EBV infection within primary B lymphocytes manifests an array of host and viral programs. Upon entry into the host cell, the linear double-stranded DNA (dsDNA) viral genome rapidly circularizes to form an episome that is retained within the nucleus.

Within hours to days, host innate immune responses are generated to restrict viral progression. Simultaneously, viral genes are expressed to counteract host defenses , co-opt B cell-activation and proliferation, and attenuate damage and stress responses instigated by virus-induced growth. These include successful infection leading to life-long infection of B cells,that can hide from immune removal.

The entire EBV genome contains at least 80 protein-coding sequences, including six EBV nuclear antigens (EBNAs); several latent membrane proteins (LMPs); and loci that encode replicative and transcriptional machinery as well as structural proteins. The EBV genome also contains functional non-coding RNAs including EBV-encoding regions (EBERs) 

EBNAs are especially important in establishing distinct forms of latency depending on their combinatorial expression. EBNA1 is essential for viral genome maintenance and B cell transformation. EBNALP is another essential factor that initiates host cell proliferation alongside its co-activated target, EBNA2 to drive early cell proliferation and viral LMP1 expression. The EBNAs hijacking B cell activation, expansion, and differentiation programs. Thus, EBV co-opts antigen-responsive host immune mechanisms for the ulterior purposes of viral replication and propagation.

While the EBNAs engage cell proliferation machinery inside the cell, the LMPs (LMP1, LMP2A, and LMP2B) do so at cell membranes by simulating antigen-induced signal transduction pathways that would generate memory B cell production as if stimulated via infection. LMP1 promotes B cell activation through mimicry of a constitutively active CD40 receptor, which is a co-stimulating factor required in addition to antigen recognition of the target. These induce cell proliferation, cell survival pathways, LMP2A promotes cell survival through mimicry of a stimulated B cell receptor (BCR), which activates signaling cascades complementary to those induced by LMP1. LMP2A expression further predisposes EBV+ B cells to survival by lowering antigen affinity selection thresholds in vivo  Therefore it creates memory B cells against a target the B cell may never have seen and makes it easier to activate them. If these B cells happen to able to target nerve proteins, then this maybe all you need for MS to start, and would implicate EBV as being important inother immune mediated conditions.

Clearly, key EBV gene products manipulate diverse host programs at early stages to achieve sustained latency.

This study uses analysis of the what the cells are producing at the single cell level. When you do this the picture you have becomes more complex and in this study they identify eight B cell clusters following infection by EBV. Some of them are probably transition states as the B cells develop germinal centre (GC) made up to the Dark zone (DZ) and Light zone (LZ)

Cluster analysis of expression of suggested 8 B cell subsets (C1-C8), T cells (C9) and monocytes (C10). The unifected naive B cells (C8) and memory cells (C3) show different signatures as they develop following EBV infection.

SoRell et al. 2022

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  • “This one is hard core science that is way above my pay-gade”

    I always knew you weren’t a proper professor. I suppose the title was part of the government’s levelling up agenda.

  • If I were back in college, MD seems like the kind of Prof I would have wanted because he seems “on-the-level” and with a sense of humor.

    As to EBV, several distantly related ideas come to mind when the subject is brought up-
    Evolutionarily speaking, how long has it been around and therefore how long have we been being infected by it? I suppose if the answer is “forever”, then procreation occurs before MS for most, which makes sense, so evolution wouldn’t weed things out but still I wonder.

    If EBV is the major culprit, can we prove that the 10% who don’t get it also seldom if never, get MS? Or has it already been proven?

    I had strep throat so bad in my teens that I went to the hospital at least twice. Bad tonsils I’m thinking, hmm…. Then spinal memongitious, hmmm…

    If everyone has had it, then I suppose the “having it” is primarily a non-event, no different than a cold. As to “kissing disease”, I did all that early on such that I didn’t do any of it in the years leading up to my initial MS symptoms. (Maybe that’s why?)

    As to the article, it reiterates to me that the whole thing is so complicated and convoluted that trying to understand “why” may be an exercise in futility. Vitamin D, B & T cells askew, blood brain barrier not sufficient, environmental contaminants (smoking, drinking, on and on and on), genetics [the big one], diet, EBV, and what have I forgot? And then the thousands and thousands of combinations of these factors which equals to me, what one calls “bad luck”, or perhaps “damn bad luck”. Most don’t get MS but still experience these same factors,… why? But my cousin got MS too; she was “pure”, me? pretty “contaminated”. Why?

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