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Herpesviruses dUTPases: A New Family of PAMP Proteins with Implications for human diseases

Discussion in 'Latest ME/CFS Research' started by Kati, Dec 31, 2016.

  1. Kati

    Kati Patient in training

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    Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease
    Marshall V. Williams 1,2, Brandon Cox 2 and Maria Eugenia Ariza 1,2,*
    1
    Department of Cancer Biology and Genetics, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
    2
    Institute for Behavioral Medicine Research, Ohio State University, Columbus, OH 43210, USA

    Academic Editor: Angus Wilson
    Received: 16 December 2016 / Accepted: 21 December 2016 / Published: 28 December 2016


    Abstract

    The human herpesviruses are ubiquitous viruses and have a prevalence of over 90% in the adult population.

    Following a primary infection they establish latency and can be reactivated over a person's lifetime.

    While it is well accepted that human herpesviruses are implicated in numerous diseases ranging from dermatological and autoimmune disease to cancer, the role of lytic proteins in the pathophysiology of herpesvirus-associated diseases remains largely understudies.

    Only recently have we begun to appreciate the importance of lytic proteins produced during reactivation of the virus, in particular the deoxyuridine triphosphate nucleotidohydrolases (dUTPase), as key modulators of the host innate and adaptive immune responses.

    In this review, we provide evidence from animal and human studies of the Epstein-Barr virus as a prototype, supporting the notion that herpesviruses dUTPases are a family of proteins with unique immunoregulatory functions that can alter the inflammatory microenvironment and thus exacerbate the immune pathology of herpesvirus-related diseases including myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune diseases, and cancer.

    https://www.ncbi.nlm.nih.gov/pubmed/28036046
    Open access: full text here
     
    Last edited: Jan 1, 2017
    Tammy, Gemini, frederic83 and 11 others like this.
  2. Kati

    Kati Patient in training

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    Upon reading the paper there is good emphasis on ME/CFS, which I am highlighting here:
    (Sorry for condensed text)

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem illness of unconfirmed etiology [79]. While the onset of greater than 50% of ME/CFS cases is associated with acute “flu-like” symptoms [80], the data concerning a causal relationship between a virus and ME/CFS has not been conclusively demonstrated and remains a challenge. Conflicting results regarding the potential role of viruses in ME/CFS may be due in part to the heterogeneity of the patient populations, and in part to multiple case definitions. Perhaps the most significant problem that has led to contradictory data came from the type of approaches/assay endpoints used to examine the relationship between viruses and ME/CFS, and the interpretation of the data. These approaches consisted primarily of serological studies using many different virus proteins as antigens; some that are expressed early during the replication cycle of the virus and others that are expressed late. Since the antibody pattern against a virus early protein would not be the same as the antibody pattern against a virus late protein, serology studies using different virus proteins (early vs. late) as antigens could lead to variable results [81,82,83,84,85,86,87,88,89,90,91]. Other studies have employed culture methods and polymerase chain reaction (PCR) methods to determine increased viral load when compared to controls [64,81]. This approach is complicated in the case of the herpesviruses since most adults are latently infected with these viruses and spontaneous asymptomatic reactivation occurs periodically during a person’s lifetime. Furthermore, PCR and culturing approaches will not demonstrate abortive lytic replication, which is reported to occur with several herpesviruses [76,77,78,92,93]. Surprisingly, none of these studies have approached the possibility that two or more herpesviruses may act synergistically and that virus-encoded proteins, rather than the viruses themselves, may act as drivers of or contribute to the pathophysiological alterations observed in a subset of patients with ME/CFS.

    A major problem associated with studies concerning CFS is that while patients exhibit similar symptomology, the triggers and thus the pathways associated with the development of these symptoms may be different. Furthermore, no animal models have been developed that mimic CFS. Our studies have demonstrated that there are elevated antibody levels to the EBV-dUTPase in a subset of ME/CFS patients. Recently, we extended these studies to include ME/CFS patients from a “good day bad day study” and of the 74 patients examined (four longitudinal samples from each patient) 32.34% (n = 24) were negative for antibodies to HHV-6, EBV-, and the human nuclear encoded dUTPase proteins. Some patients expressed antibodies to only HHV-6 (2.7%), EBV (5.41%), or human (6.76%) dUTPases, some co-expressed antibodies (20.27%) to the HHV-6 and EBV dUTPases, but the majority (28.38%) co-expressed antibodies to the HHV-6, EBV-, and human dUTPases [94]. These results not only suggest that there is reactivation of multiple herpesviruses in a subset of patients with ME/CFS, but also that the dUTPases are produced physiologically at sufficient levels to elicit a humoral response. More importantly, as we have shown previously, these viral dUTPases can induce the secretion of pro-inflammatory TH1/TH17 cytokines known to be increased in some ME/CFS patients. Thus, the presence of physiological levels of multiple viral dUTPases may promote/enhance the immune dysregulation observed in some ME/CFS patients. Focusing on the EBV-dUTPase, we have also demonstrated using a mouse model that the EBV- dUTPase induced sickness and anxiety-like behaviors, impaired learning, and memory responses and that chronic restraint stress exacerbated these symptoms [30,33,95].

    A common finding in some patients with ME/CFS is a reduction in NK cell numbers and function. While HHV-8 is not associated with ME/CFS, Madrid and Ganem [34] reported that the dUTPase encoded by the ORF54 gene of HHV-8 downregulated, independent of its enzymatic activity, NKp44L, an uncharacterized ligand for the NK cell activating receptor NKp44. In addition, the ORF54 protein downregulated the expression of specific cytokine receptors, including IL-23R and IFNAR1, suggesting that the HHV-8 dUTPase may alter membrane protein trafficking. Similar results were not observed with EBV or HSV dUTPases. Interestingly, Schmiedel et al. [96] recently reported that HHV-6B downregulates NK cell activation and, although they did not identify the viral protein(s) responsible for this effect, their results suggest it is an early protein. Conversely, our in vitro studies using human primary NK cells demonstrated that direct treatment of NK cells with the EBV-dUTPase did not have an effect on the ability of NK cells to kill K-562 target cells but it did synergize with IL-2 to strongly stimulate the production of IFN-γ (unpublished data).

    There are multiple reports in the literature suggesting a role for HHV-6 [81,82,83,84,85,86] and EBV [87,88,89,90,91] in ME/CFS, but none have examined whether multiple herpesviruses may be reactivated simultaneously in patients, thus contributing to the pathophysiology. The hypothesis that reactivation of multiple herpesviruses may be involved with ME/CFS is supported by clinical studies demonstrating improvement of symptomology in a subset of patients following long-term therapy with valganciclovir, a potent inhibitor of herpesvirus replication, and relapse upon discontinuation of treatment [97,98,99,100]. Further support for a possible involvement of EBV in a subset of patients with ME/CFS comes from studies that reported improvement of symptoms following single treatment and maintenance therapy with Rituximab, an anti-CD20 antibody that effectively depletes B cells but not plasma cells [101,102,103]. According to the investigators, the two- to eight-month delay in symptoms following initiation of therapy suggested that the time delay was needed to eliminate circulating autoantibodies that naturally precedes the observed improvements in ME/CFS [103]. Another possibility relates to the biology of EBV. EBV remains latent in a pool of memory B cells. Differentiation of memory B cells to plasma cells results in the reactivation of the latent virus, primarily abortive lytic replication [76,77,78]. Thus, the delay in clinical improvement may reflect the time that it takes to deplete the memory B cell pool.
    Altogether these data suggest that the expression of these herpesvirus dUTPases may contribute to the symptomology observed in a subset of ME/CFS patients. Furthermore, our data suggest that not only could anti-HHV-6 and EBV-dUTPase antibodies be useful as potential biomarkers for ME/CFS, but also the interaction of these dUTPases with TLR2 or TLR2/TLR1 could be a novel target for the development of therapeutic agents.
     
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  3. anciendaze

    anciendaze Senior Member

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    I'm having trouble downloading the pdf, even though it says it is open access. Could someone who has succeeded post this as an attachment?
     
  4. Kati

    Kati Patient in training

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    Try this one: http://www.mdpi.com/2076-0817/6/1/2/htm
    I will update the link on my original post
     
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  5. edawg81

    edawg81 Senior Member

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    Upstate, NY
    I get the feeling this was from the Dr. Lerner's camp of thought. "Abortive lyctic replication". Glad to see that theory still being discussed. A lot more reseach is needed though.
     
  6. Kati

    Kati Patient in training

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    These authors a have never published with Dr Learner.
    Here you can see a list of publications from Dr Learner: http://www.treatmentcenterforcfs.com/cfs_publications/index.html

    A search on one of the main author, ME Ariza, yielded the folloing publications which shows a deep interest in herpesviruses and DUtPase:
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Ariza ME[Author]&cauthor=true&cauthor_uid=28036046

    I see no connections with dr Lerner whatsoever.
     
  7. Janice Hargreaves

    Janice Hargreaves

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    I found this paper very interesting. Has there been anymore research into this?
     

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