User talk:Kmdenmark/EBV-dUTPase

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Deleted from EBV page: In 2016, a study by Williams, et al, looked at lytic proteins produced during reactivation of the Epstein-Barr virus, in particular the deoxyuridine triphosphate nucleotidohydrolases (dUTPase), as key modulators of the host innate and adaptive immune responses. They considered "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."[1]

[1]

Williams, 2016 study:

4.1. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

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.

myalgic encephalomyelitis (ME) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

myalgic encephalomyelitis (ME) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

assay 1. (verb) analysis (as of an ore or drug) to determine the presence, absence, or quantity of one or more components. 2. (noun) In biochemistry, any laboratory protocol used to test a sample for one or more qualities.

antibodies Antibodies or immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

antibodies Antibodies or immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

physiological Concerning living organisms, such as cells or the human body.  Physio logical (as in physio) is not to be confused with psych ological (emotional stress).

cytokine any class of immunoregulatory proteins secreted by cells, especially immune cells. Cytokines are small proteins important in cell signaling that modulate the immune system. (Learn more: me-pedia.org)

mouse model The use of special strains of mice to study a human disease or condition, and how to prevent and treat it

membrane The word "membrane" can have different meanings in different fields of biology. In cell biology, a membrane is a layer of molecules that surround its contents. Examples of cell-biology membranes include the "cell membrane" that surrounds a cell, the "mitochondrial membranes" that form the outer layers of mitochondria, and the "viral envelope" that surrounds enveloped viruses. In anatomy or tissue biology, a membrane is a barrier formed by a layer of cells. Examples of anatomical membranes include the pleural membranes that surrounds the lungs, the pericardium which surrounds the heart, and some of the layers within the blood-brain barrier.

γ γ / Γ. Greek letter gamma/gamme (symbol), third letter of the Greek alphabet.

B cell B lymphocyte, or a type of white blood cell, which is involved in the immune response by secreting antibodies to ward off infections. In mammals, they are mostly matured in the bone marrow.

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