Upregulation of the 2-5A Synthetase/RNase L Antiviral Pathway Associated with Chronic Fatigue Syndrome

Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
Clinical Infectious Diseases (Impact Factor: 8.89). 01/1994; 18 Suppl 1(Supplement 1):S96-104. DOI: 10.1093/clinids/18.Supplement_1.S96
Source: PubMed


Levels of 2',5'-oligoadenylate (2-5A) synthetase, bioactive 2-5A, and RNase L were measured in extracts of peripheral blood mononuclear cells (PBMCs) from 15 individuals with chronic fatigue syndrome (CFS) before and during therapy with the biological response modifier poly(I).poly(C12U) and were compared with levels in healthy controls. Patients differed significantly from controls in having a lower mean basal level of latent 2-5A synthetase (P < .0001), a higher pretreatment level of bioactive 2-5A (P = .002), and a higher level of pretherapy RNase L activity (P < .0001). PBMC extracts from 10 persons with CFS had a mean basal level of activated 2-5A synthetase higher than the corresponding control value (P = .009). All seven pretherapy PBMC extracts tested were positive for the replication of human herpesvirus 6 (HHV-6). Therapy with poly(I).poly(C12U) resulted in a significant decrease in HHV-6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNase L pathway in temporal association with clinical and neuropsychological improvement. The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of CFS. The response to therapy suggests direct or indirect antiviral activity of poly(I).poly(C12U) in this situation.

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    • "Free radicals, certain viruses, and inflammatory cytokines can also activate NF-nB and there is recent evidence pointing to an up-regulation of NF-nB in CFS patients [24]. HDL may also have antiviral properties [25] and the significantly reduced levels measured in our CFS patient group may reflect impaired antiviral defence pathways that are characteristic of this patient population [26] [27] as well as exposing them to increased cardiovascular risk. "
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    ABSTRACT: The aetiology of chronic fatigue syndrome (CFS) is unknown; however, recent evidence suggests excessive free radical (FR) generation may be involved. This study investigated for the first time levels of 8-iso-prostaglandin-F(2 alpha)-isoprostanes alongside other plasma markers of oxidative stress in CFS patients and control subjects. Forty-seven patients (18 males, 29 females, mean age 48 [19--63] years) who fulfilled the Centres for Disease Control classification for CFS and 34 healthy volunteers (13 males, 21 females, 46 [19--63] years) were enrolled in the study. The CFS patients were divided into two groups; one group had previously defined cardiovascular (CV) risk factors of obesity and hypertension (group 1) and the second were normotensive and nonobese (group 2). Patients had significantly increased levels of isoprostanes (group 1, P=0.007; group 2, P=0.03, unpaired t test compared to controls) and oxidised low-density lipoproteins (group 2, P=0.02) indicative of a FR attack on lipids. CFS patients also had significantly lower high-density lipoproteins (group 1, P=0.011; group 2, P=0.005). CFS symptoms correlated with isoprostane levels, but only in group 2 low CV risk CFS patients (isoprostanes correlated with; total symptom score P=0.005; joint pain P=0.002; postexertional malaise P=0.027, Pearson). This is the first time that raised levels of the gold standard measure of in vivo oxidative stress (isoprostanes) and their association with CFS symptoms have been reported.
    Free Radical Biology and Medicine 10/2005; 39(5):584-9. DOI:10.1016/j.freeradbiomed.2005.04.020 · 5.74 Impact Factor
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    • "Despite the fact that viral infection has been ruled out as a general cause for the condition (Soto and Straus, 2000), the issue remains controversial because a dysregulation of the IFN/2-5A antiviral pathway has been repeatedly found in the PBMC of CFS patients. This dysregulation involves an upregulation of both 2-5OAS and RNase L activity (Ikuta et al., 2003; Suhadolnik et al., 1994a,b), along with the presence of an abnormal truncated 2-5A-binding protein of 37-kDa (Suhadolnik et al., 1997). This LMW protein binds 2-5A (De Meirleir et al., 2000; Shetzline and Suhadolnik, 2001), displays an enhanced 2- 5A-dependent catalytic activity when compared to the 83- kDa native enzyme (Shetzline and Suhadolnik, 2001) and is likely to share the 2-5A-binding and catalytic sites with the 83-kDa protein (Shetzline et al., 2002). "
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    ABSTRACT: A dysregulation in the 2',5'-oligoadenylate (2-5A)-dependent RNase L antiviral pathway has been detected in peripheral blood mononuclear cells (PBMC) of chronic fatigue syndrome (CFS) patients, which is characterized by upregulated 2-5A synthetase and RNase L activities, as well as by the presence of a low molecular weight (LMW) 2-5A-binding protein of 37-kDa related to RNase L. This truncated protein has been shown to originate from proteolytic cleavage of the native 83-kDa RNase L by m-calpain and human leukocyte elastase (HLE). We investigated the possible role of 2-5A oligomers in the proteolytic action toward the endonuclease and show that incubation of CFS PBMC extracts with 2-5A trimer and tetramer, but not with the dimer, results in a significant protection of the native 83-kDa RNase L against cleavage by endogenous and purified proteases. Similar results are obtained with a purified recombinant RNase L. An analysis of the size of 2-5A oligomers produced by the catalytic activity of the 2-5A synthetase present in PBMC extracts further shows that samples containing the 37-kDa RNase L preferentially produce 2-5A dimers instead of higher oligomers. Taken together, our results indicate that homodimerization of RNase L by 2-5A oligomers higher than the dimer prevents its cleavage by proteolytic enzymes. The presence of the truncated 37-kDa RNase L in PBMC extracts is therefore likely to result, not only from the abnormal activation of inflammatory proteases, but also from a dysregulation in 2-5A synthetase induction or activation towards the preferential production of 2-5A dimers.
    Experimental and Molecular Pathology 07/2005; 78(3):239-46. DOI:10.1016/j.yexmp.2005.01.003 · 2.71 Impact Factor
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    • "Our current understanding of pathoimmunity of CFS, together with the observations by Vikman et al. [23], provides a hypothetical explanation Pain in patients with chronic fatigue syndrome 559 for chronic widespread pain as seen in a large subgroup of CFS patients. The deregulation of the 2 0 ,5 0 -oligoadenylate (2-5A) synthetase/RNase L pathway in subsets of CFS patients has been reported at length in the scientific literature [24] [25]. Both elastases and calpain are capable of initiating high molecular weight RNase L (83 kDa) proteolysis, generating two major fragments with molecular masses of 37 (a truncated low molecular weight RNase L) and 30 kDa, respectively, [26] (Fig. 1). "
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    ABSTRACT: Previous studies have provided evidence supportive of the clinical importance of widespread pain in patients with chronic fatigue syndrome (CFS): pain severity may account for 26-34% of the variability in the CFS patient's activity limitations and participation restrictions. The etiology of widespread pain in CFS remains to be elucidated, but sensitisation of the central nervous system has been suggested to take part of CFS pathophysiology. It is hypothesised that a nitric oxide (NO)-dependent reduction in inhibitory activity of the central nervous system and consequent central sensitisation accounts for chronic widespread pain in CFS patients. In CFS patients, deregulation of the 2',5'-oligoadenylate synthetase/RNase L pathway is accompanied by activation of the protein kinase R enzyme. Activation of the protein kinase R and subsequent nuclear factor-kappaB activation might account for the increased production of NO, while infectious agents frequently associated with CFS (Coxsackie B virus, Epstein-Barr Virus, Mycoplasma) might initiate or accelerate this process. In addition, the evidence addressing behavioural changes in CFS patients fits the central sensitisation-hypothesis: catastrophizing, avoidance behaviour, and somatization may result in, or are initiated by sensitisation of the central nervous system.
    Medical Hypotheses 02/2005; 64(3):558-62. DOI:10.1016/j.mehy.2004.07.037 · 1.07 Impact Factor
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