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Antiviral Pathway Activation in Chronic Fatigue Syndrome and Acute Infection

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www.ProHealth.com • May 14, 2002




Source: Clinical Infectious Diseases
2002; 34:1420-1421
Date: May 15, 2002
URL: http://www.journals.uchicago.edu/CID/journal/available.html
http://www.journals.uchicago.edu/CID/journal/contents/v34n10.html
http://www.journals.uchicago.edu/CID/journal/issues/v34n10/011633/011633.html
Ref: The paper below is a reaction to the paper of Gow et al. of
november 8, 2001 - to be downloaded from the ME-NET list archive:
http://listserv.surfnet.nl/SCRIPTS/WA.EXE?A2=ind0111B&L=me-net&P=R3111


[Correspondence]


Kenny De Meirleir,1 Robert J. Suhadolnik,3 Bernard Lebleu,2 and Patrick Englebienne 1

1 Free University, Brussels, Belgium;
2 Institut de Genetique Moleculaire, Universite de Montpellier, France; and 3 Temple University School of Medicine, Philadelphia, Pennsylvania

Reprints or correspondence: Dr. Patrick Englebienne, Free University of
Brussels, Brugman University Hospital, Dept. of Nuclear Medicine, Place van
Gehuchten 4, B-1020 Brussels, Belgium (penglebi@ulb.ac.be).


SIR - We read the very engaging report by Gow et al. [1] with the utmost interest. However, we feel that this article raises more questions than clear-cut answers regarding the hypothesis that motivated the study
- that is, that the previously reported activation of the antiviral pathway in chronic fatigue syndrome (CFS) might be linked to infection rather than to CFS specifically. To verify their hypothesis, Gow and colleagues used PCR to measure the genetic expression of 3 IFN-regulated genes - namely, the latent ribonuclease (RNase L), RNA-regulated protein kinase (PKR), 2,5 synthetase, and the RNase L inhibitor (RLI) - in patients with acute infection (in their study, severe gastroenteritis; group 1), patients with CFS (group 2), and healthy control subjects (group 3).

First, surprisingly enough, although they recognized that acute infection is supposed to induce the expression of the genes selected for their study (see figure 1 of [1]), Gow and colleagues failed to find any significant increase in the expression of 2 major genes (RNase L and 2,5
synthetase) in group 1, as compared with groups 2 and 3; they observed only increased mRNA for PKR and RLI. Although it is recognized that genetic expression of PKR, RNase L, and 2,5 synthetase is under the control of interferon, RLI is definitely not [2]. Upregulation of RLI genetic expression with a normal genetic expression of both 2,5 synthetase and RNase L (although PKR is overexpressed!) during acute infection, as was observed in the study of Gow et al. [1], would indicate not only that RNase L is not activated (normal expression of RNase L and, more importantly, of 2,5 synthetase), but that it is further inhibited by an overexpressed RLI [2]. Such a scenario, if verified, would be in complete disagreement with the current understanding of the IFN pathway [3]. Therefore, we cannot help but wonder how Gow and colleagues reconcile their observations with the acute infection status of study group 1. In our view, this inconsistency severely undermines their conclusions.

Second, Gow et al. [1] do not confirm their observations of genetic expression at the translational level, which would have increased the validity of their results. Finally, the authors interchangeably used the terms "genetic expression" and "activation," which are not necessarily interrelated notions, particularly when research involves enzymes, such as in their study. The level of genetic or protein expression of enzymes (such as PKR, RNase L, and 2,5 synthetase) is indeed not necessarily directly related to their catalytic activation, which requires the further presence of coactivators (2',5'-oligoadenylates and polynucleotides, in this case). Unfortunately, this aspect was not investigated by Gow et al. [1], and the confusion in the authors' minds regarding these 2 notions led them to misquote the articles by Suhadolnik et al. [4] and De Meirleir et al. [5].

Over the years, our teams have repeatedly observed an activation at the enzymatic level of the antiviral pathway in subsets of patients with CFS, concomitant with the appearance of a truncated 37-kDa RNase L that was produced by proteolytic cleavage and that retains catalytic activity [6, 7]. On the basis of their limited observations, Gow et al. [1] challenge our observations and further deny any rational basis to our proposal regarding the use of 37-kDa RNase L detection as a biological marker for CFS [5]. In our study, which they clearly misquoted, we did not measure the enzymatic activity of the fragment and, hence, the 2-5A pathway activation, as Gow and colleagues claimed [1]. Instead, we limited our study to the quantitative detection of the 37-kDa truncated enzyme, as measured by its capacity to bind a radioactive 2-5A probe. We observed a significant increase in the 37-kDa RNase L level in patients with CFS, compared with that observed in healthy control subjects, patients with fibromyalgia, and patients with depression. Both of the latter groups are perhaps as susceptible to chronic infections as are patients with CFS, if not more so [8]. Consequently, this does not support the claim that the presence of the 37-kDa RNase L in CFS could only be imparted to residual nonspecific increases in the antiviral pathway activation [1].

More-recent data from our laboratories [9] extend the implications of our earlier observations of the biological understanding of the CFS immune dysfunction. Our data demonstrate that there is a more-comprehensive downstream cellular role for the signal transduction by IFN in the antiviral pathway [3] than what Gow and colleagues pretend to present to the readers of Clinical Infectious Diseases.


References

1. Gow JW, Simpson K, Behan PO, Chaudhuri A, McKay IC, Behan WMH.
Antiviral pathway activation in patients with chronic fatigue syndrome and
acute infection. Clin Infect Dis 2001; 33:2080-1

2. Bisbal C, Martinand C, Silhol M, Lebleu B, Sahlezahda T.
Cloning and characterization of a RNase L inhibitor: a new component of the
interferon-regulated pathway. J Biol Chem 1995; 270:13308-17. 3. Stark GR, Kerr IM, Williams BRG, Silverman RH, Schreiber RD.

How cells respond to interferons. Annu Rev Biochem 1998; 67:227-64. 4. Suhadolnik RJ, Reichenbach NL, Hitzges P, et al.

Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled
clinical trial with poly(I)-Poly(C12U) in chronic fatigue syndrome. In Vivo
1994; 8:599-604.

5. De Meirleir K, Bisbal C, Campine I, et al.
A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic
fatigue syndrome. Am J Med 2000; 108:99-173.

6. Roelens S, Herst CV, D'Haese A, et al.

G-Actin cleavage parallels 2-5A - dependent RNase L cleavage in peripheral
monocellular cells - relevance to a possible serum-based screening test for
dysregulations in the 2-5A pathway. J Chronic Fatigue Syndrome 2001; 8:
63-82.

7. Shetzline SE, Suhadolnik RJ.

Characterization of a 2-5A - dependent 37-kDa RNase L: azido photoaffinity
labeling and 2-5A - dependent activation. J Biol Chem 2001; 276: 23707-11. 8. Goulding C, O'Connell P, Murray FE.

Prevalence of fibromyalgia, anxiety and depression in chronic hepatitis C
virus infection: relationship to RT-PCR status and mode of acquisition. Eur
J Gastroenterol Hepatol 2001; 13:507-11.

9. Englebienne P, De Meirleir K, eds. Chronic fatigue syndrome: a biological
approach. Boca Raton, FL: CRC Press, 2002.

(c) 2002 by the Infectious Diseases Society of America.



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