16. september 2003 

Deregulation of the 2,5A Synthetase RNase L Antiviral Pathway by Mycoplasma
spp. in Subsets of Chronic Fatigue Syndrome

J of Chronic Fatigue Syndrome, Vol. 11 (2) 2003, pp. 37-50

Jo Nijs, MSc; Kenny De Meirleir, MD, PhD; Danny Coomans, PhD;
Pascale De Becker, PhD; Garth L. Nicolson, PhD

Affiliations:
Jo Nijs and Pascale De Becker are affiliated with the Department of Human
Physiology, Faculty of Physical Education and Physiotherapy, Vrije
Universiteit Brussel (VUB), Belgium.
Kenny De Meirleir is affiliated with the Department of Human Physiology,
Faculty of Physical Education and Physiotherapy, and the Chronic Fatigue
Clinic, Vrije Universiteit Brussel (VUB), Belgium.
Danny Coomans is affiliated with the School of Mathematical and Physical
Sciences, James Cook University, Australia.
Garth L. Nicolson is affiliated with the Institute for Molecular Medicine,
Huntington Beach, CA, USA.

Address correspondence to: Jo Nijs, Vakgroep MFYS/Sportgeneeskunde AZ- VUB
KRO gebouw-1, Laarbeeklaan 101, 1090 Brussel, Belgium (E-mail:
mailto:Jo.Nijs@vub.ac.be ).

ABSTRACT. The deregulation of the 2,5A synthetase RNase L antiviral pathway
and the prevalence of Mycoplasma spp. in subsets of Chronic Fatigue
Syndrome (CFS) have been separately reported in the scientific literature.
We hypothesised that a co-morbid pathophysiological mechanism involving
infection by Mycoplasma spp. and the deregulation of the 2,5A
synthetase/RNase L antiviral pathway may exist in CFS. There- fore, 186
consecutive CFS patients were enrolled. Mycoplasma detection was performed
using forensic polymerase chain reaction. For RNase L determination, a
radioactive probe was used to label 2,5A binding proteins in unfractionated
peripheral blood mononuclear cell extracts. Mycoplasma-infected CFS
patients presented with significantly elevated RNase L-ratio, compared to
non-infected age- and sex-matched patients (p = 0.016). These results
suggest that mycoplasma infections may cause deregulation of the 2,5A
synthetase RNase L antiviral pathway in patients with CFS.


KEYWORDS. Chronic fatigue syndrome, mycoplasma, 2,SA synthetase RNase L
antiviral pathway


INTRODUCTION

Chronic Fatigue Syndrome (CFS) is characterised by unexplained, persistent
or relapsing chronic fatigue that is of new or definite onset (1). Several
reports suggested the importance of Mycoplasma spp. infections (2-7) and
the activation/deregulation of the 2',5' oligoadenylate (2,5A) synthetase
RNase L antiviral pathway (8-13) in subsets of CFS patients.

Mycoplasma are prokaryotes that lack a cell wall and certain cellular
organelles. They contain circular DNA and some ribosomes. These
microorganisms can cause opportunistic infections, as seen in the acquired
immune deficiency syndrome and other chronic illnesses, and may produce
some of the signs and symptoms seen in CFS (14, I5). Another feature of
chronic illnesses such as CFS is the deregulation of the 2,SA synthetase
RNase L antiviral pathway, which is characterised by the presence of a 37
kDa (low molecular weight) 2,5A binding protein, instead of the high
molecular weight form (80 kDa) (10). It is important to understand that
this low molecular weight RNase L is not indicative of an activated 2,5A
synthetase RNase L pathway, but instead suggests an improper functioning
(deregulation).

We hypothesised that a co-morbid physiopathological mechanism involving
Mycoplasma spp. infections and the deregulation of the 2,5A
synthetase/RNase L antiviral pathway may exist in subsets of CFS. Indeed,
Mycoplasma spp. are active in stimulating several components of the immune
system. They can act as polyclonal T-cell and B-cell activators (I5,16),
and they can produce components that activate macrophages in vitro (17). To
bring about their phagocytic activity, monocytes produce the proteolytic
enzyme elastase, which enables them to pass through connective tissues.
Elastase is capable of cleaving 80 kDa RNase L (18), thus causing
deregulation of the antiviral pathway. Therefore, we asked whether
deregulation of the 2,5A synthetase RNase L antiviral pathway is associated
with increased prevalence of Mycoplasma infections in CFS patients? To
investigate this research question, we compared the deregulated antiviral
pathway in Mycoplasma-infected and non-infected CFS patients defined by the
criteria of Fukuda et al. (1).

© 2003 by The Haworth Press, Inc. All rights reserved.


[Article copies available for a fee from The Haworth Document Delivery
Service: 1-800-HAWORTH. E-mail address: mailto:docdelivery@haworthpress.com
Web site: http://www.haworthpress.com/store/product.asp?sku=J092 .]