A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and chronic fatigue syndrome

Jos W M Van Der Meer,Stephan P Keijmel,Boris Novakovic,Ruud P H Raijmakers,Leo A B Joosten,Chantal P Bleeker-Rovers,Mihai G Netea,Anne F M Jansen,Rob Ter Horst,Megan E Roerink

doi:10.1186/s12967-019-1906-3

Abstract

BackgroundQ fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections. It has been hypothesized that low grade inflammation plays a role in its aetiology. In this study, we aimed to identify transcriptome profiles that could aid to better understand the pathophysiology of QFS.MethodsRNA of monocytes was collected from QFS patients (n = 10), chronic fatigue syndrome patients (CFS, n = 10), Q fever seropositive controls (n = 10), and healthy controls (n = 10) who were age- (± 5 years) and sex-matched. Transcriptome analysis was performed using RNA sequencing.ResultsMitochondrial-derived peptide (MDP)-coding genes MT-RNR2 (humanin) and MT-RNR1 (MOTS-c) were differentially expressed when comparing QFS (− 4.8 log2-fold-change P = 2.19 × 10−9 and − 4.9 log2-fold-change P = 4.69 × 10−8), CFS (− 5.2 log2-fold-change, P = 3.49 × 10−11 − 4.4 log2-fold-change, P = 2.71 × 10−9), and Q fever seropositive control (− 3.7 log2-fold-change P = 1.78 × 10−6 and − 3.2 log2-fold-change P = 1.12 × 10−5) groups with healthy controls, resulting in a decreased median production of humanin in QFS patients (371 pg/mL; Interquartile range, IQR, 325–384), CFS patients (364 pg/mL; IQR 316–387), and asymptomatic Q fever seropositive controls (354 pg/mL; 292–393).ConclusionsExpression of MDP-coding genes MT-RNR1 (MOTS-c) and MT-RNR2 (humanin) is decreased in CFS, QFS, and, to a lesser extent, in Q fever seropositive controls, resulting in a decreased production of humanin. These novel peptides might indeed be important in the pathophysiology of both QFS and CFS.

Highlights

Q fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections
All QFS patients met the following diagnostic criteria: (i) fatigue lasted ≥ 6 months; (ii) sudden onset of severe fatigue (defined as a score ≥ 35 on the subscale fatigue severity of the Checklist Individual Strength (CIS) questionnaire) [19] (Additional file 1: Table S1), or significant increase in fatigue, both related to a symptomatic acute Q fever infection; iii. chronic Q fever and other somatic or psychiatric causes of fatigue were excluded; and iv. fatigue resulted in significant functional impairment (defined as a total score ≥ 450 on the Sickness Impact Profile-8 (SIP-8) questionnaire) [20] (Additional file 1: Table S2)
All Chronic fatigue syndrome (CFS) patients were diagnosed at the Department of Internal Medicine and Expert Center for Chronic Fatigue (ECCF) of the Radboud university medical center, Nijmegen, the Netherlands, after a uniform workup according to the Centers for Disease Control (CDC) criteria for CFS [21], strengthened with scores on SIP-8 and CIS, subscale on fatigue severity, questionnaires

Summary

Introduction

Q fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections. Q fever is a zoonotic disease caused by the intracellular Gram-negative bacterium Coxiella burnetii. The bacterium primarily infects alveolar macrophages [1, 2]. By subverting host cell functions such as Toll-like receptor (TLR) recognition, apoptosis, and vesicular trafficking, C. burnetii is able to survive and replicate inside the phagolysosome of monocytes and macrophages [2]. The Coxiella Containing Vacuole (CCV), C. burnetii employs a Dot/Icm type IV secretion system through which it manipulates host cell processes [3, 4]. It is assumed that immune competent individuals are able to clear the infection eventually, making Q fever a selflimiting disease

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