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Case Reports
. 2014 Feb 14;9(2):e88716.
doi: 10.1371/journal.pone.0088716. eCollection 2014.

Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside?

Emmanuel Faure  1 , Julien Poissy  2 , Anne Goffard  3 , Clement Fournier  4 , Eric Kipnis  1 , Marie Titecat  5 , Perinne Bortolotti  1 , Laura Martinez  1 , Sylvain Dubucquoi  6 , Rodrigue Dessein  1 , Philippe Gosset  7 , Daniel Mathieu  2 , Benoit Guery  1
Affiliations
Case Reports

Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside?

Emmanuel Faure et al. PLoS One. .

Abstract

One year after the occurrence of the first case of infection by the Middle East Respiratory Syndrome coronavirus (MERS-CoV) there is no clear consensus on the best treatment to propose. The World Health Organization, as well as several other national agencies, are still working on different clinical approaches to implement the most relevant treatment in MERS-CoV infection. We compared innate and adaptive immune responses of two patients infected with MERS-CoV to understand the underlying mechanisms involved in the response and propose potential therapeutic approaches. Broncho-alveolar lavage (BAL) of the first week and sera of the first month from the two patients were used in this study. Quantitative polymerase chain reaction (qRTPCR) was performed after extraction of RNA from BAL cells of MERS-CoV infected patients and control patients. BAL supernatants and sera were used to assess cytokines and chemokines secretion by enzyme-linked immunosorbent assay. The first patient died rapidly after 3 weeks in the intensive care unit, the second patient still recovers from infection. The patient with a poor outcome (patient 1), compared to patient 2, did not promote type-1 Interferon (IFN), and particularly IFNα, in response to double stranded RNA (dsRNA) from MERS-CoV. The absence of IFNα, known to promote antigen presentation in response to viruses, impairs the development of a robust antiviral adaptive Th-1 immune response. This response is mediated by IL-12 and IFNγ that decreases viral clearance; levels of both of these mediators were decreased in patient 1. Finally, we confirm previous in vitro findings that MERS-CoV can drive IL-17 production in humans. Host recognition of viral dsRNA determines outcome in the early stage of MERS-CoV infection. We highlight the critical role of IFNα in this initial stage to orchestrate a robust immune response and bring substantial arguments for the indication of early IFNα treatment during MERS-CoV infection.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Innate immune response against MERS-CoV requires IFNα expression.
A,B,C,D,E,F qRTPCR analysis of RIG-1, MDA-5 IRF3, IRF7, IFNα and IFNβ from first week broncho-alveolar lavage (BAL) cells of MERS-CoV infected patients, patient 1 and patient 2 (black columns), Control (white column), S. pneumoniae-induced pneumonia (dark grey column) and patient 2 Herpes simplex virus-induced pneumonia (light grey column) (n = 2 to 4, duplicates). G Assessment of IFNα protein in BAL supernatants from the first week following onset of clinical symptoms in samples from patient 1 and patient 2. Control group, HSV and bacterial samples from BALs of patients without infection, with lung HSV replication and with upper respiratory tract infection respectively. (n = 2 to 4, duplicates), and assessment of IFNα protein in sera of the 30 days following MERS-CoV infection in patient 1 (black line) and patient 2 (grey line). (n = 2 to 4, duplicates). Measurement obtained between D0–3: day 0 and day 3, D4–7: day 4 and 7, D8–14: day 8 and 14, D15–21: day 15 and 21, D22–30: day 22 and 30.
Figure 2
Figure 2. Adaptive response to control MERS-CoV replication requires early IL-12/IFNγ secretion.
A Assessment of IL-12 and IFNγ protein in BAL supernatants of first week following onset of clinical symptoms of patient 1 and patient 2. Control group, HSV and bacterial were same samples as previously described. (n = 2 to 4, duplicates). B Assessment of IL-12 and IFNγ protein in sera of the 30 days following MERS-CoV infection in Patient 1 (black line) and Patient 2 (grey line). (n = 2 to 4, duplicates). C Assessment of MERS-CoV viral load by quantitative PCR in threshold Cycle (Ct) in serum. Measurement obtained between D0–3: day 0 and day 3, D4–7: day 4 and 7, D8–14: day 8 and 14, D15–21: day 15 and 21, D22–30: day 22 and 30.
Figure 3
Figure 3. Persistent increased levels of CXCL10 and IL-10 are found in the patient with poor outcome during MERS-CoV infection.
Assessment of CXCL10 and IL-10 protein in sera of the 30 days following MERS-CoV infection in patient 1 (black line) and patient 2 (grey line). (n = 2 to 4, duplicates). Measurement obtained between D0–3: day 0 and day 3, D4–7: day 4 and 7, D8–14: day 8 and 14, D15–21: day 15 and 21, D22–30: day 22 and 30.
Figure 4
Figure 4. MERS-CoV induces IL-17 secretion.
A, qRTPCR analysis of IL-17A from first week broncho-alveolar lavage (BAL) cells of MERS-CoV infected patients, Patient 1 and Patient 2 (black columns), Control (white column), S. Pneumoniae-induced pneumonia (dark grey column) and Patient 2 Herpes simplex virus-induced pneumonia (light grey column) (n = 2 to 4, duplicates). B, Assessment of IL-17A and IL-23 protein in BAL supernatants of first week following onset of clinical symptoms of patient 1 and patient 2. Control group, HSV and bacterial were same samples as previously described. (n = 2 to 4, duplicates) C, Assessment of IL-17A and IL-23 protein in sera of the 30 days following MERS-CoV infection in patient 1 (black line) and patient 2 (grey line). (n = 2 to 4, duplicates). Measurement obtained between D0–3: day 0 and day 3, D4–7: day 4 and 7, D8–14: day 8 and 14, D15–21: day 15 and 21, D22–30: day 22 and 30.
Figure 5
Figure 5. Schematic representation of key responses to MERS-CoV related to outcome.
Left panel: Coronavirus are recognized by the immune system through the activation of cytosolic and membranous pattern recognition receptors (MDA-5 and RIG-1). This activation triggers IRF 3 which leads to the production of IFNα. IFN activates anti viral effectors like T CD8+ cells allowing viral clearance. Right panel: In the absence of recognition, the decrease in IRF 3 is associated to a decreased production of IL 12 and IFNγ. IL 10 production further represses IFNγ secretion leading to a decreased CD8 T lymphocytes proliferation and an increased viral replication.
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This study was funded by CHRU Lille, Lille 2 University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.