Macrophage Activation Marker Soluble CD163 Associated with Fatal and Severe Ebola Virus Disease in Humans

Ebola virus disease (EVD) is associated with elevated cytokine levels, and hypercytokinemia is more pronounced in fatal cases. This type of hyperinflammatory state is reminiscent of 2 rheumatologic disorders known as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, which are characterized by macrophage and T-cell activation. An evaluation of 2 cohorts of patients with EVD revealed that a marker of macrophage activation (sCD163) but not T-cell activation (sCD25) was associated with severe and fatal EVD. Furthermore, substantial immunoreactivity of host tissues to a CD163-specific antibody, predominantly in areas of extensive immunostaining for Ebola virus antigens, was observed in fatal cases. These data suggest that host macrophage activation contributes to EVD pathogenesis and that directed antiinflammatory therapies could be beneficial in the treatment of EVD.

[1]  Talya Finn,et al.  Two Cases of Israeli Spotted Fever with Purpura Fulminans, Sharon District, Israel , 2018, Emerging infectious diseases.

[2]  M. Han,et al.  Seroprevalence of Severe Fever with Thrombocytopenia Syndrome Virus Antibodies in Rural Areas, South Korea , 2018, Emerging infectious diseases.

[3]  B. Cooper,et al.  Antimicrobial Resistance in Invasive Bacterial Infections in Hospitalized Children, Cambodia, 2007–2016 , 2018, Emerging infectious diseases.

[4]  C. Muñoz-Fontela,et al.  Immune barriers of Ebola virus infection. , 2018, Current opinion in virology.

[5]  M. Katze,et al.  Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm , 2017, mBio.

[6]  Rafael F. Martín-García,et al.  Role of Skin Biopsies in the Diagnosis of Hemophagocytic Lymphohistiocytosis , 2017, The American Journal of dermatopathology.

[7]  C. Agrati,et al.  Different features of Vδ2 T and NK cells in fatal and non-fatal human Ebola infections , 2017, PLoS neglected tropical diseases.

[8]  F. Gusovsky,et al.  The Toll-Like Receptor 4 Antagonist Eritoran Protects Mice from Lethal Filovirus Challenge , 2017, mBio.

[9]  Michael G. Katze,et al.  Ebolaviruses Associated with Differential Pathogenicity Induce Distinct Host Responses in Human Macrophages , 2017, Journal of Virology.

[10]  Cheng Huang,et al.  Macrophage Phenotype in Liver Injury and Repair , 2017, Scandinavian journal of immunology.

[11]  S. Günther,et al.  Ebola Virus Disease Is Characterized by Poor Activation and Reduced Levels of Circulating CD16+ Monocytes. , 2016, The Journal of infectious diseases.

[12]  S. Moestrup,et al.  Plasma Soluble CD163 Level Independently Predicts All-Cause Mortality in HIV-1-Infected Individuals. , 2016, The Journal of infectious diseases.

[13]  Timothy D. Flietstra,et al.  Kinetic Analysis of Biomarkers in a Cohort of US Patients With Ebola Virus Disease. , 2016, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  A. Horne,et al.  Macrophage activation syndrome in the era of biologic therapy , 2016, Nature Reviews Rheumatology.

[15]  Lauren A. Cowley,et al.  Unique human immune signature of Ebola virus disease in Guinea , 2016, Nature.

[16]  C. Wouters,et al.  2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis , 2016, Annals of the rheumatic diseases.

[17]  R. Davey,et al.  Clinical Management of Ebola Virus Disease in the United States and Europe. , 2016, The New England journal of medicine.

[18]  P. Wong,et al.  Macrophage Activation Syndrome-Associated Markers in Severe Dengue , 2016, International journal of medical sciences.

[19]  S. Moestrup,et al.  Plasma Soluble CD 163 Level Independently Predicts All-Cause Mortality in HIV-1 – Infected Individuals , 2016 .

[20]  T. Fletcher,et al.  Clinical presentation, biochemical, and haematological parameters and their association with outcome in patients with Ebola virus disease: an observational cohort study. , 2015, The Lancet. Infectious diseases.

[21]  S. Wang,et al.  Conditions associated with extreme hyperferritinaemia (>3000 μg/L) in adults , 2015, Internal medicine journal.

[22]  P. Periyasamy,et al.  Dengue infection associated hemophagocytic syndrome: Therapeutic interventions and outcome. , 2015, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[23]  Jay B. Varkey,et al.  Human Ebola virus infection results in substantial immune activation , 2015, Proceedings of the National Academy of Sciences.

[24]  M. Netea,et al.  Ebola Virus Disease has Features of Hemophagocytic Lymphohistiocytosis Syndrome , 2015, Front. Med..

[25]  P. Rollin,et al.  Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses , 2015, The Journal of pathology.

[26]  T. Renné,et al.  A case of severe Ebola virus infection complicated by gram-negative septicemia. , 2014, The New England journal of medicine.

[27]  Wei Jiang,et al.  Elevated Soluble CD163 Plasma Levels Are Associated with Disease Severity in Patients with Hemorrhagic Fever with Renal Syndrome , 2014, PloS one.

[28]  Timothy D. Flietstra,et al.  Ebola hemorrhagic Fever: novel biomarker correlates of clinical outcome. , 2014, The Journal of infectious diseases.

[29]  M. George Hemophagocytic lymphohistiocytosis: review of etiologies and management , 2014, Journal of blood medicine.

[30]  B. Kempkes,et al.  Macrophage Polarisation: an Immunohistochemical Approach for Identifying M1 and M2 Macrophages , 2013, PloS one.

[31]  S. Mihm,et al.  Ferritin L is the Sole Serum Ferritin Constituent and a Positive Hepatic Acute-Phase Protein , 2013, Shock.

[32]  J. Dowd,et al.  Seroprevalence of Epstein-Barr Virus Infection in U.S. Children Ages 6-19, 2003-2010 , 2013, PloS one.

[33]  S. Ehl,et al.  Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis , 2013, British journal of haematology.

[34]  N. Wauquier,et al.  Human Fatal Zaire Ebola Virus Infection Is Associated with an Aberrant Innate Immunity and with Massive Lymphocyte Apoptosis , 2010, PLoS neglected tropical diseases.

[35]  M. Hentze,et al.  Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. , 2010, Blood.

[36]  L. Doğancı,et al.  Crimean‐Congo hemorrhagic fever: Five patients with hemophagocytic syndrome , 2008, American journal of hematology.

[37]  A. Sanchez,et al.  Blood chemistry measurements and D-Dimer levels associated with fatal and nonfatal outcomes in humans infected with Sudan Ebola virus. , 2007, The Journal of infectious diseases.

[38]  P. Rollin,et al.  Cytokine and chemokine expression in humans infected with Sudan Ebola virus. , 2007, The Journal of infectious diseases.

[39]  A. Ramanan,et al.  The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. , 2007, Arthritis and rheumatism.

[40]  M. Aricò,et al.  HLH‐2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis , 2007, Pediatric blood & cancer.

[41]  S. Vogel,et al.  Pivotal Advance: Activation of cell surface Toll‐like receptors causes shedding of the hemoglobin scavenger receptor CD163 , 2006, Journal of leukocyte biology.

[42]  M. Kurrer,et al.  Soluble hemoglobin–haptoglobin scavenger receptor CD163 as a lineage‐specific marker in the reactive hemophagocytic syndrome , 2005, European journal of haematology.

[43]  P. Jahrling,et al.  Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. , 2003, The American journal of pathology.

[44]  P. Wallace,et al.  Endotoxin induces rapid metalloproteinase‐mediated shedding followed by up‐regulation of the monocyte hemoglobin scavenger receptor CD163 , 2002, Journal of leukocyte biology.

[45]  M. Georges-Courbot,et al.  Inflammatory responses in Ebola virus‐infected patients , 2002, Clinical and experimental immunology.

[46]  H. Feldmann,et al.  Infection and Activation of Monocytes by Marburg and Ebola Viruses , 2001, Journal of Virology.

[47]  R. Ahmed,et al.  Monocyte-Derived Human Macrophages and Peripheral Blood Mononuclear Cells Infected with Ebola Virus Secrete MIP-1α and TNF-α and Inhibit Poly-IC-Induced IFN-α in Vitro , 2001 .

[48]  Ali S Khan,et al.  A novel immunohistochemical assay for the detection of Ebola virus in skin: implications for diagnosis, spread, and surveillance of Ebola hemorrhagic fever. Commission de Lutte contre les Epidémies à Kikwit. , 1999, The Journal of infectious diseases.

[49]  P. Rollin,et al.  Markedly elevated levels of interferon (IFN)-γ, IFN-α, interleukin (IL)-2, IL-10, and tumor necrosis factor-α associated with fatal Ebola virus infection , 1999 .

[50]  K. Feingold,et al.  Beneficial effects of cytokine induced hyperlipidemia. , 1998, Zeitschrift für Ernährungswissenschaft.

[51]  P. Jahrling,et al.  Enzyme immunosorbent assay for Ebola virus antigens in tissues of infected primates , 1992, Journal of clinical microbiology.

[52]  R. Bechhofer,et al.  Serum CD25 Levels During Interleukin‐2 Therapy: Dose Dependence and Correlations with Clinical Toxicity and Lymphocyte Surface sCD25 Expression , 1992, Journal of immunotherapy : official journal of the Society for Biological Therapy.

[53]  S. Stray,et al.  Plasma ferritin determination as a diagnostic tool. , 1986, The Western journal of medicine.