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1
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Jayaraman A, Walachowski S, Bosmann M. The complement system: A key player in the host response to infections. Eur J Immunol 2024; 54:e2350814. [PMID: 39188171 PMCID: PMC11623386 DOI: 10.1002/eji.202350814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 08/28/2024]
Abstract
Infections are one of the most significant healthcare and economic burdens across the world as underscored by the recent coronavirus pandemic. Moreover, with the increasing incidence of antimicrobial resistance, there is an urgent need to better understand host-pathogen interactions to design effective treatment strategies. The complement system is a key arsenal of the host defense response to pathogens and bridges both innate and adaptive immunity. However, in the contest between pathogens and host defense mechanisms, the host is not always victorious. Pathogens have evolved several approaches, including co-opting the host complement regulators to evade complement-mediated killing. Furthermore, deficiencies in the complement proteins, both genetic and therapeutic, can lead to an inefficient complement-mediated pathogen eradication, rendering the host more susceptible to certain infections. On the other hand, overwhelming infection can provoke fulminant complement activation with uncontrolled inflammation and potentially fatal tissue and organ damage. This review presents an overview of critical aspects of the complement-pathogen interactions during infection and discusses perspectives on designing therapies to mitigate complement dysfunction and limit tissue injury.
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Affiliation(s)
- Archana Jayaraman
- Department of Medicine, Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Sarah Walachowski
- Department of Medicine, Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Markus Bosmann
- Department of Medicine, Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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2
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Detsika MG, Palamaris K, Dimopoulou I, Kotanidou A, Orfanos SE. The complement cascade in lung injury and disease. Respir Res 2024; 25:20. [PMID: 38178176 PMCID: PMC10768165 DOI: 10.1186/s12931-023-02657-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 12/26/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND The complement system is an important arm of immune defense bringing innate and adaptive immunity. Although originally regarded as a major complementary defense mechanism against pathogens, continuously emerging evidence has uncovered a central role of this complex system in several diseases including lung pathologies. MAIN BODY Complement factors such as anaphylatoxins C3a and C5a, their receptors C3aR, C5aR and C5aR2 as well as complement inhibitory proteins CD55, CD46 and CD59 have been implicated in pathologies such as the acute respiratory distress syndrome, pneumonia, chronic obstructive pulmonary disease, asthma, interstitial lung diseases, and lung cancer. However, the exact mechanisms by which complement factors induce these diseases remain unclear. Several complement-targeting monoclonal antibodies are reported to treat lung diseases. CONCLUSIONS The complement system contributes to the progression of the acute and chronic lung diseases. Better understanding of the underlying mechanisms will provide groundwork to develop new strategy to target complement factors for treatment of lung diseases.
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Affiliation(s)
- M G Detsika
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 3, Ploutarchou St., 10675, Athens, Greece.
| | - K Palamaris
- 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - I Dimopoulou
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 3, Ploutarchou St., 10675, Athens, Greece
| | - A Kotanidou
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 3, Ploutarchou St., 10675, Athens, Greece
| | - S E Orfanos
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 3, Ploutarchou St., 10675, Athens, Greece.
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3
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Schmidt C, Weißmüller S, Heinz CC. Multifaceted Tissue-Protective Functions of Polyvalent Immunoglobulin Preparations in Severe Infections-Interactions with Neutrophils, Complement, and Coagulation Pathways. Biomedicines 2023; 11:3022. [PMID: 38002022 PMCID: PMC10669904 DOI: 10.3390/biomedicines11113022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/30/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Severe infections induce immune defense mechanisms and initial tissue damage, which produce an inflammatory neutrophil response. Upon dysregulation of these responses, inflammation, further tissue damage, and systemic spread of the pathogen may occur. Subsequent vascular inflammation and activation of coagulation processes may cause microvascular obstruction at sites distal to the primary site of infection. Low immunoglobulin (Ig) M and IgG levels have been detected in patients with severe infections like sCAP and sepsis, associated with increased severity and mortality. Based on Ig's modes of action, supplementation with polyvalent intravenous Ig preparations (standard IVIg or IgM/IgA-enriched Ig preparations) has long been discussed as a treatment option for severe infections. A prerequisite seems to be the timely administration of Ig preparations before excessive tissue damage has occurred and coagulopathy has developed. This review focuses on nonclinical and clinical studies that evaluated tissue-protective activities resulting from interactions of Igs with neutrophils, complement, and the coagulation system. The data indicate that coagulopathy, organ failure, and even death of patients can possibly be prevented by the timely combined interactions of (natural) IgM, IgA, and IgG with neutrophils and complement.
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Affiliation(s)
- Carolin Schmidt
- Department of Corporate Clinical Research and Development, Biotest AG, 63303 Dreieich, Germany
| | | | - Corina C Heinz
- Department of Corporate Clinical Research and Development, Biotest AG, 63303 Dreieich, Germany
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4
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Modulation of Neutrophil Activity by Soluble Complement Cleavage Products—An In-Depth Analysis. Cells 2022; 11:cells11203297. [PMID: 36291163 PMCID: PMC9600402 DOI: 10.3390/cells11203297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 09/26/2022] [Accepted: 10/01/2022] [Indexed: 11/16/2022] Open
Abstract
The cellular and fluid phase-innate immune responses of many diseases predominantly involve activated neutrophil granulocytes and complement factors. However, a comparative systematic analysis of the early impact of key soluble complement cleavage products, including anaphylatoxins, on neutrophil granulocyte function is lacking. Neutrophil activity was monitored by flow cytometry regarding cellular (electro-)physiology, cellular activity, and changes in the surface expression of activation markers. The study revealed no major effects induced by C3a or C4a on neutrophil functions. By contrast, exposure to C5a or C5a des-Arg stimulated neutrophil activity as reflected in changes in membrane potential, intracellular pH, glucose uptake, and cellular size. Similarly, C5a and C5a des-Arg but no other monitored complement cleavage product enhanced phagocytosis and reactive oxygen species generation. C5a and C5a des-Arg also altered the neutrophil surface expression of several complement receptors and neutrophil activation markers, including C5aR1, CD62L, CD10, and CD11b, among others. In addition, a detailed characterization of the C5a-induced effects was performed with a time resolution of seconds. The multiparametric response of neutrophils was further analyzed by a principal component analysis, revealing CD11b, CD10, and CD16 to be key surrogates of the C5a-induced effects. Overall, we provide a comprehensive insight into the very early interactions of neutrophil granulocytes with activated complement split products and the resulting neutrophil activity. The results provide a basis for a better and, importantly, time-resolved and multiparametric understanding of neutrophil-related (patho-)physiologies.
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5
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Gianni P, Goldin M, Ngu S, Zafeiropoulos S, Geropoulos G, Giannis D. Complement-mediated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A review. World J Exp Med 2022; 12:53-67. [PMID: 36157337 PMCID: PMC9350720 DOI: 10.5493/wjem.v12.i4.53] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/27/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) causes acute microvascular thrombosis in both venous and arterial structures which is highly associated with increased mortality. The mechanisms leading to thromboembolism are still under investigation. Current evidence suggests that excessive complement activation with severe amplification of the inflammatory response (cytokine storm) hastens disease progression and initiates complement-dependent cytotoxic tissue damage with resultant prothrombotic complications. The concept of thromboinflammation, involving overt inflammation and activation of the coagulation cascade causing thrombotic microangiopathy and end-organ damage, has emerged as one of the core components of COVID-19 pathogenesis. The complement system is a major mediator of the innate immune response and inflammation and thus an appealing treatment target. In this review, we discuss the role of complement in the development of thrombotic microangiopathy and summarize the current data on complement inhibitors as COVID-19 therapeutics.
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Affiliation(s)
- Panagiota Gianni
- Department of Internal Medicine III, Hematology, Oncology, Palliative Medicine, Rheumatology and Infectious Diseases, University Hospital Ulm, Ulm 89070, Germany
| | - Mark Goldin
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, New York, NY 11549, United States
- Feinstein Institutes for Medical Research at Northwell Health, Feinstein Institutes , New York, NY 11030, United States
| | - Sam Ngu
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, New York, NY 11549, United States
| | - Stefanos Zafeiropoulos
- Elmezzi Graduate School of Molecular Medicine, Northwell Health, New York, NY 11030, United States
| | - Georgios Geropoulos
- Department of General Surgery, University College London Hospitals, London NW12BU, United Kingdom
| | - Dimitrios Giannis
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, New York, NY 11549, United States
- North Shore/Long Island Jewish General Surgery, Northwell Health, New York, NY 11021, United States
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6
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Perico L, Morigi M, Galbusera M, Pezzotta A, Gastoldi S, Imberti B, Perna A, Ruggenenti P, Donadelli R, Benigni A, Remuzzi G. SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation. Front Immunol 2022; 13:827146. [PMID: 35320941 PMCID: PMC8936079 DOI: 10.3389/fimmu.2022.827146] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Microvascular thrombosis is associated with multiorgan failure and mortality in coronavirus disease 2019 (COVID-19). Although thrombotic complications may be ascribed to the ability of SARS-CoV-2 to infect and replicate in endothelial cells, it has been poorly investigated whether, in the complexity of viral infection in the human host, specific viral elements alone can induce endothelial damage. Detection of circulating spike protein in the sera of severe COVID-19 patients was evaluated by ELISA. In vitro experiments were performed on human microvascular endothelial cells from the derma and lung exposed to SARS-CoV-2-derived spike protein 1 (S1). The expression of adhesive molecules was studied by immunofluorescence and leukocyte adhesion and platelet aggregation were assessed under flow conditions. Angiotensin converting enzyme 2 (ACE2) and AMPK expression were investigated by Western Blot analysis. In addition, S1-treated endothelial cells were incubated with anti-ACE2 blocking antibody, AMPK agonist, or complement inhibitors. Our results show that significant levels of spike protein were found in the 30.4% of severe COVID-19 patients. In vitro, the activation of endothelial cells with S1 protein, via ACE2, impaired AMPK signalling, leading to robust leukocyte recruitment due to increased adhesive molecule expression and thrombomodulin loss. This S1-induced pro-inflammatory phenotype led to exuberant C3 and C5b-9 deposition on endothelial cells, along with C3a and C5a generation that further amplified S1-induced complement activation. Functional blockade of ACE2 or complement inhibition halted S1-induced platelet aggregates by limiting von Willebrand factor and P-selectin exocytosis and expression on endothelial cells. Overall, we demonstrate that SARS-CoV-2-derived S1 is sufficient in itself to propagate inflammatory and thrombogenic processes in the microvasculature, amplified by the complement system, recapitulating the thromboembolic complications of COVID-19.
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Affiliation(s)
- Luca Perico
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Marina Morigi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Miriam Galbusera
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Anna Pezzotta
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Sara Gastoldi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Barbara Imberti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Annalisa Perna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Piero Ruggenenti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
- Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Roberta Donadelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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7
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Fukuoka K, Kishimoto M, Kawakami T, Komagata Y, Kaname S. Plasmapheresis for systemic vasculitis. Ther Apher Dial 2022; 26:493-506. [PMID: 35247230 PMCID: PMC9311821 DOI: 10.1111/1744-9987.13829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 01/26/2022] [Indexed: 11/28/2022]
Abstract
Systemic vasculitides include a variety of, and numerous diseases. In 2012, the International CHAPEL HILL Consensus Conference (CHCC2012) led to a major reorganization of the classification of vasculitis, and this is still in wide use today. Although the results of plasmapheresis for individual diseases have been sometimes shown, there are few systematic reviews that discuss the effects along with vasculitis classification. Therefore, we will discuss the efficacy and the latest evidence for each vasculitis according to the CHCC 2012 classification in this review. This review provides a comprehensive overview of the estimation of plasmapheresis in each of the vasculitides, with a particular focus on small vasculitides, which have recently discussed frequently. For some time now, plasma exchange therapy (PEX) has been frequently used and is expected to be effective in some diseases, most of which are included in small vessel vasculitides. In particular, data showing efficacy have been accumulated for immune complex vasculitis, and the recommendation seems to be high. For instance, anti‐GBM nephritis, concomitant use of PEX is essential and strongly recommended. On the other hand, for ANCA‐related vasculitis among small vessel vasculitis, RCTs have recently shown negative results. In particular, the PEXIVAS trial statistically showed that PEX has no potential to reduce the mortality and renal death in AAV, but the ASFA, ACR, and KDIGO guidelines following this trial all regard PEX as salvage therapy or selective treatment for severe cases. As plasmapheresis is often performed in combination with other therapies, it is difficult to evaluate to clarify its efficacy on its own, and this predisposition may be pronounced in vasculitis, a rare disease. Although statistically significant differences are not apparent, the diseases that show a trend toward efficacy may possibly include treatment‐sensitive subgroups. Further analysis is expected in the future.
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Affiliation(s)
- Kazuhito Fukuoka
- Kyorin University School of Medicine, department of Nephrology and Rheumatology
| | - Mitsumasa Kishimoto
- Kyorin University School of Medicine, department of Nephrology and Rheumatology
| | - Takahisa Kawakami
- Kyorin University School of Medicine, department of Nephrology and Rheumatology
| | - Yosinori Komagata
- Kyorin University School of Medicine, department of Nephrology and Rheumatology
| | - Shinya Kaname
- Kyorin University School of Medicine, department of Nephrology and Rheumatology
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8
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Abstract
Hyperactivation of the complement and coagulation systems is recognized as part of the clinical syndrome of COVID-19. Here we review systemic complement activation and local complement activation in response to the causative virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their currently known relationships to hyperinflammation and thrombosis. We also provide an update on early clinical findings and emerging clinical trial evidence that suggest potential therapeutic benefit of complement inhibition in severe COVID-19.
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Affiliation(s)
- Behdad Afzali
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
| | - Marina Noris
- Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", Ranica, Italy.
- "Centro Anna Maria Astori", Bergamo, Italy.
| | - Bart N Lambrecht
- Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
- Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
| | - Claudia Kemper
- Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
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9
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Chauss D, Freiwald T, McGregor R, Yan B, Wang L, Nova-Lamperti E, Kumar D, Zhang Z, Teague H, West EE, Vannella KM, Ramos-Benitez MJ, Bibby J, Kelly A, Malik A, Freeman AF, Schwartz DM, Portilla D, Chertow DS, John S, Lavender P, Kemper C, Lombardi G, Mehta NN, Cooper N, Lionakis MS, Laurence A, Kazemian M, Afzali B. Autocrine vitamin D signaling switches off pro-inflammatory programs of T H1 cells. Nat Immunol 2022; 23:62-74. [PMID: 34764490 PMCID: PMC7612139 DOI: 10.1038/s41590-021-01080-3] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/26/2021] [Indexed: 12/15/2022]
Abstract
The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.
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Affiliation(s)
- Daniel Chauss
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA
| | - Tilo Freiwald
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA
- Medic Clinic III, Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt, Germany
| | - Reuben McGregor
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA
- Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Auckland, New Zealand
| | - Bingyu Yan
- Department of Biochemistry, Purdue University, West Lafayette, IN, USA
| | - Luopin Wang
- Department of Computer Science, Purdue University, West Lafayette, IN, USA
| | - Estefania Nova-Lamperti
- Molecular and Translational Immunology Laboratory, Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepcion, Concepcion, Chile
| | - Dhaneshwar Kumar
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA
- Department of Computer Science, Purdue University, West Lafayette, IN, USA
| | - Zonghao Zhang
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN, USA
| | - Heather Teague
- Laboratory of Inflammation & Cardiometabolic Diseases, Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA
| | - Erin E West
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA
| | - Kevin M Vannella
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA
- Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Marcos J Ramos-Benitez
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA
- Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Jack Bibby
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA
| | - Audrey Kelly
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Amna Malik
- Department of Medicine, Imperial College London, London, UK
| | - Alexandra F Freeman
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA
| | - Daniella M Schwartz
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA
| | - Didier Portilla
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA
- Division of Nephrology and the Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA
| | - Daniel S Chertow
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA
- Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Susan John
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Paul Lavender
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Claudia Kemper
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Nehal N Mehta
- Laboratory of Inflammation & Cardiometabolic Diseases, Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA
| | - Nichola Cooper
- Department of Medicine, Imperial College London, London, UK
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA
| | - Arian Laurence
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Majid Kazemian
- Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
- Department of Computer Science, Purdue University, West Lafayette, IN, USA.
| | - Behdad Afzali
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA.
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10
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Ohta R, Sano C. Severe Immune Thrombocytopenic Purpura Following Influenza Vaccination: A Case Report. Cureus 2022; 14:e21250. [PMID: 35186538 PMCID: PMC8844186 DOI: 10.7759/cureus.21250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/14/2022] [Indexed: 11/05/2022] Open
Abstract
Immune thrombocytopenia (ITP) is a rare, acquired bleeding disorder caused by various underlying etiologies. ITP can be triggered by medication, infections, cancers, and autoimmune diseases. One of the rare triggers is vaccination. As in many cases, the symptoms are mild and the cause is idiopathic, and it may not be diagnosed without extensive investigations. It can also be difficult to differentiate between medication-induced thrombocytopenia and ITP, particularly in older patients with multiple comorbidities and receiving multiple medications. Here, we describe an older patient with acute onset ITP following influenza vaccination. An 88-year-old man presented with complaints of systemic itchiness and bleeding from his mouth. Four days prior to the symptoms appearing, he had received an influenza vaccine and did not experience any severe pain or anaphylactic symptoms. On presentation, he had multiple bleeding blisters and systemic petechiae. Blood tests revealed a platelet count of 1000/µL. A month prior, his platelet count was 1.5×105/µL. The blood culture results were negative and a bone marrow biopsy revealed multiple megakaryocytes, without blastocytes or evidence of hemophagocytosis. The patient was diagnosed with influenza vaccine-induced severe ITP and was treated with intravenous high-dose prednisolone. Although vaccine-related ITP is rare, in patients with systemic symptoms, primary care physicians should perform systematic physical examinations to detect any hemorrhage, as ITP is a possibility.
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Affiliation(s)
- Ryuichi Ohta
- Communiy Care, Unnan City Hospital, Unnan, Shimane, JPN
| | - Chiaki Sano
- Community Medicine Management, Shimane University Faculty of Medicine, Izumo, JPN
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11
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Fodil S, Annane D. Complement Inhibition and COVID-19: The Story so Far. Immunotargets Ther 2021; 10:273-284. [PMID: 34345614 PMCID: PMC8323860 DOI: 10.2147/itt.s284830] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/16/2021] [Indexed: 12/14/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is the most severe complication of COVID-19, a disease caused by severe acute respiratory syndrome coronavirus (SARS CoV) 2. The mechanisms underlying the progression from asymptomatic disease to pneumonia and ARDS are complex and by far unelucidated. As for bacterial sepsis, the release of damage associated molecular patterns and pathogen associated molecular patterns triggers activation of the complement cascade. Subsequently, overexpressed anaphylatoxins recruit inflammatory cells in the lung and other organs and contribute initiating and amplifying a vicious circle of thromboinflammation causing organs damage and eventually death. Preclinical and observational studies in patients with COVID-19 provided evidence that complement inhibition effectively may attenuate lung and systemic inflammation, restore the coagulation/fibrinolysis balance, improve organs function and eventually may save life. Ongoing Phase 2/3 trials should elucidate the benefit to risk profile of complement inhibitors and may clarify the optimal targets in the complement cascade.
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Affiliation(s)
- Sofiane Fodil
- Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Garches, 92380, France
| | - Djillali Annane
- Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Garches, 92380, France
- Laboratory of Infection & Inflammation _ U1173, School of Medicine Simone Veil, University Versailles Saint Quentin _ University Paris Saclay, INSERM, Montigny-Le-Bretonneau, 78180, France
- FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for SEPSIS), AP-HP, University Versailles Saint Quentin _ University Paris Saclay, INSERM, Garches, 92380, France
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12
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Schmidt C, Weißmüller S, Bohländer F, Germer M, König M, Staus A, Wartenberg-Demand A, Heinz CC, Schüttrumpf J. The Dual Role of a Polyvalent IgM/IgA-Enriched Immunoglobulin Preparation in Activating and Inhibiting the Complement System. Biomedicines 2021; 9:817. [PMID: 34356880 PMCID: PMC8301464 DOI: 10.3390/biomedicines9070817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 12/30/2022] Open
Abstract
Activation of the complement system is important for efficient clearance of a wide variety of pathogens via opsonophagocytosis, or by direct lysis via complement-dependent cytotoxicity (CDC). However, in severe infections dysregulation of the complement system contributes to hyperinflammation. The influence of the novel IgM/IgA-enriched immunoglobulin preparation trimodulin on the complement pathway was investigated in in vitro opsonophagocytosis, binding and CDC assays. Immunoglobulin levels before and after trimodulin treatment were placed in relation to complement assessments in humans. In vitro, trimodulin activates complement and induces opsonophagocytosis, but also interacts with opsonins C3b, C4b and anaphylatoxin C5a in a concentration-dependent manner. This was not observed for standard intravenous IgG preparation (IVIg). Accordingly, trimodulin, but not IVIg, inhibited the downstream CDC pathway and target cell lysis. If applied at a similar concentration range in healthy subjects, trimodulin treatment resulted in C3 and C4 consumption in a concentration-dependent manner, which was extended in patients with severe community-acquired pneumonia. Complement consumption is found to be dependent on underlying immunoglobulin levels, particularly IgM, pinpointing their regulative function in humans. IgM/IgA provide a balancing effect on the complement system. Trimodulin may enhance phagocytosis and opsonophagocytosis in patients with severe infections and prevent excessive pathogen lysis and release of harmful anaphylatoxins.
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Affiliation(s)
- Carolin Schmidt
- Department of Translational Research, Biotest AG, Landsteinerstraße 5, 63303 Dreieich, Germany; (C.S.); (M.K.)
| | - Sabrina Weißmüller
- Department of Translational Research, Biotest AG, Landsteinerstraße 5, 63303 Dreieich, Germany; (C.S.); (M.K.)
| | - Fabian Bohländer
- Department of Analytical Development and Validation, Biotest AG, Landsteinerstraße 5, 63303 Dreieich, Germany;
| | - Matthias Germer
- Preclinical Research, Biotest AG, Landsteinerstraße 5, 63303 Dreieich, Germany;
| | - Martin König
- Department of Translational Research, Biotest AG, Landsteinerstraße 5, 63303 Dreieich, Germany; (C.S.); (M.K.)
| | - Alexander Staus
- Corporate Biostatistics, Biotest AG, Landsteinerstraße 5, 63303 Dreieich, Germany;
| | - Andrea Wartenberg-Demand
- Corporate Clinical Research & Development, Biotest AG, Landsteinerstraße 5, 63303 Dreieich, Germany;
| | - Corina C. Heinz
- Clinical Strategy & Development, Biotest AG, Landsteinerstraße 5, 63303 Dreieich, Germany;
| | - Jörg Schüttrumpf
- Corporate R&D, Biotest AG, Landsteinerstraße 5, 63303 Dreieich, Germany;
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13
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Elevated Expression Levels of Lung Complement Anaphylatoxin, Neutrophil Chemoattractant Chemokine IL-8, and RANTES in MERS-CoV-Infected Patients: Predictive Biomarkers for Disease Severity and Mortality. J Clin Immunol 2021; 41:1607-1620. [PMID: 34232441 PMCID: PMC8260346 DOI: 10.1007/s10875-021-01061-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 05/05/2021] [Indexed: 02/08/2023]
Abstract
The complement system, a network of highly-regulated proteins, represents a vital part of the innate immune response. Over-activation of the complement system plays an important role in inflammation, tissue damage, and infectious disease severity. The prevalence of MERS-CoV in Saudi Arabia remains significant and cases are still being reported. The role of complement in Middle East Respiratory Syndrome coronavirus (MERS-CoV) pathogenesis and complement-modulating treatment strategies has received limited attention, and studies involving MERS-CoV-infected patients have not been reported. This study offers the first insight into the pulmonary expression profile including seven complement proteins, complement regulatory factors, IL-8, and RANTES in MERS-CoV infected patients without underlying chronic medical conditions. Our results significantly indicate high expression levels of complement anaphylatoxins (C3a and C5a), IL-8, and RANTES in the lungs of MERS-CoV-infected patients. The upregulation of lung complement anaphylatoxins, C5a, and C3a was positively correlated with IL-8, RANTES, and the fatality rate. Our results also showed upregulation of the positive regulatory complement factor P, suggesting positive regulation of the complement during MERS-CoV infection. High levels of lung C5a, C3a, factor P, IL-8, and RANTES may contribute to the immunopathology, disease severity, ARDS development, and a higher fatality rate in MERS-CoV-infected patients. These findings highlight the potential prognostic utility of C5a, C3a, IL-8, and RANTES as biomarkers for MERS-CoV disease severity and mortality. To further explore the prediction of functional partners (proteins) of highly expressed proteins (C5a, C3a, factor P, IL-8, and RANTES), the computational protein–protein interaction (PPI) network was constructed, and six proteins (hub nodes) were identified.
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14
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Alosaimi B, Mubarak A, Hamed ME, Almutairi AZ, Alrashed AA, AlJuryyan A, Enani M, Alenzi FQ, Alturaiki W. Complement Anaphylatoxins and Inflammatory Cytokines as Prognostic Markers for COVID-19 Severity and In-Hospital Mortality. Front Immunol 2021; 12:668725. [PMID: 34276659 PMCID: PMC8281279 DOI: 10.3389/fimmu.2021.668725] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 05/28/2021] [Indexed: 12/19/2022] Open
Abstract
COVID-19 severity due to innate immunity dysregulation accounts for prolonged hospitalization, critical complications, and mortality. Severe SARS-CoV-2 infections involve the complement pathway activation for cytokine storm development. Nevertheless, the role of complement in COVID-19 immunopathology, complement-modulating treatment strategies against COVID-19, and the complement and SARS-CoV-2 interaction with clinical disease outcomes remain elusive. This study investigated the potential changes in complement signaling, and the associated inflammatory mediators, in mild-to-critical COVID-19 patients and their clinical outcomes. A total of 53 patients infected with SARS-CoV-2 were enrolled in the study (26 critical and 27 mild cases), and additional 18 healthy control patients were also included. Complement proteins and inflammatory cytokines and chemokines were measured in the sera of patients with COVID-19 as well as healthy controls by specific enzyme-linked immunosorbent assay. C3a, C5a, and factor P (properdin), as well as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and IgM antibody levels, were higher in critical COVID-19 patients compared to mild COVID-19 patients. Additionally, compared to the mild COVID-19 patients, factor I and C4-BP levels were significantly decreased in the critical COVID-19 patients. Meanwhile, RANTES levels were significantly higher in the mild patients compared to critical patients. Furthermore, the critical COVID-19 intra-group analysis showed significantly higher C5a, C3a, and factor P levels in the critical COVID-19 non-survival group than in the survival group. Additionally, IL-1β, IL-6, and IL-8 were significantly upregulated in the critical COVID-19 non-survival group compared to the survival group. Finally, C5a, C3a, factor P, and serum IL-1β, IL-6, and IL-8 levels positively correlated with critical COVID-19 in-hospital deaths. These findings highlight the potential prognostic utility of the complement system for predicting COVID-19 severity and mortality while suggesting that complement anaphylatoxins and inflammatory cytokines are potential treatment targets against COVID-19.
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Affiliation(s)
- Bandar Alosaimi
- Research Center, King Fahad Medical City, Riyadh, Saudi Arabia
- College of Medicine, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Ayman Mubarak
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Maaweya E. Hamed
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | | | - Ahmed A. Alrashed
- Pharmaceutical Service Department, Main Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Abdullah AlJuryyan
- Pathology and Clinical Laboratory Management, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mushira Enani
- Medical Specialties Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Faris Q. Alenzi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Wael Alturaiki
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia
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15
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Abstract
Severe COVID-19 can manifest as multiorgan dysfunction with pulmonary involvement being the most common and prominent. As more reports emerge in the literature, it appears that an exaggerated immune response in the form of unfettered complement activation and a cytokine storm may be a key driver of the widespread organ injury seen in this disease. In addition, these patients are also known to be hypercoagulable with a high rate of thrombosis and a higher-than-expected failure rate of anticoagulation. While macrovascular thrombosis is common in these individuals, the frequent finding of extensive microvascular thromboses in several series and case reports, raises the possibility of thrombotic microangiopathy (TMA) as being a contributing factor in the thrombotic and multi-organ complications of the disease. If this is correct, rapidly identifying a TMA and treating the underlying pathophysiology may allow for better outcomes in these critically ill patients. To further explore this, we reviewed the published literature on COVID-19, looking for reports describing TMA-like presentations. We summarize our findings here along with a discussion about presentation, pathophysiology, and a suggested treatment algorithm.
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16
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Zhang Y, Han K, Du C, Li R, Liu J, Zeng H, Zhu L, Li A. Carboxypeptidase B blocks ex vivo activation of the anaphylatoxin-neutrophil extracellular trap axis in neutrophils from COVID-19 patients. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2021; 25:51. [PMID: 33557911 PMCID: PMC7868871 DOI: 10.1186/s13054-021-03482-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/26/2021] [Indexed: 02/06/2023]
Abstract
Background Thrombosis and coagulopathy are highly prevalent in critically ill patients with COVID-19 and increase the risk of death. Immunothrombosis has recently been demonstrated to contribute to the thrombotic events in COVID-19 patients with coagulopathy. As the primary components of immunothrombosis, neutrophil extracellular traps (NETs) could be induced by complement cascade components and other proinflammatory mediators. We aimed to explore the clinical roles of NETs and the regulation of complement on the NET formation in COVID-19. Methods We recruited 135 COVID-19 patients and measured plasma levels of C5, C3, cell-free DNA and myeloperoxidase (MPO)-DNA. Besides, the formation of NETs was detected by immunofluorescent staining and the cytotoxicity to vascular endothelial HUVEC cells was evaluated by CCK-8 assay. Results We found that the plasma levels of complements C3 and MPO-DNA were positively related to coagulation indicator fibrin(-ogen) degradation products (C3: r = 0.300, p = 0.005; MPO-DNA: r = 0.316, p = 0.002) in COVID-19 patients. Besides, C3 was positively related to direct bilirubin (r = 0.303, p = 0.004) and total bilirubin (r = 0.304, p = 0.005), MPO-DNA was positively related to lactate dehydrogenase (r = 0.306, p = 0.003) and creatine kinase (r = 0.308, p = 0.004). By using anti-C3a and anti-C5a antibodies, we revealed that the complement component anaphylatoxins in the plasma of COVID-19 patients strongly induced NET formation. The pathological effect of the anaphylatoxin-NET axis on the damage of vascular endothelial cells could be relieved by recombinant carboxypeptidase B (CPB), a stable homolog of enzyme CPB2 which can degrade anaphylatoxins to inactive products. Conclusions Over-activation in anaphylatoxin-NET axis plays a pathological role in COVID-19. Early intervention in anaphylatoxins might help prevent thrombosis and disease progression in COVID-19 patients.
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Affiliation(s)
- Yue Zhang
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Kai Han
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Chunjing Du
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Rui Li
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Jingyuan Liu
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Hui Zeng
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
| | - Liuluan Zhu
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
| | - Ang Li
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
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17
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Elyaspour Z, Zibaeenezhad MJ, Razmkhah M, Razeghian-Jahromi I. Is It All About Endothelial Dysfunction and Thrombosis Formation? The Secret of COVID-19. Clin Appl Thromb Hemost 2021; 27:10760296211042940. [PMID: 34693754 PMCID: PMC8543709 DOI: 10.1177/10760296211042940] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 08/12/2021] [Indexed: 01/08/2023] Open
Abstract
The world is in a hard battle against COVID-19. Endothelial cells are among the most critical targets of SARS-CoV-2. Dysfunction of endothelium leads to vascular injury following by coagulopathies and thrombotic conditions in the vital organs increasing the risk of life-threatening events. Growing evidences revealed that endothelial dysfunction and consequent thrombotic conditions are associated with the severity of outcomes. It is not yet fully clear that these devastating sequels originate directly from the virus or a side effect of virus-induced cytokine storm. Due to endothelial dysfunction, plasma levels of some biomarkers are changed and relevant clinical manifestations appear as well. Stabilization of endothelial integrity and supporting its function are among the promising therapeutic strategies. Other than respiratory, COVID-19 could be called a systemic vascular disease and this aspect should be scrutinized in more detail in order to reduce related mortality. In the present investigation, the effects of COVID-19 on endothelial function and thrombosis formation are discussed. In this regard, critical players, laboratory findings, clinical manifestation, and suggestive therapies are presented.
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Affiliation(s)
- Zahra Elyaspour
- Cardiovascular Research Center, Shiraz
University of Medical Sciences, Shiraz, Iran
| | | | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research,
Shiraz University of Medical Sciences, Shiraz, Iran
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18
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Sadeghmousavi S, Rezaei N. COVID-19 infection and stroke risk. Rev Neurosci 2020; 32:341-349. [PMID: 33580645 DOI: 10.1515/revneuro-2020-0066] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/09/2020] [Indexed: 12/19/2022]
Abstract
Coronavirus disease 2019 (COVID-19), due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan city, China in December 2019 and rapidly spread to other countries. The most common reported symptoms are fever, dry cough, myalgia and fatigue, headache, anorexia, and breathlessness. Anosmia and dysgeusia as well as gastrointestinal symptoms including nausea and diarrhea are other notable symptoms. This virus also can exhibit neurotropic properties and may also cause neurological diseases, including epileptic seizures, cerebrovascular accident, Guillian barre syndrome, acute transverse myelitis, and acute encephalitis. In this study, we discuss stroke as a complication of the new coronavirus and its possible mechanisms of damage.
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Affiliation(s)
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Children's Medical Center, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, 14194, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran1419783151, Iran
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19
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Ort M, Dingemanse J, van den Anker J, Kaufmann P. Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway. Front Immunol 2020; 11:599417. [PMID: 33362783 PMCID: PMC7758461 DOI: 10.3389/fimmu.2020.599417] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/09/2020] [Indexed: 12/15/2022] Open
Abstract
The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.
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Affiliation(s)
- Marion Ort
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.,Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - John van den Anker
- Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland.,Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, United States
| | - Priska Kaufmann
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
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20
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Annane D, Heming N, Grimaldi-Bensouda L, Frémeaux-Bacchi V, Vigan M, Roux AL, Marchal A, Michelon H, Rottman M, Moine P, for the Garches COVID 19 Collaborative Group. Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study. EClinicalMedicine 2020; 28:100590. [PMID: 33173853 PMCID: PMC7644240 DOI: 10.1016/j.eclinm.2020.100590] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/22/2020] [Accepted: 09/24/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Complement pathway inhibition may provide benefit for severe acute respiratory illnesses caused by viral infections such as COVID-19. We present results from a nonrandomized proof-of-concept study of complement C5 inhibitor eculizumab for treatment of severe COVID-19. METHODS All patients (N = 80) with confirmed SARS-CoV-2 infection and severe COVID-19 admitted to our intensive care unit between March 10 and May 5, 2020 were included. Forty-five patients were treated with standard care and 35 with standard care plus eculizumab through expanded-access emergency treatment. The prespecified primary outcome was day-15 survival. Clinical laboratory values and biomarkers, complement levels, and treatment-emergent serious adverse events (TESAEs) were also assessed. FINDINGS At day 15, estimated survival was 82.9% (95% CI: 70.4%‒95.3%) with eculizumab and 62.2% (48.1%‒76.4%) without eculizumab (log-rank test, P = 0.04). Patients treated with eculizumab experienced a significantly more rapid decrease in lactate, blood urea nitrogen, total and conjugated bilirubin levels and a significantly more rapid increase in platelet count, prothrombin time, and in the ratio of arterial oxygen tension over fraction of inspired oxygen versus patients treated without eculizumab. Eculizumab-associated changes in complement levels, laboratory values, and biomarkers were consistent with terminal complement inhibition, reduced hypoxia, and decreased inflammation. TESAEs of special interest occurring in >5% of patients treated with/without eculizumab were ventilator-associated pneumonia (51%/24%), bacteremia (11%/2%), gastroduodenal hemorrhage (14%/16%), and hemolysis (3%/18%). INTERPRETATION Findings from this proof-of-concept study suggest eculizumab may improve survival and reduce hypoxia in patients with severe COVID-19. Randomized studies evaluating the efficacy and safety of this treatment approach are needed. FUNDING Programme d'Investissements d'Avenir: ANR-18-RHUS60004.
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Affiliation(s)
- Djillali Annane
- FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis), RHU RECORDS (Rapid rEcognition of CORticosteroiD resistant or sensitive Sepsis), Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation – U1173, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, 104 Boulevard Raymond Poincaré, Garches 92380, France
| | - Nicholas Heming
- Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation – U1173, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, Garches, France
| | - Lamiae Grimaldi-Bensouda
- Clinical Research Unit AP-HP, Paris-Saclay, Hôpital Raymond Poincaré, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, CESP Anti-Infective Evasion and Pharmacoepidemiology Team, F-78180 Montigny-Le-Bretonneux, France
| | - Véronique Frémeaux-Bacchi
- Laboratory of Immunology, Georges-Pompidou European Hospital (APHP), Invasive Bacterial Infection Unit and National Reference Center for Meningococci, Pasteur Institute, Centre de Recherche des Cordeliers, Paris, France
| | - Marie Vigan
- Clinical Research Unit, AP-HP, Paris-Saclay, Hôpital Raymond Poincaré, Garches, France
| | - Anne-Laure Roux
- Department of Microbiology and Innovative Biomarkers Platform, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation – U1173, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, Garches, France
| | - Armance Marchal
- Laboratory of Immunology, Georges-Pompidou European Hospital (APHP), Paris, France
| | - Hugues Michelon
- Pharmacy Department, Hôpital Raymond Poincaré (APHP), University Paris Saclay, Garches, France
| | - Martin Rottman
- Department of Microbiology and Innovative Biomarkers Platform, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation – U1173, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, Garches, France
| | - Pierre Moine
- Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation – U1173, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, Garches, France
| | - for the Garches COVID 19 Collaborative Group
- FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis), RHU RECORDS (Rapid rEcognition of CORticosteroiD resistant or sensitive Sepsis), Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation – U1173, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, 104 Boulevard Raymond Poincaré, Garches 92380, France
- Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation – U1173, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, Garches, France
- Clinical Research Unit AP-HP, Paris-Saclay, Hôpital Raymond Poincaré, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, CESP Anti-Infective Evasion and Pharmacoepidemiology Team, F-78180 Montigny-Le-Bretonneux, France
- Laboratory of Immunology, Georges-Pompidou European Hospital (APHP), Invasive Bacterial Infection Unit and National Reference Center for Meningococci, Pasteur Institute, Centre de Recherche des Cordeliers, Paris, France
- Clinical Research Unit, AP-HP, Paris-Saclay, Hôpital Raymond Poincaré, Garches, France
- Department of Microbiology and Innovative Biomarkers Platform, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation – U1173, School of Medicine Simone Veil, University Versailles Saint Quentin – University Paris Saclay, INSERM, Garches, France
- Laboratory of Immunology, Georges-Pompidou European Hospital (APHP), Paris, France
- Pharmacy Department, Hôpital Raymond Poincaré (APHP), University Paris Saclay, Garches, France
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21
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Vinayagam S, Sattu K. SARS-CoV-2 and coagulation disorders in different organs. Life Sci 2020; 260:118431. [PMID: 32946915 PMCID: PMC7490584 DOI: 10.1016/j.lfs.2020.118431] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/06/2020] [Accepted: 09/09/2020] [Indexed: 02/08/2023]
Abstract
Coronavirus disease 2019 (COVID-19) is a prominent pandemic disease that emerged in China and hurriedly stretched worldwide. There are many reports on COVID-19 associated with the amplified incidence of thrombotic events. In this review, we focused on COVID-19 coupled with the coagulopathy contributes to severe outcome inclusive of comorbidities such as venous thromboembolism, stroke, diabetes, lung, heart attack, AKI, and liver injury. Initially, the COVID-19 patient associated coagulation disorders show an elevated level of the D-dimer, fibrinogen, and less lymphocyte count such as lymphopenia. COVID-19 associated with the Kawasaki disease has acute vasculitis in childhood which further affects the vessels found all over the body. COVID-19 linked with the thrombotic microangiopathy triggers the multiple vasculitis along with the arterioles thrombosis, medium, large venous and arterial vessels mediates the disseminated intravascular coagulation (DIC). SARS-Co-V-2 patients have reduced primary platelet production, increased destruction of the platelet, decreased circulating platelet leads to the condition of increased thrombocytopenia which contributes to the coagulation disorder. Endothelial dysfunction plays an important role in the coagulation disorders via increased generation of the thrombin and stops fibrinolysis further leads to hypercoagulopathy. Along with that endothelial dysfunction activates the complement system pathways and contributes to the acute and chronic inflammation via cytokine storm with the production of the cytokines and chemokines, coagulation in different organs such as lung, brain, liver, heart, kidney and further leads to multi-organ failure.
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Affiliation(s)
- Sathishkumar Vinayagam
- Department of Biotechnology, Periyar University PG, Extension Centre, Dharmapuri, Tamil Nadu 636701, India
| | - Kamaraj Sattu
- Department of Biotechnology, Periyar University PG, Extension Centre, Dharmapuri, Tamil Nadu 636701, India.
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22
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Chen C, Gao Q, Luo Y, Zhang G, Xu X, Li Z, Wang J, He Q, Sheng L, Ma X. The immunotherapy with hMASP-2 DNA nanolipoplexes against echinococcosis in experimentally protoscolex-infected mice. Acta Trop 2020; 210:105579. [PMID: 32535067 DOI: 10.1016/j.actatropica.2020.105579] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 04/19/2020] [Accepted: 06/08/2020] [Indexed: 01/05/2023]
Abstract
Cystic echinococcosis (CE), a complex and neglected zoonotic infectious disease, is mainly caused by larval tapeworm Echinococcus granulosus with a worldwide distribution. For CE, an effective drug treatment is not yet available. The present study was conducted to evaluate the efficacy of hMASP-2-based immunotherapy against hydatid cysts by using murine model. Eighteen weeks after infection with 2000 viable protoscoleces intraperitoneally, the infected mice were treated with hMASP-2 DNA nanolipoplexes (pcDNA3.1-hMASP-2) and albendazole respectively. After six weeks treatment, a significant reduction in the weight of cysts was observed both in the pcDNA3.1-hMASP-2 group and albendazole group compared with the untreated group (P < 0.05). The hMASP-2 DNA nanolipoplexes not only inhibited the development of germinal layer, but also induced the extensive degeneration and damage of the germinal layer cells. Furthermore, compared with the untreated group, the number of CD4+T cells and CD8+T cells and the level of serum IFN-γ were significantly increased (P < 0.05). The frequency of PD-1+T-cell subpopulations including CD4+PD-1+T cells and CD8+PD-1+T cells and the level of serum IL-4 were notably decreased (P < 0.05) in the pcDNA3.1-hMASP-2 treatment group. Therefore, the hMASP-2 DNA nanolipoplexes displayed an effective treatment for echinococcosis through inhibiting the development of cysts and up-regulatory T-cell immunity. This new hMASP-2-based immunotherapeutic strategy could be a potential alternative for the treatment of CE, but further studies are recommended to evaluate the full potential of these hMASP-2 DNA nanolipoplexes in the treatment of human CE.
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Affiliation(s)
- Chong Chen
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Qi Gao
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Yanping Luo
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Guochao Zhang
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Xiaoying Xu
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Zhi Li
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Jianghua Wang
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Qi He
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Li Sheng
- Department of Immunology, Medical College, Northwest Minzu University, Lanzhou, 730030, China
| | - Xingming Ma
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China; Key Lab of Preclinical Study for New Drugs of Gansu Province, Lanzhou, 730000, China.
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Chauhan AJ, Wiffen LJ, Brown TP. COVID-19: A collision of complement, coagulation and inflammatory pathways. J Thromb Haemost 2020; 18:2110-2117. [PMID: 32608159 PMCID: PMC7361520 DOI: 10.1111/jth.14981] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 12/13/2022]
Abstract
COVID-19 is frequently accompanied by a hypercoagulable inflammatory state with microangiopathic pulmonary changes that can precede the diffuse alveolar damage characteristic of typical acute respiratory distress syndrome (ARDS) seen in other severe pathogenic infections. Parallels with systemic inflammatory disorders such as atypical hemolytic uremic syndrome (aHUS) have implicated the complement pathway in the pathogenesis of COVID-19, and particularly the anaphylatoxins C3a and C5a released from cleavage of C3 and C5, respectively. C5a is a potent cell signalling protein that activates a cytokine storm-a hyper-inflammatory phenomenon-within hours of infection and the innate immune response. However, excess C5a can result in a pro-inflammatory environment orchestrated through a plethora of mechanisms that propagate lung injury, lymphocyte exhaustion, and an immune paresis. Furthermore, disruption of the homeostatic interactions between complement and extrinsic and intrinsic coagulation pathways contributes to a net pro-coagulant state in the microvasculature of critical organs. Fatal COVID-19 has been associated with a systemic inflammatory response accompanied by a pro-coagulant state and organ damage, particularly microvascular thrombi in the lungs and kidneys. Pathologic studies report strong evidence of complement activation. C5 blockade reduces inflammatory cytokines and their manifestations in animal studies, and has shown benefits in patients with aHUS, prompting investigation of this approach in the treatment of COVID-19. This review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID-19.
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Affiliation(s)
- Anoop J Chauhan
- Research and Innovation, Queen Alexandra Hospital, Portsmouth, UK
- Faculty of Science and Health, University of Portsmouth, Portsmouth, UK
- Respiratory Medicine, Queen Alexandra Hospital, Portsmouth, UK
| | - Laura J Wiffen
- Research and Innovation, Queen Alexandra Hospital, Portsmouth, UK
- Respiratory Medicine, Queen Alexandra Hospital, Portsmouth, UK
| | - Thomas P Brown
- Research and Innovation, Queen Alexandra Hospital, Portsmouth, UK
- Respiratory Medicine, Queen Alexandra Hospital, Portsmouth, UK
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24
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Noris M, Benigni A, Remuzzi G. The case of complement activation in COVID-19 multiorgan impact. Kidney Int 2020; 98:314-322. [PMID: 32461141 PMCID: PMC7246017 DOI: 10.1016/j.kint.2020.05.013] [Citation(s) in RCA: 259] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/11/2020] [Accepted: 05/15/2020] [Indexed: 01/08/2023]
Abstract
The novel coronavirus disease COVID-19 originates in the lungs, but it may extend to other organs, causing, in severe cases, multiorgan damage, including cardiac injury and acute kidney injury. In severe cases, the presence of kidney injury is associated with increased risk of death, highlighting the relevance of this organ as a target of SARS-CoV-2 infection. COVID-19-associated tissue injury is not primarily mediated by viral infection, but rather is a result of the inflammatory host immune response, which drives hypercytokinemia and aggressive inflammation that affect lung parenchymal cells, diminishing oxygen uptake, but also endothelial cells, resulting in endotheliitis and thrombotic events and intravascular coagulation. The complement system represents the first response of the host immune system to SARS-CoV-2 infection, but there is growing evidence that unrestrained activation of complement induced by the virus in the lungs and other organs plays a major role in acute and chronic inflammation, endothelial cell dysfunction, thrombus formation, and intravascular coagulation, and ultimately contributes to multiple organ failure and death. In this review, we discuss the relative role of the different complement activation products in the pathogenesis of COVID-19-associated tissue inflammation and thrombosis and propose the hypothesis that blockade of the terminal complement pathway may represent a potential therapeutic option for the prevention and treatment of lung and multiorgan damage.
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Affiliation(s)
- Marina Noris
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
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25
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Jodele S, Köhl J. Tackling COVID-19 infection through complement-targeted immunotherapy. Br J Pharmacol 2020; 178:2832-2848. [PMID: 32643798 PMCID: PMC7361469 DOI: 10.1111/bph.15187] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/09/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022] Open
Abstract
The complement system is an ancient part of innate immunity sensing highly pathogenic coronaviruses by mannan‐binding lectin (MBL) resulting in lectin pathway activation and subsequent generation of the anaphylatoxins (ATs) C3a and C5a as important effector molecules. Complement deposition on endothelial cells and high blood C5a serum levels have been reported in COVID‐19 patients with severe illness, suggesting vigorous complement activation leading to systemic thrombotic microangiopathy (TMA). Complement regulator gene variants prevalent in African‐Americans have been associated with a higher risk for severe TMA and multi‐organ injury. Strikingly, severe acute respiratory syndrome Coronavirus 2 (SARS‐CoV‐2)‐infected African‐Americans suffer from high mortality. These findings allow us to apply our knowledge from other complement‐mediated diseases to COVID‐19 infection to better understand severe disease pathogenesis. Here, we discuss the multiple aspects of complement activation, regulation, crosstalk with other parts of the immune system, and the options to target complement in COVID‐19 patients to halt disease progression and death.
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Affiliation(s)
- Sonata Jodele
- Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Jörg Köhl
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
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26
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Marchetti M. COVID-19-driven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure. Ann Hematol 2020; 99:1701-1707. [PMID: 32583086 PMCID: PMC7312112 DOI: 10.1007/s00277-020-04138-8] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 06/09/2020] [Indexed: 02/07/2023]
Abstract
COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide. The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels. This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases. This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials.
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Affiliation(s)
- Monia Marchetti
- Hematology Department, Az Osp SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
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27
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Jongerius I, Porcelijn L, van Beek AE, Semple JW, van der Schoot CE, Vlaar APJ, Kapur R. The Role of Complement in Transfusion-Related Acute Lung Injury. Transfus Med Rev 2019; 33:236-242. [PMID: 31676221 PMCID: PMC7127679 DOI: 10.1016/j.tmrv.2019.09.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 01/02/2023]
Abstract
Transfusion-related acute lung injury (TRALI) is a life-threatening complication of acute respiratory distress occurring within 6 hours of blood transfusion. TRALI is one of the leading causes of transfusion-related fatalities and specific therapies are unavailable. Neutrophils are recognized as the major pathogenic cells, whereas T regulatory cells and dendritic cells appear to be important for protection against TRALI. The pathogenesis, however, is complex and incompletely understood. It is frequently postulated that the complement system plays an important role in the TRALI pathogenesis. In this article, we assess the evidence regarding the involvement of complement in TRALI from both human and animal studies. We hypothesize about the potential connection between the complement system and neutrophils in TRALI. Additionally, we draw parallels between TRALI and other acute pulmonary disorders of acute lung injury and acute respiratory distress syndrome regarding the involvement of complement. We conclude that, even though a role for complement in the TRALI pathogenesis seems plausible, studies investigating the role of complement in TRALI are remarkably limited in number and also present conflicting findings. Different types of TRALI animal models, diverse experimental conditions, and the composition of the gastrointestinal microbiota may perhaps all be factors which contribute to these discrepancies. More systematic studies are warranted to shed light on the contribution of the complement cascade in TRALI. The underlying clinical condition of the patient, which influences the susceptibility to TRALI, as well as the transfusion factor (antibody-mediated vs non–antibody-mediated), will be important to take into consideration when researching the contribution of complement. This should significantly increase our understanding of the role of complement in TRALI and may potentially result in promising new treatment strategies.
Studies investigating complement and TRALI are limited in number and present conflicting findings. Systematic investigation is needed to better understand the contribution of the complement cascade in TRALI. Future studies in this area should consider both the clinical susceptibility of the patient as well as the effect of transfusion factors.
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Affiliation(s)
- Ilse Jongerius
- Sanquin Research, Department of Immunopathology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Emma Children's Hospital, Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Amsterdam UMC, Amsterdam, the Netherlands
| | - Leendert Porcelijn
- Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands
| | - Anna E van Beek
- Sanquin Research, Department of Immunopathology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Emma Children's Hospital, Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Amsterdam UMC, Amsterdam, the Netherlands
| | - John W Semple
- Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - C Ellen van der Schoot
- Sanquin Research, Department of Experimental Immunohematology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Alexander P J Vlaar
- Department of Intensive Care Medicine, Amsterdam UMC, AMC, Amsterdam, the Netherlands; Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Amsterdam UMC, AMC, Amsterdam, the Netherlands
| | - Rick Kapur
- Sanquin Research, Department of Experimental Immunohematology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
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28
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Vanderven HA, Wragg K, Ana-Sosa-Batiz F, Kristensen AB, Jegaskanda S, Wheatley AK, Wentworth D, Wines BD, Hogarth PM, Rockman S, Kent SJ. Anti-Influenza Hyperimmune Immunoglobulin Enhances Fc-Functional Antibody Immunity During Human Influenza Infection. J Infect Dis 2019; 218:1383-1393. [PMID: 29860297 DOI: 10.1093/infdis/jiy328] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 05/30/2018] [Indexed: 11/13/2022] Open
Abstract
Background New treatments for severe influenza are needed. Passive transfer of influenza-specific hyperimmune pooled immunoglobulin (Flu-IVIG) boosts neutralizing antibody responses to past strains in influenza-infected subjects. The effect of Flu-IVIG on antibodies with Fc-mediated functions, which may target diverse influenza strains, is unclear. Methods We studied the capacity of Flu-IVIG, relative to standard IVIG, to bind to Fcγ receptors and mediate antibody-dependent cellular cytotoxicity in vitro. The effect of Flu-IVIG infusion, compared to placebo infusion, was examined in serial plasma samples from 24 subjects with confirmed influenza infection in the INSIGHT FLU005 pilot study. Results Flu-IVIG contains higher concentrations of Fc-functional antibodies than IVIG against a diverse range of influenza hemagglutinins. Following infusion of Flu-IVIG into influenza-infected subjects, a transient increase in Fc-functional antibodies was present for 1-3 days against infecting and noninfecting strains of influenza. Conclusions Flu-IVIG contains antibodies with Fc-mediated functions against influenza virus, and passive transfer of Flu-IVIG increases anti-influenza Fc-functional antibodies in the plasma of influenza-infected subjects. Enhancement of Fc-functional antibodies to a diverse range of influenza strains suggests that Flu-IVIG infusion could prove useful in the context of novel influenza virus infections, when there may be minimal or no neutralizing antibodies in the Flu-IVIG preparation.
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Affiliation(s)
- Hillary A Vanderven
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia.,Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Douglas, Queensland, Australia
| | - Kathleen Wragg
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia
| | - Fernanda Ana-Sosa-Batiz
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia
| | - Anne B Kristensen
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia
| | - Sinthujan Jegaskanda
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia
| | - Adam K Wheatley
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia
| | | | | | | | - Steve Rockman
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia.,Seqirus Ltd, Parkville
| | - Stephen J Kent
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia.,Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Health, Central Clinical School, Monash University.,Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Parkville, Victoria, Australia
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29
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Wang K, Lai C, Li T, Wang C, Wang W, Ni B, Bai C, Zhang S, Han L, Gu H, Zhao Z, Duan Y, Yang X, Xing L, Zhao L, Zhou S, Xia M, Jiang C, Wang X, Yang P. Basic fibroblast growth factor protects against influenza A virus-induced acute lung injury by recruiting neutrophils. J Mol Cell Biol 2019; 10:573-585. [PMID: 29121325 DOI: 10.1093/jmcb/mjx047] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 11/02/2017] [Indexed: 12/18/2022] Open
Abstract
Influenza virus (IAV) infection is a major cause of severe respiratory illness that affects almost every country in the world. IAV infections result in respiratory illness and even acute lung injury and death, but the underlying mechanisms responsible for IAV pathogenesis have not yet been fully elucidated. In this study, the basic fibroblast growth factor 2 (FGF2) level was markedly increased in H1N1 virus-infected humans and mice. FGF2, which is predominately derived from epithelial cells, recruits and activates neutrophils via the FGFR2-PI3K-AKT-NFκB signaling pathway. FGF2 depletion or knockout exacerbated influenza-associated disease by impairing neutrophil recruitment and activation. More importantly, administration of the recombinant FGF2 protein significantly alleviated the severity of IAV-induced lung injury and promoted the survival of IAV-infected mice. Based on the results from experiments in which neutrophils were depleted and adoptively transferred, FGF2 protected mice against IAV infection by recruiting neutrophils. Thus, FGF2 plays a critical role in preventing IAV-induced lung injury, and FGF2 is a promising potential therapeutic target during IAV infection.
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Affiliation(s)
- Keyu Wang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Chengcai Lai
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Tieling Li
- Chinese PLA General Hospital, Beijing, China
| | - Cheng Wang
- Chinese PLA General Hospital, Beijing, China
| | - Wei Wang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
| | - Bing Ni
- Institute of Immunology, Third Military Medical University, Chongqing, China
| | - Changqing Bai
- Beijing 307 Hospital of PLA Affiliated with the Chinese Academy of Medical Sciences, Beijing, China
| | | | - Lina Han
- Chinese PLA General Hospital, Beijing, China
| | - Hongjing Gu
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Zhongpeng Zhao
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Yueqiang Duan
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Xiaolan Yang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Li Xing
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Lingna Zhao
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Shanshan Zhou
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Min Xia
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Chengyu Jiang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiliang Wang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Penghui Yang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.,Beijing 302 Hospital of PLA, Beijing, China
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30
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Gianchecchi E, Torelli A, Montomoli E. The use of cell-mediated immunity for the evaluation of influenza vaccines: an upcoming necessity. Hum Vaccin Immunother 2019; 15:1021-1030. [PMID: 30614754 PMCID: PMC6605831 DOI: 10.1080/21645515.2019.1565269] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Influenza vaccines are a fundamental tool for preventing the disease and reducing its consequences, particularly in specific high-risk groups. In order to be licensed, influenza vaccines have to meet strict criteria established by European Medicines Agency. Although the licensure of influenza vaccines started 65 years ago, Hemagglutination Inhibition and Single Radial Hemolysis are the only serological assays that can ascertain correlates of protection. However, they present evident limitations. The present review focuses on the evaluation of cell-mediated immunity (CMI), which plays an important role in the host immune response in protecting against virus-related illness and in the establishment of long-term immunological memory. Although correlates of protection are not currently available for CMI, it would be advisable to investigate this kind of immunological response for the evaluation of next-generation vaccines.
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Affiliation(s)
| | - A Torelli
- a VisMederi srl , Siena , Italy.,b Department of Life Sciences , University of Siena , Siena , Italy
| | - E Montomoli
- a VisMederi srl , Siena , Italy.,c Department of Molecular and Developmental Medicine , University of Siena , Siena , Italy
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31
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Bitzan M, Zieg J. Influenza-associated thrombotic microangiopathies. Pediatr Nephrol 2018; 33:2009-2025. [PMID: 28884355 PMCID: PMC6153504 DOI: 10.1007/s00467-017-3783-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/11/2017] [Accepted: 08/08/2017] [Indexed: 12/26/2022]
Abstract
Thrombotic microangiopathy (TMA) refers to phenotypically similar disorders, including hemolytic uremic syndromes (HUS) and thrombotic thrombocytopenic purpura (TTP). This review explores the role of the influenza virus as trigger of HUS or TTP. We conducted a literature survey in PubMed and Google Scholar using HUS, TTP, TMA, and influenza as keywords, and extracted and analyzed reported epidemiological and clinical data. We identified 25 cases of influenza-associated TMA. Five additional cases were linked to influenza vaccination and analyzed separately. Influenza A was found in 83%, 10 out of 25 during the 2009 A(H1N1) pandemic. Two patients had bona fide TTP with ADAMTS13 activity <10%. Median age was 15 years (range 0.5-68 years), two thirds were male. Oligoanuria was documented in 81% and neurological involvement in 40% of patients. Serum C3 was reduced in 5 out of 14 patients (36%); Coombs test was negative in 7 out of 7 and elevated fibrin/fibrinogen degradation products were documented in 6 out of 8 patients. Pathogenic complement gene mutations were found in 7 out of 8 patients tested (C3, MCP, or MCP combined with CFB or clusterin). Twenty out of 24 patients recovered completely, but 3 died (12%). Ten of the surviving patients underwent plasma exchange (PLEX) therapy, 5 plasma infusions. Influenza-mediated HUS or TTP is rare. A sizable proportion of tested patients demonstrated mutations associated with alternative pathway of complement dysregulation that was uncovered by this infection. Further research is warranted targeting the roles of viral neuraminidase, enhanced virus-induced complement activation and/or ADAMTS13 antibodies, and rational treatment approaches.
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Affiliation(s)
- Martin Bitzan
- Division of Nephrology, The Montreal Children's Hospital, McGill University Health Centre, 1001, boul. Décarie-Room B RC.6651, Montréal, QC, H4A 3J1, Canada.
| | - Jakub Zieg
- 0000 0004 1937 116Xgrid.4491.8Department of Pediatric Nephrology, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic
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Respiratory Syncytial Virus Exacerbates OVA-mediated asthma in mice through C5a-C5aR regulating CD4 +T cells Immune Responses. Sci Rep 2017; 7:15207. [PMID: 29123203 PMCID: PMC5680322 DOI: 10.1038/s41598-017-15471-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 10/27/2017] [Indexed: 12/15/2022] Open
Abstract
Asthma exacerbation could be induced by respiratory syncytial virus (RSV), and the underlying pathogenic mechanism is related to complement activation. Although complement might regulate CD4+T cells immune responses in asthma model, this regulation existed in RSV-induced asthma model remains incompletely characterrized. In this study, we assessed the contribution of C5a-C5aR to CD4+T cell immune responses in RSV-infected asthma mice. Female BALB/C mice were sensitized and challenged with ovalbumin (OVA) while treated with RSV infection and C5a receptor antagonist (C5aRA) during challenge period. RSV enhanced lung damage, airway hyperresponsiveness, and C5aR expressions in asthma mice, while C5aRA alleviated these pathologic changes. The percentages of Th1, Th2 and Th17 cells were increased, while the percentage of Treg cells was decreased in RSV-infected asthma mice compared with asthma mice. IFN-γ, IL-4, IL-10 and IL-17A levels have similar trend with Th1, Th2, Th17 and Treg cells. Notably, above changes of CD4+T cells and their related cytokines were reversed by C5aRA. Together, the data indicates that RSV infection could apparently increase C5a and C5aR expression in the pathogenesis of RSV-infected asthma mice, meanwhile C5aRA prevents some of the CD4+T cells immune changes that are induced by RSV.
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Vanderven HA, Liu L, Ana-Sosa-Batiz F, Nguyen TH, Wan Y, Wines B, Hogarth PM, Tilmanis D, Reynaldi A, Parsons MS, Hurt AC, Davenport MP, Kotsimbos T, Cheng AC, Kedzierska K, Zhang X, Xu J, Kent SJ. Fc functional antibodies in humans with severe H7N9 and seasonal influenza. JCI Insight 2017; 2:92750. [PMID: 28679958 DOI: 10.1172/jci.insight.92750] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 05/19/2017] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Both seasonal and novel avian influenza viruses can result in severe infections requiring hospitalization. Anti-influenza antibodies (Abs) with Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity (ADCC), are of growing interest in control of influenza but have not previously been studied during severe human infections. As such, the objective of this study was to examine Fc-mediated Ab functions in humans hospitalized with influenza infection. METHODS Serum Ab response was studied in subjects hospitalized with either pandemic H7N9 avian influenza virus in China (n = 18) or circulating seasonal influenza viruses in Melbourne, Australia (n = 16). Recombinant soluble Fc receptor dimer ELISAs, natural killer (NK) cell activation assays, and Ab-dependent killing assays with influenza-infected target cells were used to assess the Fc functionality of anti-influenza hemagglutinin (HA) Abs during severe human influenza infection. RESULTS We found that the peak generation of Fc functional HA Abs preceded that of neutralizing Abs for both severe H7N9 and seasonal influenza infections. Subjects who succumbed to complications of H7N9 infection demonstrated reduced HA-specific Fc receptor-binding Abs (in magnitude and breadth) immediately prior to death compared with those who survived. Subjects who recovered from H7N9 and severe seasonal influenza infections demonstrated increased Fc receptor-binding Abs not only against the homologous infecting strain but against HAs from different influenza A subtypes. CONCLUSION Collectively, survivors of severe influenza infection rapidly generate a functional Ab response capable of mediating ADCC against divergent influenza viruses. Broadly binding HA Abs with Fc-mediated functions may be a useful component of protective immunity to severe influenza infection. FUNDING The National Health and Medical Research Council ([NHMRC] grants 1023294, 1041832, and 1071916), the Australian Department of Health, and the joint University of Melbourne/Fudan University International Research and Research Training Fund provided funding for this study.
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Affiliation(s)
- Hillary A Vanderven
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Lu Liu
- Shanghai Public Health Clinical Centre (SPHCC) and Institute of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fernanda Ana-Sosa-Batiz
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Thi Ho Nguyen
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Yanmin Wan
- Shanghai Public Health Clinical Centre (SPHCC) and Institute of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bruce Wines
- Burnet Institute, Melbourne, Victoria, Australia
| | | | - Danielle Tilmanis
- WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Arnold Reynaldi
- Infection Analytics Program, Kirby Institute for Infection and Immunity, University of New South Wales Australia, Sydney, New South Wales, Australia
| | - Matthew S Parsons
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Aeron C Hurt
- WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Miles P Davenport
- Infection Analytics Program, Kirby Institute for Infection and Immunity, University of New South Wales Australia, Sydney, New South Wales, Australia
| | - Tom Kotsimbos
- Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Allen C Cheng
- Infection Prevention and Healthcare Epidemiology Unit, Alfred Health and School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Katherine Kedzierska
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Xiaoyan Zhang
- Shanghai Public Health Clinical Centre (SPHCC) and Institute of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianqing Xu
- Shanghai Public Health Clinical Centre (SPHCC) and Institute of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Shanghai Medical College, Fudan University, Shanghai, China
| | - Stephen J Kent
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.,Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Health, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Parkville, Victoria, Australia
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Jegaskanda S, Vanderven HA, Wheatley AK, Kent SJ. Fc or not Fc; that is the question: Antibody Fc-receptor interactions are key to universal influenza vaccine design. Hum Vaccin Immunother 2017; 13:1-9. [PMID: 28332900 DOI: 10.1080/21645515.2017.1290018] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
A universal vaccine that provides long-lasting protection from both epidemic and pandemic influenza viruses remains the "holy grail" of influenza vaccine research. Though virus neutralization assays are the current benchmark of measuring vaccine effectiveness, it is clear that Fc-receptor functions can drastically improve the effectiveness of antibodies and vaccines in vivo. Antibodies that kill virus-infected cells and/or elicit an antiviral environment, termed antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, provide a link between the innate and adaptive immune response. New technologies allowing the rapid isolation and characterization of monoclonal antibodies (mAb) have yielded a plethora of mAbs which target conserved regions of influenza virus, such as the hemagglutinin (HA) stem region. Many such mAbs have been used to gain a better understanding of Fc-receptor functions in vivo. In parallel, several studies have characterized the induction of polyclonal ADCC following influenza vaccination and infection in humans. Taken together, these studies suggest that ADCC-mediating antibodies (ADCC-Abs) significantly contribute to host immunity against influenza virus and may be a mechanism to exploit for rational vaccine and therapeutic design. We discuss recent research on influenza-specific ADCC and potential future avenues to extend our understanding.
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Affiliation(s)
- Sinthujan Jegaskanda
- a Department of Microbiology and Immunology , University of Melbourne, Peter Doherty Institute for Infection and Immunity , Melbourne , Victoria , Australia
| | - Hillary A Vanderven
- a Department of Microbiology and Immunology , University of Melbourne, Peter Doherty Institute for Infection and Immunity , Melbourne , Victoria , Australia
| | - Adam K Wheatley
- a Department of Microbiology and Immunology , University of Melbourne, Peter Doherty Institute for Infection and Immunity , Melbourne , Victoria , Australia
| | - Stephen J Kent
- a Department of Microbiology and Immunology , University of Melbourne, Peter Doherty Institute for Infection and Immunity , Melbourne , Victoria , Australia.,b ARC Centre for Excellence in Convergent Bio-Nano Science and Technology , University of Melbourne , Melbourne , Australia.,c Melbourne Sexual Health Centre, Department of Infectious Diseases, Alfred Health, Central Clinical School , Monash University , Melbourne , Australia
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35
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Fujimoto Y, Tomioka Y, Takakuwa H, Uechi GI, Yabuta T, Ozaki K, Suyama H, Yamamoto S, Morimatsu M, Mai LQ, Yamashiro T, Ito T, Otsuki K, Ono E. Cross-protective potential of anti-nucleoprotein human monoclonal antibodies against lethal influenza A virus infection. J Gen Virol 2016; 97:2104-2116. [PMID: 27260213 DOI: 10.1099/jgv.0.000518] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The nucleoprotein (NP) possesses regions that are highly conserved among influenza A viruses, and has therefore been one of the target viral proteins for development of a universal influenza vaccine. It has been expected that human or humanized antibodies will be made available for the prophylaxis, pre-emptive and acute treatment of viral infection. However, it is still unclear whether anti-NP human antibody can confer protection against influenza virus infection. In this study, we generated transgenic mice expressing anti-NP human mAbs derived from lymphocytes of a patient infected with H5N1 highly pathogenic avian influenza (HPAI) virus, and experimental infections were conducted to examine antiviral effects of the anti-NP antibodies against H5N1 HPAI viral infections with a high fatality rate in mammals. Transgenic mouse lines expressing the anti-NP human mAbs at more than 1 mg ml-1 showed marked resistance to H5N1 virus infections. In addition, resistance to infection with an H1N1 subtype that shows strong pathogenicity to mice was also confirmed. Although the anti-NP mAbs expressed in the transgenic mice did not neutralize the virus, the mAbs could bind to NP located on the surface of infected cells. These results suggested a possibility that the non-neutralizing anti-NP human mAbs could induce indirect antiviral effects, such as antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. Taken together, these results demonstrated that anti-NP human mAbs play an important role in heterosubtypic protection against lethal influenza virus infections in vivo.
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Affiliation(s)
- Yoshikazu Fujimoto
- Department of Biomedicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.,Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yukiko Tomioka
- Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan
| | - Hiroki Takakuwa
- Avian Influenza Research Center, Kyoto Sangyo University, Kyoto 603-8555, Japan
| | - Gen-Ichiro Uechi
- Institute of Tropical Medicine, Nagasaki University, Nagasaki 851-2125, Japan
| | - Toshiyo Yabuta
- Avian Influenza Research Center, Kyoto Sangyo University, Kyoto 603-8555, Japan
| | - Kinuyo Ozaki
- Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Haruka Suyama
- Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Sayo Yamamoto
- Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masami Morimatsu
- Laboratory of Experimental Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Le Quynh Mai
- Department of Virology, National Institute of Hygiene and Epidemiology, No. 1 Yersin Street, Hanoi, Vietnam
| | - Tetsu Yamashiro
- Institute of Tropical Medicine, Nagasaki University, Nagasaki 851-2125, Japan
| | - Toshihiro Ito
- Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan
| | - Koichi Otsuki
- Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.,Avian Influenza Research Center, Kyoto Sangyo University, Kyoto 603-8555, Japan
| | - Etsuro Ono
- Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.,Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.,Department of Biomedicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Vanderven HA, Ana-Sosa-Batiz F, Jegaskanda S, Rockman S, Laurie K, Barr I, Chen W, Wines B, Hogarth PM, Lambe T, Gilbert SC, Parsons MS, Kent SJ. What Lies Beneath: Antibody Dependent Natural Killer Cell Activation by Antibodies to Internal Influenza Virus Proteins. EBioMedicine 2016; 8:277-290. [PMID: 27428437 PMCID: PMC4919476 DOI: 10.1016/j.ebiom.2016.04.029] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 04/15/2016] [Accepted: 04/25/2016] [Indexed: 02/01/2023] Open
Abstract
The conserved internal influenza proteins nucleoprotein (NP) and matrix 1 (M1) are well characterised for T cell immunity, but whether they also elicit functional antibodies capable of activating natural killer (NK) cells has not been explored. We studied NP and M1-specific ADCC activity using biochemical, NK cell activation and killing assays with plasma from healthy and influenza-infected subjects. Healthy adults had antibodies to M1 and NP capable of binding dimeric FcγRIIIa and activating NK cells. Natural symptomatic and experimental influenza infections resulted in a rise in antibody dependent NK cell activation post-infection to the hemagglutinin of the infecting strain, but changes in NK cell activation to M1 and NP were variable. Although antibody dependent killing of target cells infected with vaccinia viruses expressing internal influenza proteins was not detected, opsonising antibodies to NP and M1 likely contribute to an antiviral microenvironment by stimulating innate immune cells to secrete cytokines early in infection. We conclude that effector cell activating antibodies to conserved internal influenza proteins are common in healthy and influenza-infected adults. Given the significance of such antibodies in animal models of heterologous influenza infection, the definition of their importance and mechanism of action in human immunity to influenza is essential.
Functional antibodies to influenza matrix 1 and nucleoprotein are common in healthy and influenza-infected humans. Opsonising antibodies to matrix 1 and nucleoprotein can bind FcγRIIIa dimers and activate natural killer cells. Influenza infection increased natural killer cell activation to hemagglutinin but changes to the internal proteins varied Influenza virus causes both seasonal outbreaks and global pandemics. The current influenza vaccine provides minimal protection against divergent strains of the virus not found in the vaccine. While neutralising antibodies induced by vaccination are able to confer strain-specific protection, antibodies directed against conserved influenza proteins may be able to provide some cross-protection. Animal models suggest a protective role for anti-nucleoprotein antibodies. Exploring the functional capacity of human antibodies against internal influenza proteins to engage Fc receptors and activate innate immune cells may present a unique approach in the development of a more universal influenza vaccine.
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Affiliation(s)
- Hillary A Vanderven
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Fernanda Ana-Sosa-Batiz
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Sinthujan Jegaskanda
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Steven Rockman
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; Seqirus Ltd, Parkville, Australia
| | - Karen Laurie
- WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Ian Barr
- WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Weisan Chen
- La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, Bundoora, Australia
| | | | | | | | | | - Matthew S Parsons
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Stephen J Kent
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; Melbourne Sexual Health Centre, Department of Infectious Diseases, Alfred Health, Central Clinical School, Monash University, Melbourne, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Parkville, Australia.
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37
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The role of C5a in acute lung injury induced by highly pathogenic viral infections. Emerg Microbes Infect 2015; 4:e28. [PMID: 26060601 PMCID: PMC4451266 DOI: 10.1038/emi.2015.28] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 03/12/2015] [Accepted: 03/31/2015] [Indexed: 12/14/2022]
Abstract
The complement system, an important part of innate immunity, plays a critical role in pathogen clearance. Unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic virus including influenza A viruses H5N1, H7N9, and severe acute respiratory syndrome (SARS) coronavirus. In highly pathogenic virus-induced acute lung diseases, high levels of chemotactic and anaphylatoxic C5a were produced as a result of excessive complement activaiton. Overproduced C5a displays powerful biological activities in activation of phagocytic cells, generation of oxidants, and inflammatory sequelae named "cytokine storm", and so on. Blockade of C5a signaling have been implicated in the treatment of ALI induced by highly pathogenic virus. Herein, we review the literature that links C5a and ALI, and review our understanding of the mechanisms by which C5a affects ALI during highly pathogenic viral infection. In particular, we discuss the potential of the blockade of C5a signaling to treat ALI induced by highly pathogenic viruses.
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38
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Sun S, Zhao G, Liu C, Fan W, Zhou X, Zeng L, Guo Y, Kou Z, Yu H, Li J, Wang R, Li Y, Schneider C, Habel M, Riedemann NC, Du L, Jiang S, Guo R, Zhou Y. Treatment with anti-C5a antibody improves the outcome of H7N9 virus infection in African green monkeys. Clin Infect Dis 2014; 60:586-95. [PMID: 25433014 PMCID: PMC7112341 DOI: 10.1093/cid/ciu887] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
This study demonstrated that aberrant complement activation plays an important role in pathogenesis of acute lung injury induced by influenza A(H7N9) virus infection and that anti-C5a antibody treatment might be an effective new strategy for acute viral pneumonia. Background. Patients infected with influenza A(H7N9) virus present with acute lung injury (ALI) that is due to severe pneumonia and systemic inflammation. It is often fatal because there are few effective treatment options. Complement activation has been implicated in the pathogenesis of virus-induced lung injury; therefore, we investigated the effect of targeted complement inhibition on ALI induced by H7N9 virus infection. Methods. A novel neutralizing specific antihuman C5a antibody (IFX-1) was used. This antibody blocked the ability of C5a to induce granulocytes to express CD11b while not affecting the ability of C5b to form the membrane attack complex. African green monkeys were inoculated with H7N9 virus and treated intravenously with IFX-1. Results. The virus infection led to intense ALI and systemic inflammatory response syndrome (SIRS) in association with excessive complement activation. Anti-C5a treatment in H7N9-infected monkeys substantially attenuated ALI: It markedly reduced the lung histopathological injury and decreased the lung infiltration of macrophages and neutrophils. Moreover, the treatment decreased the intensity of SIRS; the body temperature changes were minimal and the plasma levels of inflammatory mediators were markedly reduced. The treatments also significantly decreased the virus titers in the infected lungs. Conclusions. Antihuman C5a antibody treatment remarkably reduced the ALI and systemic inflammation induced by H7N9 virus infection. Complement inhibition may be a promising adjunctive therapy for severe viral pneumonia.
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MESH Headings
- Acute Lung Injury/immunology
- Acute Lung Injury/pathology
- Acute Lung Injury/therapy
- Acute Lung Injury/virology
- Animals
- Antibodies, Neutralizing/therapeutic use
- Body Temperature
- Chlorocebus aethiops/virology
- Complement Activation
- Complement C5a/antagonists & inhibitors
- Complement C5a/immunology
- Disease Models, Animal
- Humans
- Influenza A Virus, H7N9 Subtype/isolation & purification
- Influenza A Virus, H7N9 Subtype/pathogenicity
- Influenza, Human/immunology
- Influenza, Human/pathology
- Influenza, Human/therapy
- Influenza, Human/virology
- Lung/pathology
- Lung/virology
- Macrophages, Alveolar/immunology
- Neutrophils/immunology
- Orthomyxoviridae Infections/immunology
- Orthomyxoviridae Infections/pathology
- Orthomyxoviridae Infections/therapy
- Orthomyxoviridae Infections/virology
- Pneumonia, Viral/immunology
- Pneumonia, Viral/pathology
- Pneumonia, Viral/therapy
- Pneumonia, Viral/virology
- Systemic Inflammatory Response Syndrome/pathology
- Systemic Inflammatory Response Syndrome/therapy
- Systemic Inflammatory Response Syndrome/virology
- Treatment Outcome
- Viral Load
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Affiliation(s)
- Shihui Sun
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology
| | - Guangyu Zhao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology
| | - Chenfeng Liu
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology
| | - Wei Fan
- Laboratory Animal Center, Academy of Military Medical Science
| | - Xiaojun Zhou
- Laboratory Animal Center, Academy of Military Medical Science
| | - Lin Zeng
- Laboratory Animal Center, Academy of Military Medical Science
| | - Yan Guo
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology
| | - Zhihua Kou
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology
| | - Hong Yu
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology
| | - Junfeng Li
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology
| | - Renxi Wang
- Laboratory of Immunology, Beijing Institute of Basic Medical Sciences, China
| | - Yan Li
- Laboratory of Immunology, Beijing Institute of Basic Medical Sciences, China
| | | | | | | | - Lanying Du
- Lindsley F. Kimball Research Institute, New York Blood Center, New York
| | - Shibo Jiang
- Lindsley F. Kimball Research Institute, New York Blood Center, New York
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College, Fudan University, China
| | | | - Yusen Zhou
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology
- Correspondence: Yusen Zhou, PhD, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China ()
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Jegaskanda S, Reading PC, Kent SJ. Influenza-specific antibody-dependent cellular cytotoxicity: toward a universal influenza vaccine. THE JOURNAL OF IMMUNOLOGY 2014; 193:469-75. [PMID: 24994909 DOI: 10.4049/jimmunol.1400432] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
There is an urgent need for universal influenza vaccines that can control emerging pandemic influenza virus threats without the need to generate new vaccines for each strain. Neutralizing Abs to the influenza virus hemagglutinin glycoprotein are effective at controlling influenza infection but generally target highly variable regions. Abs that can mediate other functions, such as killing influenza-infected cells and activating innate immune responses (termed "Ab-dependent cellular cytotoxicity [ADCC]-mediating Abs"), may assist in protective immunity to influenza. ADCC-mediating Abs can target more conserved regions of influenza virus proteins and recognize a broader array of influenza strains. We review recent research on influenza-specific ADCC Abs and their potential role in improved influenza-vaccination strategies.
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Affiliation(s)
- Sinthujan Jegaskanda
- Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia; and
| | - Patrick C Reading
- Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia; and World Health Organization Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria 3051, Australia
| | - Stephen J Kent
- Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia; and
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40
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Jegaskanda S, Vandenberg K, Laurie KL, Loh L, Kramski M, Winnall WR, Kedzierska K, Rockman S, Kent SJ. Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity in intravenous immunoglobulin as a potential therapeutic against emerging influenza viruses. J Infect Dis 2014; 210:1811-22. [PMID: 24916185 DOI: 10.1093/infdis/jiu334] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Intravenous immunoglobulin (IVIG) is a purified pool of human antibodies from thousands of donors that is used to prevent or treat primary immune deficiency, several infectious diseases, and autoimmune diseases. The antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) against heterologous influenza strains may be present in IVIG preparations. METHODS We tested 8 IVIG preparations prior to the 2009 H1N1 swine-origin influenza pandemic and 10 IVIG preparations made after 2010 for their ability to mediate influenza-specific ADCC. RESULTS ADCC mediating antibodies to A(H1N1)pdm09 hemagglutinin (HA) and neuraminidase (NA) were detected in IVIG preparations prior to the 2009-H1N1 pandemic. The HA-specific ADCC targeted both the HA1 and HA2 regions of A(H1N1)pdm09 HA and was capable of recognizing a broad range of HA proteins including those from recent avian influenza strains A(H5N1) and A(H7N9). The low but detectable ADCC recognition of A(H7N9) was likely due to rare individuals in the population contributing cross-reactive antibodies to IVIG. CONCLUSIONS IVIG preparations contain broadly cross-reactive ADCC mediating antibodies. IVIG may provide at least some level of protection for individuals at high risk of severe influenza disease, especially during influenza pandemics prior to the development of effective vaccines.
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Affiliation(s)
- Sinthujan Jegaskanda
- Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, University of Melbourne
| | | | - Karen L Laurie
- WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, North Melbourne, Victoria, Australia
| | - Liyen Loh
- Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, University of Melbourne
| | - Marit Kramski
- Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, University of Melbourne
| | - Wendy R Winnall
- Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, University of Melbourne
| | - Katherine Kedzierska
- Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, University of Melbourne
| | - Steven Rockman
- Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, University of Melbourne BioCSL Ltd, Parkville, Victoria
| | - Stephen J Kent
- Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, University of Melbourne
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Tong HH, Lambert G, Li YX, Thurman JM, Stahl GL, Douthitt K, Clancy C, He Y, Bowman AS. Deletion of the complement C5a receptor alleviates the severity of acute pneumococcal otitis media following influenza A virus infection in mice. PLoS One 2014; 9:e95160. [PMID: 24740152 PMCID: PMC3989264 DOI: 10.1371/journal.pone.0095160] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 03/24/2014] [Indexed: 12/04/2022] Open
Abstract
There is considerable evidence that influenza A virus (IAV) promotes adherence, colonization, and superinfection by S. pneumoniae (Spn) and contributes to the pathogenesis of otitis media (OM). The complement system is a critical innate immune defense against both pathogens. To assess the role of the complement system in the host defense and the pathogenesis of acute pneumococcal OM following IAV infection, we employed a well-established transtympanically-induced mouse model of acute pneumococcal OM. We found that antecedent IAV infection enhanced the severity of acute pneumococcal OM. Mice deficient in complement C1qa (C1qa−/−) or factor B (Bf −/−) exhibited delayed viral and bacterial clearance from the middle ear and developed significant mucosal damage in the eustachian tube and middle ear. This indicates that both the classical and alternative complement pathways are critical for the oto-immune defense against acute pneumococcal OM following influenza infection. We also found that Spn increased complement activation following IAV infection. This was characterized by sustained increased levels of anaphylatoxins C3a and C5a in serum and middle ear lavage samples. In contrast, mice deficient in the complement C5a receptor (C5aR) demonstrated enhanced bacterial clearance and reduced severity of OM. Our data support the concept that C5a-C5aR interactions play a significant role in the pathogenesis of acute pneumococcal OM following IAV infection. It is possible that targeting the C5a-C5aR axis might prove useful in attenuating acute pneumococcal OM in patients with influenza infection.
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Affiliation(s)
- Hua Hua Tong
- Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
| | - Garrett Lambert
- Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
| | - Yong Xing Li
- Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
| | - Joshua M Thurman
- Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Gregory L Stahl
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kelsey Douthitt
- Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
| | - Caitlin Clancy
- Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
| | - Yujuan He
- Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America; Department of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing, Sichuan, P. R. China
| | - Andrew S Bowman
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
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Sasaki S, Holmes TH, Albrecht RA, García-Sastre A, Dekker CL, He XS, Greenberg HB. Distinct cross-reactive B-cell responses to live attenuated and inactivated influenza vaccines. J Infect Dis 2014; 210:865-74. [PMID: 24676204 DOI: 10.1093/infdis/jiu190] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The immunological bases for the efficacies of the 2 currently licensed influenza vaccines, live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV), are not fully understood. The goal of this study was to identify specific B-cell responses correlated with the known efficacies of these 2 vaccines. METHODS We compared the B-cell and antibody responses after immunization with 2010/2011 IIV or LAIV in young adults, focusing on peripheral plasmablasts 6-8 days after vaccination. RESULTS The quantities of vaccine-specific plasmablasts and plasmablast-derived polyclonal antibodies (PPAbs) in IIV recipients were significantly higher than those in LAIV recipients. No significant difference was detected in the avidity of vaccine-specific PPAbs between the 2 vaccine groups. Proportionally, LAIV induced a greater vaccine-specific immunoglobulin A plasmablast response, as well as a greater plasmablast response to the conserved influenza nuclear protein, than IIV. The cross-reactive plasmablast response to heterovariant strains, as indicated by the relative levels of cross-reactive plasmablasts and the cross-reactive PPAb binding reactivity, was also greater in the LAIV group. CONCLUSIONS Distinct quantitative and qualitative patterns of plasmablast responses were induced by LAIV and IIV in young adults; a proportionally greater cross-reactive response was induced by LAIV.
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Affiliation(s)
- Sanae Sasaki
- Department of Microbiology and Immunology VA Palo Alto Health Care System, California
| | | | - Randy A Albrecht
- Department of Microbiology Global Health and Emerging Pathogens Institute
| | - Adolfo García-Sastre
- Department of Microbiology Global Health and Emerging Pathogens Institute Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Xiao-Song He
- Department of Medicine, Stanford University School of Medicine, Stanford VA Palo Alto Health Care System, California
| | - Harry B Greenberg
- Department of Microbiology and Immunology Department of Medicine, Stanford University School of Medicine, Stanford VA Palo Alto Health Care System, California
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Standard trivalent influenza virus protein vaccination does not prime antibody-dependent cellular cytotoxicity in macaques. J Virol 2013; 87:13706-18. [PMID: 24109221 DOI: 10.1128/jvi.01666-13] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Yearly vaccination with the trivalent inactivated influenza vaccine (TIV) is recommended, since current vaccines induce little cross neutralization to divergent influenza strains. Whether the TIV can induce antibody-dependent cellular cytotoxicity (ADCC) responses that can cross-recognize divergent influenza virus strains is unknown. We immunized 6 influenza-naive pigtail macaques twice with the 2011-2012 season TIV and then challenged the macaques, along with 12 control macaques, serially with H1N1 and H3N2 viruses. We measured ADCC responses in plasma to a panel of H1 and H3 hemagglutinin (HA) proteins and influenza virus-specific CD8 T cell (CTL) responses using a sensitive major histocompatibility complex (MHC) tetramer reagent. The TIV was weakly immunogenic and, although binding antibodies were detected by enzyme-linked immunosorbent assay (ELISA), did not induce detectable influenza virus-specific ADCC or CTL responses. The H1N1 challenge elicited robust ADCC to both homologous and heterologous H1 HA proteins, but not influenza virus HA proteins from different subtypes (H2 to H7). There was no anamnestic influenza virus-specific ADCC or CTL response in vaccinated animals. The subsequent H3N2 challenge did not induce or boost ADCC either to H1 HA proteins or to divergent H3 proteins but did boost CTL responses. ADCC or CTL responses were not induced by TIV vaccination in influenza-naive macaques. There was a marked difference in the ability of infection compared to that of vaccination to induce cross-reactive ADCC and CTL responses. Improved vaccination strategies are needed to induce broad-based ADCC immunity to influenza.
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Kritas S, Saggini A, Varvara G, Murmura G, Caraffa A, Antinolfi P, Toniato E, Pantalone A, Neri G, Frydas S, Rosati M, Tei M, Speziali A, Saggini R, Pandolfi F, Cerulli G, Theoharides T, Conti P. Impact of Mast Cells on the Skin. Int J Immunopathol Pharmacol 2013; 26:855-9. [DOI: 10.1177/039463201302600403] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
When through the skin a foreign antigen enters it provokes an immune response and inflammatory reaction. Mast cells are located around small vessels that are involved in vasaldilation. They mature under the influence of local tissue to various cytokines. Human skin mast cells play an essential role in diverse physiological and pathological processes and mediate immediate hypersensitive reaction and allergic diseases. Injection of anti-IgE in the skin or other agents that directly activate mast cells may cause the decrease in vascular tone, leakage of plasma and may lead to a fall in blood pressure with fatal anaphylactic shock. Skin mast cells are also implicated as effector cells in response to multiple parasites such as Leishmania which is primarily characterized by its tissue cutaneous tropism. Activated macrophages by IFNγ, cytotoxic T cells, activated mast cells and several cytokines are involved in the elimination of the parasites and immunoprotection. IL-33 is one of the latest cytokines involved in IgE-induced anaphylaxis and in the pathogenesis of allergic skin disorders. IL-33 has been shown in epidermis of patients with psoriasis and its skin expression causes atopic dermatitis and it is crucial for the development of this disease. Here we review the impact of mast cells on the skin.
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Affiliation(s)
- S.K. Kritas
- Department of Microbiology and Infectious Diseases, School of Veterinary Medicine, Aristotle University of Thessaloniki, Macedonia, Greece
| | - A. Saggini
- Department of Dermatology, University of Rome Tor Vergata, Rome, Italy
| | - G. Varvara
- Dental School, University of Chieti-Pescara, Italy
| | - G. Murmura
- Dental School, University of Chieti-Pescara, Italy
| | - A. Caraffa
- Orthopedic Division, University of Perugia, Perugia, Italy
| | - P. Antinolfi
- Orthopedic Division, University of Perugia, Perugia, Italy
| | - E. Toniato
- Immunology Division, Medical School, University of Chieti-Pescara, Chieti, Italy
| | - A. Pantalone
- Orthopedic Division, University of Chieti-Pescara, Chieti, Italy
| | - G. Neri
- Department of Neurosciences and Imaging, Faculty of Medicine and Surgery, G. d'Annunzio University Chieti-Pescara, Chieti, Italy
| | - S. Frydas
- Department of Parasitology, School of Veterinary Medicine, University of Thessaloniki, Macedonia, Greece
| | - M. Rosati
- Gynecology Clinic, Pescara Hospital, Pescara, Italy
| | - M. Tei
- Nicola's Foundation, Onlus, Arezzo, Italy
| | - A. Speziali
- Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - R. Saggini
- Department of Neurosciences and Imaging, Faculty of Medicine and Surgery, G. d'Annunzio University Chieti-Pescara, Chieti, Italy
| | - F. Pandolfi
- Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - G. Cerulli
- Nicola's Foundation, Onlus, Arezzo, Italy
| | - T.C. Theoharides
- Department of Pharmacology and Experimental Therapeutics, Biochemistry and Internal Medicine Tufts University School of Medicine, Tufts-New England Medical Center, Boston, MA, USA
| | - P. Conti
- Immunology Division, Medical School, University of Chieti-Pescara, Chieti, Italy
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Yamashita N, Tsukahara H, Tsuge M, Nagaoka Y, Yashiro M, Saito Y, Fujii Y, Oka T, Morishima T. Pathogenic mechanisms of influenza A(H1N1)pdm09 infection elucidated on gene expression profiling. Pediatr Int 2013; 55:572-7. [PMID: 23701225 DOI: 10.1111/ped.12139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Revised: 02/18/2013] [Accepted: 05/09/2013] [Indexed: 01/26/2023]
Abstract
BACKGROUND The pathogenic mechanisms underlying influenza A(H1N1)pdm09-associated central nervous system (CNS) manifestations and pneumonia remain unclear. This study examined A(H1N1)pdm09 host responses using gene expression profiles of patients' peripheral blood. METHODS Sixteen A(H1N1)pdm09-infected children in three groups were examined: a CNS group, with convulsion and altered consciousness (n = 6); a pneumonia (Pneu) group (n = 5); and a group of infected control patients (n = 5). The signal ratios of the acute to recovery phases in CNS or Pneu were analyzed versus those of the control. RESULTS The CNS (619 transcripts) and Pneu (656 transcripts) groups had significantly increased signal ratios compared to the control group. Regarding the increased ratios of transcripts shown by multiple probes, contactin-associated protein-like 3 transcripts, oleoyl-ACP hydrolase transcripts, and interleukin 1 type 1 receptor were observed in CNS and Pneu. Increased ratios of prostaglandin-endoperoxide synthase 2 and α-synuclein were characteristic of CNS. Alkaline phosphatase and the Fc fragment of IgA receptor were characteristic of Pneu. Regarding enriched gene ontology terms, 'response to lipopolysaccharide', 'innate immune response', and 'intrinsic to membrane' were observed commonly in CNS and Pneu. Enriched gene ontology terms related to 'hemoglobin' and 'hemostasis' were, respectively, characteristic of CNS and Pneu. CONCLUSION These symptom-associated transcripts might be some clues to the pathogenesis of the A(H1N1)pdm09 infection.
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Affiliation(s)
- Nobuko Yamashita
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Sun S, Zhao G, Liu C, Wu X, Guo Y, Yu H, Song H, Du L, Jiang S, Guo R, Tomlinson S, Zhou Y. Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection. Am J Respir Cell Mol Biol 2013; 49:221-30. [PMID: 23526211 DOI: 10.1165/rcmb.2012-0428oc] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The acute lung injury (ALI) that occurs after the highly pathogenic avian influenza H5N1 virus infection is associated with an abnormal host innate immune response. Because the complement system plays a central role in innate immunity and because aberrant complement activation is associated with a variety of autoimmune and inflammatory diseases, we investigated the complement involvement in the pathogenesis of ALI induced by H5N1 virus infection. We showed that ALI in H5N1-infected mice was caused by excessive complement activation, as demonstrated by deposition of C3, C5b-9, and mannose-binding lectin (MBL)-C in lung tissue, and by up-regulation of MBL-associated serine protease-2 and the complement receptors C3aR and C5aR. Treatment of H5N1-infected mice with a C3aR antagonist led to significantly reduced inflammation in lungs, alleviating ALI. Furthermore, complement inhibition with an anti-C5a antibody or complement depletion with cobra venom factor after H5N1 challenge resulted in a similar level of protection to that seen in C3aR antagonist-treated mice. These results indicate that excessive complement activation plays an important role in mediating H5N1-induced ALI and that inhibition of complement may be an effective clinical intervention and adjunctive treatment for H5N1-induced ALI.
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Affiliation(s)
- Shihui Sun
- 1 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
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Jegaskanda S, Laurie KL, Amarasena TH, Winnall WR, Kramski M, De Rose R, Barr IG, Brooks AG, Reading PC, Kent SJ. Age-associated cross-reactive antibody-dependent cellular cytotoxicity toward 2009 pandemic influenza A virus subtype H1N1. J Infect Dis 2013; 208:1051-61. [PMID: 23812238 DOI: 10.1093/infdis/jit294] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND During the 2009 pandemic of influenza A virus subtype H1N1 (A[H1N1]pdm09) infection, older individuals were partially protected from severe disease. It is not known whether preexisting antibodies with effector functions such as antibody-dependent cellular cytotoxicity (ADCC) contributed to the immunity observed. METHODS We tested serum specimens obtained from 182 individuals aged 1-72 years that were collected either immediately before or after the A(H1N1)pdm09 pandemic for ADCC antibodies to the A(H1N1)pdm09 hemagglutinin (HA) protein. RESULTS A(H1N1)pdm09 HA-specific ADCC antibodies were detected in almost all individuals aged >45 years (28/31 subjects) before the 2009 A(H1N1) pandemic. Conversely, only approximately half of the individuals aged 1-14 years (11/31) and 15-45 years (17/31) had cross-reactive ADCC antibodies before the 2009 A(H1N1) pandemic. The A(H1N1)pdm09-specific ADCC antibodies were able to efficiently mediate the killing of influenza virus-infected respiratory epithelial cells. Further, subjects >45 years of age had higher ADCC titers to a range of seasonal H1N1 HA proteins, including from the 1918 virus, compared with younger individuals. CONCLUSIONS ADCC antibodies may have contributed to the protection exhibited in older individuals during the 2009 A(H1N1) pandemic. This work has significant implications for improved vaccination strategies for future influenza pandemics.
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Affiliation(s)
- Sinthujan Jegaskanda
- Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia
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Garcia CC, Weston-Davies W, Russo RC, Tavares LP, Rachid MA, Alves-Filho JC, Machado AV, Ryffel B, Nunn MA, Teixeira MM. Complement C5 activation during influenza A infection in mice contributes to neutrophil recruitment and lung injury. PLoS One 2013; 8:e64443. [PMID: 23696894 PMCID: PMC3655967 DOI: 10.1371/journal.pone.0064443] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 04/15/2013] [Indexed: 01/30/2023] Open
Abstract
Influenza virus A (IAV) causes annual epidemics and intermittent pandemics that affect millions of people worldwide. Potent inflammatory responses are commonly associated with severe cases of IAV infection. The complement system, an important mechanism of innate and humoral immune responses to infections, is activated during primary IAV infection and mediates, in association with natural IgM, viral neutralization by virion aggregation and coating of viral hemmagglutinin. Increased levels of the anaphylatoxin C5a were found in patients fatally infected with the most recent H1N1 pandemic virus. In this study, our aim was to evaluate whether targeting C5 activation alters inflammatory lung injury and viral load in a murine model of IAV infection. To address this question C57Bl/6j mice were infected intranasally with 10(4) PFU of the mouse adapted Influenza A virus A/WSN/33 (H1N1) or inoculated with PBS (Mock). We demonstrated that C5a is increased in bronchoalveolar lavage fluid (BALF) upon experimental IAV infection. To evaluate the role of C5, we used OmCI, a potent arthropod-derived inhibitor of C5 activation that binds to C5 and prevents release of C5a by complement. OmCI was given daily by intraperitoneal injection from the day of IAV infection until day 5. Treatment with OmCI only partially reduced C5a levels in BALF. However, there was significant inhibition of neutrophil and macrophage infiltration in the airways, Neutrophil Extracellular Traps (NETs) formation, death of leukocytes, lung epithelial injury and overall lung damage induced by the infection. There was no effect on viral load. Taken together, these data suggest that targeting C5 activation with OmCI during IAV infection could be a promising approach to reduce excessive inflammatory reactions associated with the severe forms of IAV infections.
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Affiliation(s)
- Cristiana C. Garcia
- Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Remo C. Russo
- Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Departamento de Fisiologia e Biofísica, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Luciana P. Tavares
- Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Milene A. Rachid
- Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Departamento de Patologia Geral, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - José C. Alves-Filho
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Alexandre V. Machado
- Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - Bernhard Ryffel
- CNRS UMR7355, CNRS and University Orleans, France and IIDMM, University of Cape Town, Cape Town, South Africa
| | - Miles A. Nunn
- Centre for Ecology and Hydrology, Wallingford, United Kingdom
| | - Mauro M. Teixeira
- Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Innate immune function and mortality in critically ill children with influenza: a multicenter study. Crit Care Med 2013; 41:224-36. [PMID: 23222256 DOI: 10.1097/ccm.0b013e318267633c] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To prospectively evaluate relationships among serum cytokine levels, innate immune responsiveness, and mortality in a multicenter cohort of critically ill children with influenza infection. DESIGN Prospective, multicenter, observational study. SETTING Fifteen pediatric ICUs among members of the Pediatric Acute Lung Injury and Sepsis Investigators network. PATIENTS Patients ≤18 yrs old admitted to a PICU with community-acquired influenza infection. A control group of outpatient children was also evaluated. INTERVENTIONS ICU patients underwent sampling within 72 hrs of ICU admission for measurement of a panel of 31 serum cytokine levels and quantification of whole blood ex vivo lipopolysaccharide-stimulated tumor necrosis factor-α production capacity using a standardized stimulation protocol. Outpatient control subjects also underwent measurement of tumor necrosis factor-α production capacity. MEASUREMENTS AND MAIN RESULTS Fifty-two patients (44 survivors, eight deaths) were sampled. High levels of serum cytokines (granulocyte macrophage colony-stimulating factor, interleukin-6, interleukin-8, interferon-inducible protein-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1α) were associated with mortality (p < 0.0016 for each comparison) as was the presence of secondary infection with Staphylococcus aureus (p = 0.007), particularly methicillin-resistant S. aureus (p < 0.0001). Nonsurvivors were immunosuppressed with leukopenia and markedly reduced tumor necrosis factor-α production capacity compared with outpatient control subjects (n = 21, p < 0.0001) and to ICU survivors (p < 0.0001). This association remained after controlling for multiple covariables. A tumor necrosis factor-α response <250 pg/mL was highly predictive of death and longer duration of ICU stay (p < 0.0001). Patients with S. aureus coinfection demonstrated the greatest degree of immunosuppression (p < 0.0001). CONCLUSIONS High serum levels of cytokines can coexist with marked innate immune suppression in children with critical influenza. Severe, early innate immune suppression is highly associated with both S. aureus coinfection and mortality in this population. Multicenter innate immune function testing is feasible and can identify these high-risk children.
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Jegaskanda S, Job ER, Kramski M, Laurie K, Isitman G, de Rose R, Winnall WR, Stratov I, Brooks AG, Reading PC, Kent SJ. Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity antibodies in the absence of neutralizing antibodies. THE JOURNAL OF IMMUNOLOGY 2013; 190:1837-48. [PMID: 23319732 DOI: 10.4049/jimmunol.1201574] [Citation(s) in RCA: 192] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
A better understanding of immunity to influenza virus is needed to generate cross-protective vaccines. Engagement of Ab-dependent cellular cytotoxicity (ADCC) Abs by NK cells leads to killing of virus-infected cells and secretion of antiviral cytokines and chemokines. ADCC Abs may target more conserved influenza virus Ags compared with neutralizing Abs. There has been minimal interest in influenza-specific ADCC in recent decades. In this study, we developed novel assays to assess the specificity and function of influenza-specific ADCC Abs. We found that healthy influenza-seropositive young adults without detectable neutralizing Abs to the hemagglutinin of the 1968 H3N2 influenza strain (A/Aichi/2/1968) almost always had ADCC Abs that triggered NK cell activation and in vitro elimination of influenza-infected human blood and respiratory epithelial cells. Furthermore, we detected ADCC in the absence of neutralization to both the recent H1N1 pandemic strain (A/California/04/2009) as well as the avian H5N1 influenza hemagglutinin (A/Anhui/01/2005). We conclude that there is a remarkable degree of cross-reactivity of influenza-specific ADCC Abs in seropositive humans. Targeting cross-reactive influenza-specific ADCC epitopes by vaccination could lead to improved influenza vaccines.
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Affiliation(s)
- Sinthujan Jegaskanda
- Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia
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