Prof. Dr. med. Michael Osthoff Department of Clinical Research Profiles & Affiliations OverviewResearch Publications Projects & Collaborations Projects & Collaborations OverviewResearch Publications Projects & Collaborations Profiles & Affiliations Projects & Collaborations 4 foundShow per page10 10 20 50 Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78 Research Project | 4 Project MembersSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since December 2019 causing a worldwide pandemic of coronavirus disease 2019 (COVID-19). Systemic hyper-inflammation is a hallmark of severe stages of COVID-19 leading to acute lung injury (ALI), need for mechanical ventilation and ultimately death. The mechanism responsible for virus-induced hyper-activation of the host immune system remains to be fully elucidated. Unregulated complement system activation induced by CoVs plays a crucial role in the pathogenesis of acute lung injury in COVID-19. Similarly, involvement of the kinin-kallikrein system in capillary leakage and subsequent pulmonary angioedema has been suspected. In particular, a reduced activity of angiotensin converting enzyme 2 (ACE2) caused by SARS-CoV-2 leads to a relative abundance of bradykinin degradation products and local pulmonary edema. Lastly, over-activation of the contact activation system may be involved in the observed thromboinflammation. C1 esterase inhibitor (C1INH) is a potent inhibitor of these three plasmatic cascades and has been shown to reduce pulmonary inflammation and death in a CoV mouse model and in human studies of severe sepsis. Aims: To assess the safety and efficacy of recombinant C1INH (conestat alfa, Ruconest®) in addition to standard of care (SOC) in patients hospitalized with severe SARS-CoV-2 compared to SOC only.Hypothesis: Administration of conestat alfa for 72 hours in addition to SOC in patients with severe SARS-CoV-2 pneumonia is safe and associated with a reduced clinical severity on day 7 and a lower risk of disease progression to mechanical ventilation compared to SOC.Methodology: The PROTECT-COVID-19 trial is a randomized, open-label, parallel-group, controlled, multi-center clinical trial. Consecutive patients admitted with COVID-19 not requiring intensive care support will be randomized in a 2:1 ratio to treatment with conestat alfa for 72 hours in addition to SOC or SOC only. The primary endpoint will be the disease severity on the 7-point Ordinal WHO scale on day 7. Secondary endpoints include time to clinical improvement, the proportion of participants alive and not having required invasive or non-invasive ventilation and the incidence of ALI within 14 days after enrolment. Treatment safety and the activity of the above mentioned plasmatic cascades will be assessed. For a 2:1-randomization, a nonparametric analysis by the stratified logrank-test, and an adaptive group sequential analysis, the overall sample size is estimated as 120 = 80 + 40. Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels ap = 0.0221.Potential significance: Targeting multiple inflammatory cascades with conestat alfa early during COVID-19 is an innovative approach to prevent disease progression by ameliorating excessive (thrombo-) inflammation. Interventions that prevent deterioration and mechanical ventilation in COVID-19 are highly desired in a pandemic situation with limited ICU and ventilation support capacity. If treatment with conesta alfa proves to ameliorate pulmonary inflammation and injury, this may be relevant not only on an individual but also on a population level. Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78 Research Project | 1 Project MembersImported from Grants Tool 4601479 P5_mobile_sensitive_SARS-CoV-2_test Research Project | 3 Project MembersThe current pandemic outbreak of the SARS-CoV-2 virus that causes the disease COVID-19 is demonstrating the vulnerability of our globalized society for such threats. 1 Governments around the globe were forced to implement counter measures that put a high burden on public life and our economy in order to prevent the collapse of our healthcare system and the death of thousands of patients. 2 One of the main reasons such measures were needed are the inadequacies of our current disease detection system. State-of-the-art systems, while very accurate, are too slow and too expensive to effectively detect infected subjects and help prevent the spread of a pandemic disease. While the digital remote consulting and assessment of symptomatic patients via phone or video call has been adopted, a remote diagnostic test remains lacking. 3 Thus, our current paradigm to wait until symptoms appear before people are tested in centralized facilities is fundamentally flawed to fight diseases like COVID-19. SARS-CoV-2 can be transmitted by patients long before symptoms appear or even by asymptomatic patients. 4,5 As the incubation period lasts several days, 6 these issues lead to the creation of a blind spot: i.e. many patients that are transmitting the disease are currently not diagnosable. The only way to remedy this blind spot, to contain and further prevent pandemic diseases before a vaccine is available, is a new type of test that is mobile, fast, cheap, lab-independent and accurate. The possibility to test large parts of the population at home, avoiding high costs and high strain for the healthcare system, will significantly contribute to immediate containment of such diseases and prevention of the loss of lives, without the need for counter measures that cause large economic damage such as ones we are currently experiencing. Within this proposed project, the group of Prof. Vörös (ETH Zürich), who is leading this project, will develop a rapid test system based on lateral flow assays, with drastically improved sensitivity, while maintaining the point-of-need principle (i.e. rapid turn-around time and immediate availability of the test result). With this test, a clinical sensitivity of close to 100% for the detection of SARS-CoV-2 from nasopharyngeal or throat swab samples seems likely. Our group will then benchmark this technology with real samples against clinically validated methods. The aim of the planned study is to clinically validate the developed test and determine its performance characteristics compared to the current gold standard [a laboratory-developed, qualitative SARS-CoV-2 real-time polymerase chain reaction (PCR)] and in two scenarios (professional-collected vs. self-collected swabs). Patients with suspicion of COVID-19 presenting to the outpatient clinic of the University Hospital Basel or having been diagnosed with COVID-19 after admission to the hospital will be asked for participation in this validation study if a SARS-CoV-2 test is deemed necessary by the treating physicians. Additionally, patients with confirmed viral upper or lower respiratory tract infections will be included. This proposed new test is a unique tool with a high potential to dramatically impact the spread of infectious diseases such as COVID-19 and to decrease mortality and the high economic burden of pandemic diseases. References: Ghebreyesus, A. T. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. Dayrit, M. & Mendoza, R. U. Social Cohesion vs COVID-19. SSRN Electron. J. (2020) doi:10.2139/ssrn.3555152. Greenhalgh, T., Koh, G. C. H. & Car, J. Covid-19: a remote assessment in primary care. BMJ 368 , m1182 (2020). Zou, L. et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N. Engl. J. Med. NEJMc2001737 (2020) doi:10.1056/NEJMc2001737. Corman, V. M. et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance 25 , 2000045 (2020). Bai, Y. et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA (2020) doi:10.1001/jama.2020.2565 Significance of mannose-binding lectin and the lectin pathway in acute and recurrent ischemia/repefusion injury Research Project | 4 Project MembersMannose-binding lectin (MBL), a circulating pattern-recognition protein of the lectin pathway of complement is involved in the clearance of microorganisms and apoptotic cells. The concentration of functional MBL multimers is profoundly influenced by several polymorphisms in the MBL2 gene on chromosome 10, resulting in remarkable variations in serum MBL concentrations in apparently healthy individuals. Beyond infections, recent experimental studies have acknowledged additional important roles of MBL in atherosclerosis and ischemia/reperfusion (IR) injury. However, human data are scarce. This proposal aims to characterise in more depth the role of MBL and the lectin pathway in three human diseases, in which acute or repetitive I/R injury and/or atherosclerosis contribute to pathophysiology and outcome: systemic lupus erythematosus.primary (SLE), systemic sclerosis (SSc), and primary open angle glaucoma (POAG). In the SLE cohort sub-study, association of MBL deficiency with vascular events will be investigated in subjects from the well characterized Swiss SLE cohort. This is of importance, as SLE patients have an increased cardiovascular mortality and morbidity compared to the average individual. In the SSc cohort sub-study, activity of the lectin pathway including levels of MBL and the ficolins will be correlated with disease activity and organ involvement in individuals from a large European SSc cohort. Our preliminary data from a previous small Australian SSc cohort indicates that MBL deficiency might be associated with less organ damage. Hence, it might be worth to explore inhibition of the MBL or the lectin pathway in the future. In the POAG case-control sub-study, activity of the complement system in general and the lectin pathway in particular will be examined in POAG cases compared to healthy controls. This is of interest, as vascular dysfunction and repetitive I/R injury seem to be a hallmark in the pathogenesis of POAG, and current treatment options are limited. This project will lead to a more comprehensive understanding of the pathogenesis and the importance of MBL and the lectin pathway in I/R injury in SLE, SSc and POAG. Furthermore, it might facilitate future therapeutic interventions like inhibition of MBL or the lectin pathway to ameliorate I/R injury in these settings. 1 1 OverviewResearch Publications Projects & Collaborations
Projects & Collaborations 4 foundShow per page10 10 20 50 Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78 Research Project | 4 Project MembersSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since December 2019 causing a worldwide pandemic of coronavirus disease 2019 (COVID-19). Systemic hyper-inflammation is a hallmark of severe stages of COVID-19 leading to acute lung injury (ALI), need for mechanical ventilation and ultimately death. The mechanism responsible for virus-induced hyper-activation of the host immune system remains to be fully elucidated. Unregulated complement system activation induced by CoVs plays a crucial role in the pathogenesis of acute lung injury in COVID-19. Similarly, involvement of the kinin-kallikrein system in capillary leakage and subsequent pulmonary angioedema has been suspected. In particular, a reduced activity of angiotensin converting enzyme 2 (ACE2) caused by SARS-CoV-2 leads to a relative abundance of bradykinin degradation products and local pulmonary edema. Lastly, over-activation of the contact activation system may be involved in the observed thromboinflammation. C1 esterase inhibitor (C1INH) is a potent inhibitor of these three plasmatic cascades and has been shown to reduce pulmonary inflammation and death in a CoV mouse model and in human studies of severe sepsis. Aims: To assess the safety and efficacy of recombinant C1INH (conestat alfa, Ruconest®) in addition to standard of care (SOC) in patients hospitalized with severe SARS-CoV-2 compared to SOC only.Hypothesis: Administration of conestat alfa for 72 hours in addition to SOC in patients with severe SARS-CoV-2 pneumonia is safe and associated with a reduced clinical severity on day 7 and a lower risk of disease progression to mechanical ventilation compared to SOC.Methodology: The PROTECT-COVID-19 trial is a randomized, open-label, parallel-group, controlled, multi-center clinical trial. Consecutive patients admitted with COVID-19 not requiring intensive care support will be randomized in a 2:1 ratio to treatment with conestat alfa for 72 hours in addition to SOC or SOC only. The primary endpoint will be the disease severity on the 7-point Ordinal WHO scale on day 7. Secondary endpoints include time to clinical improvement, the proportion of participants alive and not having required invasive or non-invasive ventilation and the incidence of ALI within 14 days after enrolment. Treatment safety and the activity of the above mentioned plasmatic cascades will be assessed. For a 2:1-randomization, a nonparametric analysis by the stratified logrank-test, and an adaptive group sequential analysis, the overall sample size is estimated as 120 = 80 + 40. Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels ap = 0.0221.Potential significance: Targeting multiple inflammatory cascades with conestat alfa early during COVID-19 is an innovative approach to prevent disease progression by ameliorating excessive (thrombo-) inflammation. Interventions that prevent deterioration and mechanical ventilation in COVID-19 are highly desired in a pandemic situation with limited ICU and ventilation support capacity. If treatment with conesta alfa proves to ameliorate pulmonary inflammation and injury, this may be relevant not only on an individual but also on a population level. Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78 Research Project | 1 Project MembersImported from Grants Tool 4601479 P5_mobile_sensitive_SARS-CoV-2_test Research Project | 3 Project MembersThe current pandemic outbreak of the SARS-CoV-2 virus that causes the disease COVID-19 is demonstrating the vulnerability of our globalized society for such threats. 1 Governments around the globe were forced to implement counter measures that put a high burden on public life and our economy in order to prevent the collapse of our healthcare system and the death of thousands of patients. 2 One of the main reasons such measures were needed are the inadequacies of our current disease detection system. State-of-the-art systems, while very accurate, are too slow and too expensive to effectively detect infected subjects and help prevent the spread of a pandemic disease. While the digital remote consulting and assessment of symptomatic patients via phone or video call has been adopted, a remote diagnostic test remains lacking. 3 Thus, our current paradigm to wait until symptoms appear before people are tested in centralized facilities is fundamentally flawed to fight diseases like COVID-19. SARS-CoV-2 can be transmitted by patients long before symptoms appear or even by asymptomatic patients. 4,5 As the incubation period lasts several days, 6 these issues lead to the creation of a blind spot: i.e. many patients that are transmitting the disease are currently not diagnosable. The only way to remedy this blind spot, to contain and further prevent pandemic diseases before a vaccine is available, is a new type of test that is mobile, fast, cheap, lab-independent and accurate. The possibility to test large parts of the population at home, avoiding high costs and high strain for the healthcare system, will significantly contribute to immediate containment of such diseases and prevention of the loss of lives, without the need for counter measures that cause large economic damage such as ones we are currently experiencing. Within this proposed project, the group of Prof. Vörös (ETH Zürich), who is leading this project, will develop a rapid test system based on lateral flow assays, with drastically improved sensitivity, while maintaining the point-of-need principle (i.e. rapid turn-around time and immediate availability of the test result). With this test, a clinical sensitivity of close to 100% for the detection of SARS-CoV-2 from nasopharyngeal or throat swab samples seems likely. Our group will then benchmark this technology with real samples against clinically validated methods. The aim of the planned study is to clinically validate the developed test and determine its performance characteristics compared to the current gold standard [a laboratory-developed, qualitative SARS-CoV-2 real-time polymerase chain reaction (PCR)] and in two scenarios (professional-collected vs. self-collected swabs). Patients with suspicion of COVID-19 presenting to the outpatient clinic of the University Hospital Basel or having been diagnosed with COVID-19 after admission to the hospital will be asked for participation in this validation study if a SARS-CoV-2 test is deemed necessary by the treating physicians. Additionally, patients with confirmed viral upper or lower respiratory tract infections will be included. This proposed new test is a unique tool with a high potential to dramatically impact the spread of infectious diseases such as COVID-19 and to decrease mortality and the high economic burden of pandemic diseases. References: Ghebreyesus, A. T. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. Dayrit, M. & Mendoza, R. U. Social Cohesion vs COVID-19. SSRN Electron. J. (2020) doi:10.2139/ssrn.3555152. Greenhalgh, T., Koh, G. C. H. & Car, J. Covid-19: a remote assessment in primary care. BMJ 368 , m1182 (2020). Zou, L. et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N. Engl. J. Med. NEJMc2001737 (2020) doi:10.1056/NEJMc2001737. Corman, V. M. et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance 25 , 2000045 (2020). Bai, Y. et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA (2020) doi:10.1001/jama.2020.2565 Significance of mannose-binding lectin and the lectin pathway in acute and recurrent ischemia/repefusion injury Research Project | 4 Project MembersMannose-binding lectin (MBL), a circulating pattern-recognition protein of the lectin pathway of complement is involved in the clearance of microorganisms and apoptotic cells. The concentration of functional MBL multimers is profoundly influenced by several polymorphisms in the MBL2 gene on chromosome 10, resulting in remarkable variations in serum MBL concentrations in apparently healthy individuals. Beyond infections, recent experimental studies have acknowledged additional important roles of MBL in atherosclerosis and ischemia/reperfusion (IR) injury. However, human data are scarce. This proposal aims to characterise in more depth the role of MBL and the lectin pathway in three human diseases, in which acute or repetitive I/R injury and/or atherosclerosis contribute to pathophysiology and outcome: systemic lupus erythematosus.primary (SLE), systemic sclerosis (SSc), and primary open angle glaucoma (POAG). In the SLE cohort sub-study, association of MBL deficiency with vascular events will be investigated in subjects from the well characterized Swiss SLE cohort. This is of importance, as SLE patients have an increased cardiovascular mortality and morbidity compared to the average individual. In the SSc cohort sub-study, activity of the lectin pathway including levels of MBL and the ficolins will be correlated with disease activity and organ involvement in individuals from a large European SSc cohort. Our preliminary data from a previous small Australian SSc cohort indicates that MBL deficiency might be associated with less organ damage. Hence, it might be worth to explore inhibition of the MBL or the lectin pathway in the future. In the POAG case-control sub-study, activity of the complement system in general and the lectin pathway in particular will be examined in POAG cases compared to healthy controls. This is of interest, as vascular dysfunction and repetitive I/R injury seem to be a hallmark in the pathogenesis of POAG, and current treatment options are limited. This project will lead to a more comprehensive understanding of the pathogenesis and the importance of MBL and the lectin pathway in I/R injury in SLE, SSc and POAG. Furthermore, it might facilitate future therapeutic interventions like inhibition of MBL or the lectin pathway to ameliorate I/R injury in these settings. 1 1
Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78 Research Project | 4 Project MembersSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since December 2019 causing a worldwide pandemic of coronavirus disease 2019 (COVID-19). Systemic hyper-inflammation is a hallmark of severe stages of COVID-19 leading to acute lung injury (ALI), need for mechanical ventilation and ultimately death. The mechanism responsible for virus-induced hyper-activation of the host immune system remains to be fully elucidated. Unregulated complement system activation induced by CoVs plays a crucial role in the pathogenesis of acute lung injury in COVID-19. Similarly, involvement of the kinin-kallikrein system in capillary leakage and subsequent pulmonary angioedema has been suspected. In particular, a reduced activity of angiotensin converting enzyme 2 (ACE2) caused by SARS-CoV-2 leads to a relative abundance of bradykinin degradation products and local pulmonary edema. Lastly, over-activation of the contact activation system may be involved in the observed thromboinflammation. C1 esterase inhibitor (C1INH) is a potent inhibitor of these three plasmatic cascades and has been shown to reduce pulmonary inflammation and death in a CoV mouse model and in human studies of severe sepsis. Aims: To assess the safety and efficacy of recombinant C1INH (conestat alfa, Ruconest®) in addition to standard of care (SOC) in patients hospitalized with severe SARS-CoV-2 compared to SOC only.Hypothesis: Administration of conestat alfa for 72 hours in addition to SOC in patients with severe SARS-CoV-2 pneumonia is safe and associated with a reduced clinical severity on day 7 and a lower risk of disease progression to mechanical ventilation compared to SOC.Methodology: The PROTECT-COVID-19 trial is a randomized, open-label, parallel-group, controlled, multi-center clinical trial. Consecutive patients admitted with COVID-19 not requiring intensive care support will be randomized in a 2:1 ratio to treatment with conestat alfa for 72 hours in addition to SOC or SOC only. The primary endpoint will be the disease severity on the 7-point Ordinal WHO scale on day 7. Secondary endpoints include time to clinical improvement, the proportion of participants alive and not having required invasive or non-invasive ventilation and the incidence of ALI within 14 days after enrolment. Treatment safety and the activity of the above mentioned plasmatic cascades will be assessed. For a 2:1-randomization, a nonparametric analysis by the stratified logrank-test, and an adaptive group sequential analysis, the overall sample size is estimated as 120 = 80 + 40. Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels ap = 0.0221.Potential significance: Targeting multiple inflammatory cascades with conestat alfa early during COVID-19 is an innovative approach to prevent disease progression by ameliorating excessive (thrombo-) inflammation. Interventions that prevent deterioration and mechanical ventilation in COVID-19 are highly desired in a pandemic situation with limited ICU and ventilation support capacity. If treatment with conesta alfa proves to ameliorate pulmonary inflammation and injury, this may be relevant not only on an individual but also on a population level.
Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78 Research Project | 1 Project MembersImported from Grants Tool 4601479
P5_mobile_sensitive_SARS-CoV-2_test Research Project | 3 Project MembersThe current pandemic outbreak of the SARS-CoV-2 virus that causes the disease COVID-19 is demonstrating the vulnerability of our globalized society for such threats. 1 Governments around the globe were forced to implement counter measures that put a high burden on public life and our economy in order to prevent the collapse of our healthcare system and the death of thousands of patients. 2 One of the main reasons such measures were needed are the inadequacies of our current disease detection system. State-of-the-art systems, while very accurate, are too slow and too expensive to effectively detect infected subjects and help prevent the spread of a pandemic disease. While the digital remote consulting and assessment of symptomatic patients via phone or video call has been adopted, a remote diagnostic test remains lacking. 3 Thus, our current paradigm to wait until symptoms appear before people are tested in centralized facilities is fundamentally flawed to fight diseases like COVID-19. SARS-CoV-2 can be transmitted by patients long before symptoms appear or even by asymptomatic patients. 4,5 As the incubation period lasts several days, 6 these issues lead to the creation of a blind spot: i.e. many patients that are transmitting the disease are currently not diagnosable. The only way to remedy this blind spot, to contain and further prevent pandemic diseases before a vaccine is available, is a new type of test that is mobile, fast, cheap, lab-independent and accurate. The possibility to test large parts of the population at home, avoiding high costs and high strain for the healthcare system, will significantly contribute to immediate containment of such diseases and prevention of the loss of lives, without the need for counter measures that cause large economic damage such as ones we are currently experiencing. Within this proposed project, the group of Prof. Vörös (ETH Zürich), who is leading this project, will develop a rapid test system based on lateral flow assays, with drastically improved sensitivity, while maintaining the point-of-need principle (i.e. rapid turn-around time and immediate availability of the test result). With this test, a clinical sensitivity of close to 100% for the detection of SARS-CoV-2 from nasopharyngeal or throat swab samples seems likely. Our group will then benchmark this technology with real samples against clinically validated methods. The aim of the planned study is to clinically validate the developed test and determine its performance characteristics compared to the current gold standard [a laboratory-developed, qualitative SARS-CoV-2 real-time polymerase chain reaction (PCR)] and in two scenarios (professional-collected vs. self-collected swabs). Patients with suspicion of COVID-19 presenting to the outpatient clinic of the University Hospital Basel or having been diagnosed with COVID-19 after admission to the hospital will be asked for participation in this validation study if a SARS-CoV-2 test is deemed necessary by the treating physicians. Additionally, patients with confirmed viral upper or lower respiratory tract infections will be included. This proposed new test is a unique tool with a high potential to dramatically impact the spread of infectious diseases such as COVID-19 and to decrease mortality and the high economic burden of pandemic diseases. References: Ghebreyesus, A. T. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. Dayrit, M. & Mendoza, R. U. Social Cohesion vs COVID-19. SSRN Electron. J. (2020) doi:10.2139/ssrn.3555152. Greenhalgh, T., Koh, G. C. H. & Car, J. Covid-19: a remote assessment in primary care. BMJ 368 , m1182 (2020). Zou, L. et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N. Engl. J. Med. NEJMc2001737 (2020) doi:10.1056/NEJMc2001737. Corman, V. M. et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance 25 , 2000045 (2020). Bai, Y. et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA (2020) doi:10.1001/jama.2020.2565
Significance of mannose-binding lectin and the lectin pathway in acute and recurrent ischemia/repefusion injury Research Project | 4 Project MembersMannose-binding lectin (MBL), a circulating pattern-recognition protein of the lectin pathway of complement is involved in the clearance of microorganisms and apoptotic cells. The concentration of functional MBL multimers is profoundly influenced by several polymorphisms in the MBL2 gene on chromosome 10, resulting in remarkable variations in serum MBL concentrations in apparently healthy individuals. Beyond infections, recent experimental studies have acknowledged additional important roles of MBL in atherosclerosis and ischemia/reperfusion (IR) injury. However, human data are scarce. This proposal aims to characterise in more depth the role of MBL and the lectin pathway in three human diseases, in which acute or repetitive I/R injury and/or atherosclerosis contribute to pathophysiology and outcome: systemic lupus erythematosus.primary (SLE), systemic sclerosis (SSc), and primary open angle glaucoma (POAG). In the SLE cohort sub-study, association of MBL deficiency with vascular events will be investigated in subjects from the well characterized Swiss SLE cohort. This is of importance, as SLE patients have an increased cardiovascular mortality and morbidity compared to the average individual. In the SSc cohort sub-study, activity of the lectin pathway including levels of MBL and the ficolins will be correlated with disease activity and organ involvement in individuals from a large European SSc cohort. Our preliminary data from a previous small Australian SSc cohort indicates that MBL deficiency might be associated with less organ damage. Hence, it might be worth to explore inhibition of the MBL or the lectin pathway in the future. In the POAG case-control sub-study, activity of the complement system in general and the lectin pathway in particular will be examined in POAG cases compared to healthy controls. This is of interest, as vascular dysfunction and repetitive I/R injury seem to be a hallmark in the pathogenesis of POAG, and current treatment options are limited. This project will lead to a more comprehensive understanding of the pathogenesis and the importance of MBL and the lectin pathway in I/R injury in SLE, SSc and POAG. Furthermore, it might facilitate future therapeutic interventions like inhibition of MBL or the lectin pathway to ameliorate I/R injury in these settings.
