scholarly journals Identification of Immune complement function as a determinant of adverse SARS-CoV-2 infection outcome

2020 ◽  
Author(s):  
Vijendra Ramlall ◽  
Phyllis M. Thangara ◽  
Nicholas P. Tatonetti ◽  
Sagi D. Shapira
Keyword(s):  
Protein Structure ◽  
Structure Function ◽  
Macular Degeneration ◽  
Complement Activation ◽  
Function Analysis ◽  
Factor H ◽  
Negative Regulator ◽  
Complement Factor ◽  
A Genome ◽  
History Of

Abstract Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutics and public health intervention strategies. Viral-host interactions can guide discovery of regulators of disease outcomes, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of the coronavirus proteome. To determine if conditions associated with dysregulation of the complement or coagulation systems impact adverse clinical outcomes associated with SARS-CoV-2 infection, we performed a retrospective observational study of 11,116 patients suspected of SARS-CoV-2 infection. We found that history of macular degeneration (a proxy for complement activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis, and hemorrhage) are risk factors for morbidity and mortality in SARS-CoV-2 infected patients – effects that could not be explained by age or sex. In addition, using data from the UK Biobank, we implemented a candidate driven approach to evaluate linkage between severe SARS-CoV-2 disease and genetic variation associated with complement and coagulation pathways. Among our findings, our scan identified an eQTL for CD55 (a negative regulator of complement activation) and SNPs in Complement Factor H (CFH) and Complement Component 4 Binding Protein Alpha (C4BPA), which play central roles in complement activation and innate immunity and were previously linked to Age Related Macular Degeneration (AMD) in a Genome-Wide Association Study (GWAS). In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to several putative genetic markers of susceptibility. The results highlight the value of using a multi-modal analytical approach, combining molecular information from virus protein structure-function analysis with clinical informatics and genomics to reveal determinants and predictors of immunity, susceptibility, and clinical outcome associated with infection.

scholarly journals Identification of Immune complement function as a determinant of adverse SARS-CoV-2 infection outcome

2020 ◽  
Author(s):  
Vijendra Ramlall ◽  
Phyllis M. Thangaraj ◽  
Cem Meydan ◽  
Jonathan Foox ◽  
Daniel Butler ◽  
...  
Keyword(s):  
Protein Structure ◽  
Structure Function ◽  
Function Analysis ◽  
Transcriptional Profiling ◽  
Public Health Intervention ◽  
Virus Protein ◽  
Type I ◽  
Host Interactions ◽  
History Of ◽  
Viral Host Interactions

SummaryUnderstanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutics and public health intervention strategies. Viral-host interactions can guide discovery of regulators of disease outcomes, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of the coronavirus proteome. To determine if conditions associated with dysregulation of the complement or coagulation systems impact adverse clinical outcomes, we performed a retrospective observational study of 11,116 patients who presented with suspected SARS-CoV-2 infection. We found that history of macular degeneration (a proxy for complement activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis, and hemorrhage) are risk factors for morbidity and mortality in SARS-CoV-2 infected patients - effects that could not be explained by age, sex, or history of smoking. Further, transcriptional profiling of nasopharyngeal (NP) swabs from 650 control and SARS-CoV-2 infected patients demonstrated that in addition to innate Type-I interferon and IL-6 dependent inflammatory immune responses, infection results in robust engagement and activation of the complement and coagulation pathways. Finally, we conducted a candidate driven genetic association study of severe SARS-CoV-2 disease. Among the findings, our scan identified putative complement and coagulation associated loci including missense, eQTL and sQTL variants of critical regulators of the complement and coagulation cascades. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multi-modal analytical approach, combining molecular information from virus protein structure-function analysis with clinical informatics, transcriptomics, and genomics to reveal determinants and predictors of immunity, susceptibility, and clinical outcome associated with infection.

scholarly journals Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration

2020 ◽  
Vol 11 ◽  
Author(s):  
Matteo Stravalaci ◽  
Francesca Davi ◽  
Raffaella Parente ◽  
Marco Gobbi ◽  
Barbara Bottazzi ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complement Activation ◽  
Hot Spot ◽  
Alternative Pathway ◽  
Retinal Pigment ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Rpe Cells ◽  
Age Related

Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H (CFH) gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a “hot spot” for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.

Complement factor H R1210C among Japanese patients with age-related macular degeneration

2015 ◽  
Vol 59 (5) ◽  
pp. 273-278 ◽  
Author(s):  
Masahiro Miyake ◽  
Masaaki Saito ◽  
Kenji Yamashiro ◽  
Tetsuju Sekiryu ◽  
Nagahisa Yoshimura
Keyword(s):  
Macular Degeneration ◽  
Japanese Patients ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor H ◽  
Complement Factor ◽  
Age Related

scholarly journals Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 622
Author(s):  
Iswariyaraja Sridevi Gurubaran ◽  
Hanna Heloterä ◽  
Stephen Marry ◽  
Ali Koskela ◽  
Juha M. T. Hyttinen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Model ◽  
Macular Degeneration ◽  
Complement Component ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Related Factor ◽  
Complement Factor ◽  
Age Related ◽  
Dry Amd

Aging-associated chronic oxidative stress and inflammation are known to be involved in various diseases, e.g., age-related macular degeneration (AMD). Previously, we reported the presence of dry AMD-like signs, such as elevated oxidative stress, dysfunctional mitophagy and the accumulation of detrimental oxidized materials in the retinal pigment epithelial (RPE) cells of nuclear factor erythroid 2-related factor 2, and a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (NFE2L2/PGC1α) double knockout (dKO) mouse model. Here, we investigated the dynamics of inflammatory markers in one-year-old NFE2L2/PGC1α dKO mice. Immunohistochemical analysis revealed an increase in levels of Toll-like receptors 3 and 9, while those of NOD-like receptor 3 were decreased in NFE2L2/PGC1α dKO retinal specimens as compared to wild type animals. Further analysis showed a trend towards an increase in complement component C5a independent of component C3, observed to be tightly regulated by complement factor H. Interestingly, we found that thrombin, a serine protease enzyme, was involved in enhancing the terminal pathway producing C5a, independent of C3. We also detected an increase in primary acute phase C-reactive protein and receptor for advanced glycation end products in NFE2L2/PGC1α dKO retina. Our main data show C5 and thrombin upregulation together with decreased C3 levels in this dry AMD-like model. In general, the retina strives to mount an orchestrated inflammatory response while attempting to maintain tissue homeostasis and resolve inflammation.

LOC387715/HTRA1 and Complement Factor H Variants in Patients with Age-Related Macular Degeneration Seen at the Mayo Clinic

2007 ◽  
Vol 28 (4) ◽  
pp. 203-207 ◽  
Author(s):  
Jose S. Pulido ◽  
Lisa M. Peterson ◽  
Lejla Mutapcic ◽  
Sandra Bryant ◽  
W. Edward Highsmith
Keyword(s):  
Macular Degeneration ◽  
Mayo Clinic ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor H ◽  
Complement Factor ◽  
Age Related
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