Nikhil Prasad Fact checked by:Thailand Medical News Team Dec 05, 2024 6 days, 23 hours, 3 minutes ago
Medical News: A groundbreaking study reveals a novel mechanism through which SARS-CoV-2, the virus responsible for COVID-19, manipulates the human immune system. Researchers Stefanos A. Tsiftsoglou from Aristotle University of Thessaloniki and Eleni Gavriilaki from Hippocration General Hospital have uncovered a unique interplay between heme, a critical molecule in the body, and Complement Factor H (CFH), a key regulator of the immune system's complement pathway. Their findings provide new insights into how this virus might evade immune defenses.
Schematic illustration of the Heme-CFH 402H interactions related to infection by SARS-CoV-2.
A. I. Domain organisation of CFH and topography of the putative heme-binding motif (HBM) of interest in CCP7 domain. II. CFH is a multipotent complement regulator with repetitive ancient CCP domains facilitating advanced fluid and solid-phase modes of regulation. The disease associated CFH 402H exhibits weakened interactions with various forms of glucosaminoglycans (GAGs) like heparan sulphate on certain cell types. Loose interactions result in weaker cell surface complement control related to various pathologies namely AMD and aHUS.
B. Heme on the spike may act as a bait to competitively attract the CFH 402H that exhibits a weakened interaction with the heparan sulphate cell surface coat and enable the virus to facilitate its heparan sulphate-dependent cell entry in target cells carrying a specific entry receptor like ACE2, TMEM106B and others.
C. The CFH residue 402 is surprisingly located centrally within a putative heme-binding motif (HBM) in domain CCP7 (398YNQNYGRKF406). The H402 substitution (398YNQNHGRKF406) introduces reduced affinity of CFH for the cell surface heparan sulphate and possibly enhanced affinity for heme in proximity through strengthened ionic interactions. This interaction might be therapeutically disrupted (T1, as shown by arrow) with Sucrose octasulfate reported in the CFH structural. The latter might be combined with next gen AP inhibitors for therapeutic (T2) control of AP deregulation in states of infections or certain clinical pathologies or with Amphiphilic Heparinoids presented recently as advanced antivirals.
What is Complement Factor H?
Complement factor H (CFH) is a key component in the body’s immune defense system, particularly the alternative complement pathway. This pathway acts as a first line of defense against pathogens. The CFH protein ensures that the pathway does not attack the body’s own cells, acting as a safeguard against autoimmune reactions. Variants in the CFH gene, such as the 402H polymorphism, have been linked to diseases like age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (aHUS), conditions characterized by immune dysregulation.
The Interplay Between Heme and CFH
The research focuses on CFH, particularly the variant known as CFH 402H, which plays a pivotal role in regulating the complement alternative pathway - a critical component of the immune system. SARS-CoV-2 appears to use heme, a molecule involved in oxygen transport, to manipulate CFH and disrupt this pathway. This
Medical News report explores how such disruption contributes to severe complications in COVID-19 patients.
CFH typically prevents overactivation of the complement system, which could otherwise damage healthy cells. However, the study demonstrates that SARS-CoV-2 hijacks this mechanism. The virus binds heme within a domain on its spike protein and uses it to attract CFH, particularly the 402H variant. This action interferes with CFH's normal function, promoting immune deregulation and viral persistence.
How SARS-CoV-2 Exploits CFH
The study examines how SARS-CoV-2 may manipulate CFH to bypass immune defenses. The study identified that the virus's spike protein contains a heme-binding motif. This motif can attract CFH 402H, a variant with a higher affinity for heme. By binding to CFH, the virus masks itself, avoiding opsonization (marking for destruction by immune cells) and potentially enhancing infection. This tactic could also disrupt CFH’s normal role on cell surfaces, further weakening the immune response.
The Genetic Connection
The researchers highlight the role of genetic predispositions in this interaction. The CFH 402H variant, encoded by the minor allele of the rs1061170 gene, has been associated with various immune and inflammatory diseases, including age-related macular degeneration and atypical hemolytic uremic syndrome. Individuals with this genetic variant may experience more severe immune responses during SARS-CoV-2 infection.
Furthermore, the study notes that this genetic variation also influences heme binding. The CFH 402H variant has a higher affinity for heme, exacerbating its potential to disrupt immune regulation when exposed to the virus.
Experimental Evidence
Using computational modeling and genetic data analysis, the researchers identified specific motifs within CFH that are prone to heme interaction. They demonstrated that SARS-CoV-2's spike protein exploits these motifs, allowing the virus to evade immune detection.
Their findings also reveal that heme released from damaged cells during infection can further exacerbate this immune dysregulation. This vicious cycle of immune activation and complement consumption could explain many severe COVID-19 symptoms, such as systemic inflammation and organ damage.
Clinical Implications
Understanding this mechanism opens doors for targeted therapeutic strategies. Drugs designed to inhibit the interaction between CFH and heme could potentially reduce the severity of COVID-19 symptoms. Additionally, therapies targeting the complement pathway, such as complement inhibitors, might be beneficial for patients with severe cases.
The research emphasizes the importance of genetic screening. Identifying individuals with the CFH 402H variant could help predict susceptibility to severe COVID-19 and guide personalized treatment strategies.
Conclusions
This study sheds light on the intricate ways SARS-CoV-2 interacts with the human immune system, leveraging heme and CFH to enhance its survival and propagation. The insights gained underscore the need for a deeper understanding of host-pathogen interactions to develop effective treatments for COVID-19 and other infectious diseases.
By unraveling the genetic and molecular underpinnings of this mechanism, researchers have provided a potential roadmap for new therapeutic interventions. Future studies are needed to validate these findings and explore their implications in broader populations and other complement-mediated diseases.
The study findings were published in the peer-reviewed journal: Infection, Genetics and Evolution.
https://www.sciencedirect.com/science/article/pii/S1567134824001503
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