Understanding Covid-19 Pathophysiology

Our new study shows that SARS-CoV-2 spike protein accumulates & persists in the body for years after infection, especially in the skull-meninges-brain axis, potentially driving long COVID. mRNA vaccines help but cannot stop it🔬🧠🦠🧵👇 🔬 Using our cutting-edge DISCO tissue clearing technology, we mapped spike protein presence in mouse models and human post-mortem tissues. Key findings: 1️⃣ Spike protein accumulates in the skull marrow niches and skull-meninges connections (SMCs), a newly discovered route into the brain. 2️⃣ Spike protein persists in brain tissue even when PCR tests show no viral presence, indicating a longer half-life than viral particles. 3️⃣ The spike protein is associated with vascular, inflammatory changes and neuronal injury, leading to proteomic changes linked to neurodegeneration. 4️⃣ Long COVID patients exhibited elevated neurodegeneration markers in cerebrospinal fluid, such as Tau protein and NfL. 5️⃣ mRNA vaccines (e.g., BioNTech/Pfizer) significantly reduced spike protein accumulation but did not eliminate it completely. These findings open pathways for new diagnostic and therapeutic strategies to tackle long COVID and its neurological sequelae. For instance: • Neural injury markers in cerebrospinal fluid could help evaluate long COVID. • Spike protein removal or inhibition could become a therapeutic focus. Read the full study in Cell Host & Microbe: 🔗 https://lnkd.in/dPYc5uVW Let’s work together to uncover more about the lasting impact of COVID-19 and drive solutions for those suffering from its long-term effects. #COVID19 #LongCOVID #Neuroscience #DISCO #Clearing #Immunology #AIinScience #Proteomics

COVID’s immune system lessons As COVID-19 began to surge five years ago, no one knew what to expect. Neither did the immune system. Confronted with a new #virus, humanity was immunologically naïve. The emergence of #SARS-CoV-2 provided a rare opportunity to study the immune system in action. Scientists are still taking stock of the data they gathered on how the #immune system reacted to SARS-CoV-2, but four lessons have already emerged. Lesson No. 1: Antibodies aren’t everything. Immune response against the virus relied heavily on T cells, not just antibodies. #Antibodies against SARS-CoV-2 waned in the months after vaccination, but #vaccinated people continued to make T cells that recognized the virus. That T-cell protection remained strong, even against viral #variants that dodged the antibody defenses raised by the first generation of COVID #vaccines. Lesson No. 2: Early-warning immune alarm reaches the whole body. The body’s early-warning alarm, the innate #immuneresponse, rings out across the whole body, not just around the site of #infection. Signs of #interferon responses were found throughout the body, even in organs far away from infected cells with people #infected with SARS-CoV-2. The same also found later in #flu virus. Lesson No. 3: The nose knows. It is important to understand immune responses in specific #tissues, and especially in the place where infection often starts: the nose. Antibodies and #Tcells differ sharply from tissue to tissue. #Injected vaccines, which generate antibodies in the bloodstream, might not be ideal for blocking infection in the nose. Lesson No. 4: Post-viral illness need attention. #Researchers have learnt that a variety of factors, such as SARS-CoV-2 hiding dormant in the body, might contribute to #longCOVID. Viral infection can trigger the immune system to produce antibodies against the body’s own #proteins and how post-viral #illnesses can cause the reactivation of other dormant #viruses in the body, such as Epstein–Barr virus. Pic Credit: KTSDesign/Science Photo Library References: [1] https://lnkd.in/gs7PD-tj [2] https://lnkd.in/gmAvtWzf; [3] https://lnkd.in/gYB2EhcW [4] https://lnkd.in/gip6HamY; [5] https://lnkd.in/gAX6nkqz

Research identifies a new way in which Covid-19 enters human cells. Study identifies how SARS-CoV-2 binds the Receptor for Advanced Glycation Endproducts (the RAGE receptor) and how this interaction drives innate immune response. University of Padua and collaborating institutions. Italy. Published: 13 November 2023. Excerpt: Published in Cell Press, study is the result of collaboration between researchers coordinated by Prof. Antonella Viola, Department of Biomedical Sciences, University of Padua and researchers from Human Technopole Research Foundation, Milan coordinated by Prof. Giuseppe Testa, with support of European Institute of Oncology and the University of Milan. Note: The study demonstrates how the RAGE receptor found on the surface of specific human immune cells penetrates and pathologically alters their function. This study also shows how involvement of RAGE determines degree of severity with which COVID-19 can manifest. Data was from patients hospitalized for COVID-19 during first phase of the pandemic at Complex Operative Unit for Infectious Diseases and Tropical Diseases in Padua, led by Dr Anna Maria Cattelan. The research team in Padua isolated and characterized immune cells from blood of COVID-19 patients at three different time points during and after infection, i.e. on admission, at discharge and one month after release. Analysis continued in Milan, where researchers used technologies to analyze what happens inside a single cell by looking at expression of all 20,000 genes encoded by its DNA. The amount of data observed for each patient is comparable to the amount of information in a 140-megapixel image, a resolution at the frontier of the possibilities of commonly available cameras. Images captured over different points of hospitalization amplified the amount of data and provided insight to each patients’ response to the SARS-CoV-2 virus. Analysis showed the RAGE receptor induces specific alterations in gene regulation, enhancing inflammatory effect of the virus and contributing to disease exacerbation. Identifying this new mode of interaction between the virus and human cells is crucial for developing targeted therapeutic strategies, mainly to protect individuals at risk of severe complications, such as the elderly or frail individuals. This discovery could lay the foundations for a more targeted and effective approach to counteracting the spread of the virus in vulnerable groups. Publication: Cell Reports Medicine 21 November 2023, RAGE engagement by SARS-CoV-2 enables monocyte infection and underlies COVID-19 severity https://lnkd.in/eJ4dyyG5 https://lnkd.in/ePBwaKHb

"Researchers at the University of California San Francisco have identified fibrin, a natural protein involved in blood clotting, as a major driver of the COVID-19 disease, according to a new study. Fibrin binds to proteins from the SARS-CoV-2 virus to form blood clots that are difficult to break down, the authors found. This clotting then drives the various inflammatory and neurological symptoms seen in COVID-19 and long COVID, the researchers found. Previous studies have theorized that blood clotting is a consequence of inflammation. However, the new Nature study, published on Wednesday, shows the reverse: that the clotting comes first. 'We know of many other viruses that unleash a similar cytokine storm in response to infection, but without causing blood clotting activity like we see with COVID,' Dr. Warner Greene, senior investigator and director emeritus at Gladstone and co-author of the study, said in a press release. 'Our study is the first to report causality for fibrin as the root of inflammation and brain pathology after COVID infection,' Katerina Akassoglou, senior author and professor of neurology at UCSF, told The Epoch Times on email. By blocking fibrin using a novel antibody, the researchers were able to reduce clotting and neurological symptoms, offering a new potential therapeutic for patients. Furthermore, the new study offers an explanation for the increase in cancers following COVID-19 infections. The researchers found that the abnormal clotting between COVID-19 spike proteins and fibrins reduces cancer-fighting immune cells known as natural killer (NK) cells."

Long COVID has become a significant public health concern, with coagulation and neurological complications persisting beyond the acute phase of infection, contributing to morbidity and mortality. Coagulopathy, which can occur even in young patients with mild or breakthrough infections, is linked to neurological issues and remains resistant to standard anticoagulation treatments. This suggests unknown mechanisms in COVID-19 pathogenesis. Fibrin, a key component of blood clots, is implicated in the hypercoagulable state seen in COVID-19, promoting inflammation and neuropathology by disrupting the blood-brain barrier (BBB) and activating immune responses. This research highlights fibrin's role in exacerbating viral load and thromboinflammation, particularly by modulating natural killer (NK) cell activity. The scientists propose a potential antibody-based therapy targeting fibrin to mitigate these effects, which could offer a novel approach to treating both acute and long COVID. This therapy, unlike traditional anticoagulants, does not increase bleeding risk and is currently undergoing clinical trials. Further studies are needed to explore its efficacy and safety, but fibrin immunotherapy could be a promising strategy to address the neurological and inflammatory challenges of COVID-19 without compromising normal blood clotting. https://lnkd.in/eQeZyhKs

A large study by Brazilian researchers has shed light on the biological pathways affected by SARS-CoV-2 infections in seven different human cell types, including some primary cells. The researchers evaluated changes in the proteome of infected CACO-2 (intestinal), Hep-G2 (liver), SH-Sy5Y (neuronal), astrocytes, monocytes, T-cells, and adipose cells. This massive study identified 1,652 differentially regulated proteins and 151 biological pathways altered in the SARS-CoV-2 infectome. Disturbances in energy production, energy metabolism (mainly glycolysis), infectious diseases, protein metabolism (both synthesis and degradation processes), and signaling/homeostatic pathways were identified in nearly all cell types. Notably, the CNS infectome (neuron-like cells and astrocytes) revealed the largest number of modifications, with 810 differentially regulated proteins. In brief, the study provides important insights into the pathways altered following SARS-CoV-2 infections. These modifications may help explain some of the pathological manifestations of the virus in different tissues. #covid19 #proteome #infectome #health #globalhealth #publichealth #medicine #biotechnology #pharmaceuticals #FDA #immunology #cellbiology

Check out a our new paper published today: https://lnkd.in/e5kyFTTf 🚨 New Insights on Severe COVID-19 🚨 This groundbreaking study redefines the "cytokine storm" in lethal COVID-19, linking it to mitochondrial dysfunction and over activation of the RAAS pathway, causing multi-organ damage. It also reveals lymphoid organ fibrosis, which may underlie chronic immune dysfunction seen in long COVID. 🧬 Transcriptomics + histopathology across human autopsies & animal models illuminate how immune & mitochondrial signaling drive severe outcomes. Key findings highlight: Mitochondrial gene suppression & mtDNA release triggering immune responses. RAAS-driven vascular damage & fibrosis disrupting lymph node function. Potential links to long COVID immune dysregulation. 🌐 Pathway insights pave the way for new therapies targeting mitochondria and RAAS to mitigate COVID-19 severity & its long-term effects. Read more in PNAS #COVID19 #Mitochondria #LongCOVID Joseph W. Guarnieri Robert Schwartz Christopher Mason Pedro Vieira Jonathan Schisler Deanne Taylor Robert Meller Victoria Baxter JangKeun Kim Cem Meydan Nídia Sequeira Trovão, PhD Eve Syrkin Wurtele

● Vagus nerves are infected and inflamed during severe COVID-19 is important new information. ● The vagus nerve inflammatory reflex—which normally inhibits the intensity of inflammation to maintain homeostasis could be impaired in COVID-19. Cytokine storm occurring in severe COVID-19 may occur from the failure of the inflammatory reflex as a result of vagus nerve inflammation. This insight may well provide novel opportunities to study new treatments of cytokine storm in COVID-19. ● Well-regulated acute inflammation mediates host defense and healing processes, but the onset of hyperinflammation is deleterious because it mediates lethal tissue injury. Cytokine storm and hyperinflammation are hallmarks of the clinical syndrome of acute COVID-19. ● Recent experimental and clinical evidence established that the nervous system occupies an essential role in regulating inflammation homeostasis by transmitting reflex signals in the vagus nerve. It is reasonable to consider whether vagus nerve dysfunction contributes to a regulatory failure underlying the resultant inflammatory tissue destruction during severe COVID-19. ● The vagus nerve inflammatory reflex evolved in the mammalian nervous system as a functional reflex circuit to prevent cytokine storm and hyperinflammation. The inflammatory reflex is activated by the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), including cytokines and chemokines. ● These induce sensory, afferent signals arising in the vagus nerve or other sensory neurons that are relayed to the nucleus tractus solitarius in the brain stem, which in turn activates outgoing, motor signals in the adjacent dorsal motor nucleus of the vagus (DMV). Cholinergic neurons from the DMV descend to the peripheral organs, which inhibit cytokine storm and prevent hyperinflammation, tissue injury, and death. This motor arc from the DMV that inhibits inflammation is also known as the “cholinergic anti-inflammatory pathway.” ● The presented paper consider evidence whether the vagus system can get infected and may cause damage to the vagus nerve inflammatory reflex and thus contributes to hyperinflammation in severe COVID-19. https://lnkd.in/g75T_eUc ● The discovery that the vagus nerve can be infected by SARS-CoV-2 also raises other new questions, which should be studied in the pathogenesis of long COVID or post-COVID-19 syndrome. This is particularly interesting, because there is significant clinical evidence of autonomic dysfunction in long COVID, and significant clinical evidence of increased inflammation. ● It is a testable hypothesis that damage to the vagus nerve and resulting dysfunction of the cholinergic anti-inflammatory pathway is a critical physiologic mechanism contributing to the clinical syndrome. #covid #vagusnerve #cytokinestorm #PAMPs #DAMPs #cholinergic #antiinflammatory