ABSTRACT
Endothelial cells (ECs) lining the blood vessels of all organs express the SARS-CoV2 receptor. In the absence of preexisting tissue damage, the virus would need to pass through the ECs to blood vessels to infect other tissues. Thus, EC are a target for SARS-CoV-2 infection and a conduit for viral dissemination to distant organs. We hypothesized that ECs infection and/ or injury are the mechanisms of COVID-19 pathology and multi-organ dissemination and injury. Methods: Human studies: We used lung, heart, kidney, and small bowel specimens obtained during autopsies (n=5) from COVID-19 patients and uninfected subjects. Studies: 1) histologic evaluation of endothelial damage and endotheliitis, 2) immunohistochemistry for vWF, PAI-1, VCAM-1, & ICAM-1. Studies in cultured human microvascular ECs (HMVECs): We cultured lung and cardiac HMVECs in the presence or absence of SARSCoV- 2 S1 and/or S2 protein (10 ng/ml) for 0 - 24 hr. Studies:1) cell viability and proliferation;2) angiogenesis on Matrigel and cell migration;3) mitochondrial membrane potential (MMP);4) RNA seq analysis;5) Western blotting for vWF, PAI-1, VCAM-1, and ICAM-1. We examined the protective effect of melatonin, Coenzyme Q10 and nerve growth factor on S1/S2 protein induced HMVEC cell damage. Results: Histopathologic examination revealed presence of endothelial abnormalities and endotheliitis with marked presence of inflammatory cells in vessel wall & lumen, and fibrinous microthrombi) in lung, heart & kidney in autopsy specimens of COVID-19 patients. Immunostaining visualized increased vWF, PAI-1, VCAM- 1, & ICAM-1 in COVID-19. In in vitro study, S1 and S2 proteins induced endothelial injury, reduced angiogenesis and phosphorylated/activated Erk and Akt proteins in cultured HMVECs. Treatment of HMVECs for 1 & 4 hours with S2 but not S1 protein increased ICAM-1 levels by 1.4- to 1.8-fold (P < 0.001). RNA Seq analysis showed that treatment of HMVECs with S1 and S2 proteins upregulated VCAM-1, ICAM-1 and E-selectin mRNA in cultured HMVECs. Melatonin, Coenzyme Q10 and NGF stimulated angiogenesis in HMVECs by 2.4-, 1.3-&1.4-fold (all P < 0.001). Conclusions: 1) Significant endothelial abnormalities, blood vessel damage and endotheliitis are present in lung, heart and kidney autopsy specimens of COVID-19 patients, 2) There is increased expression of vWF, PAI-1, VCAM-1, and ICAM- 1 in lung, heart, and kidney specimens of COVID-19 patients, 3) Treatment of cultured HMVECs with SARS-CoV-2 S1 and S2 proteins upregulates VCAM-1, ICAM-1 and Eselectin expression, 4) SARS-CoV-2 S1 and S2 proteins induce endothelial injury in cultured HMVECs, and 5) melatonin, Coenzyme Q10 and NGF stimulated EC function. These studies uncovered novel mechanism – endothelial dysfunction underlying SARS-CoV-2 and identified melatonin, Coenzyme Q10 and NGF as potential drugs for treatment of COVID- 19-induced EC injury
ABSTRACT
Objective: Stroke has been reported to be a potential neurological complication of COVID-19 infection in adults, however, only a few reports have been made in the pediatric population. We describe a case of a 12-year-old female with post-COVID-19 syndrome who was found to have an ischemic stroke on MRI as well as positive for lupus anticoagulant. Background: COVID-19 has been documented to potentiate a prothrombotic and proinflammatory state. It is postulated this occurs via endothelial cell disruption and clotting cascade activation. However, cases have reported the presence of prothrombotic antibodies in patients with COVID-19 infections. The persistent presence of these antibodies has important clinical implications, including an increased thrombotic risk. Design/Methods: Chart review Results: A 12-year-old female with history of migraines presented to the neurology clinic for increased frequency and severity of headaches. Patient reported to have COVID-19 infection one year prior with symptoms of fatigue, arthralgias, sore throat, and headaches. Following infection, patient had resolution of most symptoms but continued having increased headaches and difficulty concentrating. Headaches have been occurring multiple times per week, lasting hours to days, and are associated with nausea, vomiting, and photophobia. Patient has no focal neurological deficits. Brain MRI showed small focal encephalomalacia with surrounding gliosis and volume loss in the anterior right basal ganglia and adjacent external capsule consistent with a small chronic infarct. On thrombophilia work-up patient was positive for lupus anticoagulant and had a heterozygous MTHFR variant. Patient was started on baby aspirin and her headaches have been controlled with prophylactic co-enzyme Q-10 and naproxen. Conclusions: Due to the known prothrombotic risk of COVID-19 infections, there should be a high index of suspicion for stroke symptoms among pediatric patients with COVID-19. Improved clinical surveillance and increased screening for prothrombotic antibodies could ensure better outcomes, including timely treatment and prevention of complications.
ABSTRACT
The immune system is comprised of lymph glands, lymph nodes, thymus gland, spleen, bone marrow, lymphocytes, and molecules such as antibodies and cytokines. It has a vast array of functionally different cells such as T and B lymphocytes, macrophages, neutrophils and mast cells. The ontogenesis of the immune system is comprised of the innate immune cells and the adaptive immune cells, where innate immune cells are the first defense mechanisms to respond to pathogenic environmental factors. There are multiple components of the adaptive immune cells, including immunoglobulins (Igs), T-cell receptors (TCR), and major histocompatibility complex (MHC) responsible for adaptive immunity. However, many elements of both the innate and adaptive immune systems are conserved in our bodies. The adaptive immunity is a type of immunity that develops when a person’s immune cells respond to a pathogen such as microorganism or vaccination. Environmental factors such as pathogenic bacteria or viruses, solar exposure, age, exercise, stress, diet, sleep quality and air pollutants can influence the immune system. There may be marked decline in the immune function due to attack of COVID-19. Most patients with mild COVID-19 develop an appropriate immune response that culminates with viral clearance. However, severe disease manifestations have been linked to lymphopenia and immune hyper-responsiveness leading to cytokine storm. It has been observed that in COVID-19, alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immune-paralysis. Western diets are known to have adverse effects on the immune function. However, Mediterranean-type diets rich in short-and long-chain polyunsaturated fatty acids (PUFA), vegetables, nuts and fruits, dairy products and fish and red wine, due to high content of vitamins, minerals and flavonoids may be useful in boosting immunity. Moderate physical activity may also cause an extensive increase in numerous and varied lipid super-pathway metabolites, including oxidized derivatives called oxylipins. Emerging evidence suggests that dietary supplements containing flavonoids, carotenoids, coenzyme Q10 (CoQ10), vitamins, minerals and antioxidants modulate gene and protein expression and thereby modify endogenous metabolic pathways, and consequently enhance the immunity. Mediterranean-type diet and multiple bioactive nutrients, fatty acids, amino acids, vitamins and minerals as well as moderate physical activity may be crucial for enhancing immunomodulation.
ABSTRACT
Introduction: Many patients (“long-haulers”) suffer lingering illness following COVID-19. The aim of this presentation is to evaluate the evidence of nutrient deficiencies affecting immune function and chronic symptoms from covid19 infection in a subgroup of patients. We will discuss the potential benefit of supplementing with multi-nutrients as an integrative approach to reducing long-hauler symptoms. Methods: A narrative review followed a search of Medline/Pubmed, CINAHL, Google Scholar for studies published between January 2000 and March 2021, using key terms “coronavirus”, “COVID-19”, “immune system”, “inflammation”, “microbiome”, “oxidative stress”, “mitochondrial function”, “micronutrients”, “vitamin”, “minerals”, and “antioxidants”. Six reviews were selected which examined on the role of nutrients in immune and neurological function, including inflammatory processes, microbiome homeostasis, and mitochondrial function. Results: Symptoms of long-haulers may be similar to myalgic encephalomyelitis/chronic fatigue syndrome associated with mitochondria dysfunction due to oxidative stress. Similar findings of chronic inflammation and microbiome dysbiosis associated with mood disorders also suggest the association between nutrient deficiencies and immuno-neurological functions. Nutrients required for optimal immune function included: antioxidants such as CoQ10 is required for mitochondrial function and is depleted quickly during acute immune response. Vitamins C and E and selenium also have antioxidant properties that can decrease proinflammatory cytokines and increase leukocyte and NK cell function. The B vitamins are involved in decrease pro-inflammatory cytokines and increase NK cell activities. Similarly, these nutrients are required for optimal neurological functioning in the CNS. Conclusion: Initial evidence suggests chronic inflammatory processes in the CNS may contribute to the symptoms of covid-19 long-haulers. Given the complementary roles of different nutrient in immune response and CNS pathways, integrating multiple nutrients as treatment for long-haulers warrants further study. Keywords: post-covid syndrome, long hauler, micronutrient treatment;narrative review