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1.
Trained Immunity: An Overview and the Impact on COVID-19.
Brueggeman, JM, Zhao, J, Schank, M, Yao, ZQ, Moorman, JP
Frontiers in immunology. 2022;:837524
Abstract
Effectively treating infectious diseases often requires a multi-step approach to target different components involved in disease pathogenesis. Similarly, the COVID-19 pandemic has become a global health crisis that requires a comprehensive understanding of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection to develop effective therapeutics. One potential strategy to instill greater immune protection against COVID-19 is boosting the innate immune system. This boosting, termed trained immunity, employs immune system modulators to train innate immune cells to produce an enhanced, non-specific immune response upon reactivation following exposure to pathogens, a process that has been studied in the context of in vitro and in vivo clinical studies prior to the COVID-19 pandemic. Evaluation of the underlying pathways that are essential to inducing protective trained immunity will provide insight into identifying potential therapeutic targets that may alleviate the COVID-19 crisis. Here we review multiple immune training agents, including Bacillus Calmette-Guérin (BCG), β-glucan, and lipopolysaccharide (LPS), and the two most popular cell types involved in trained immunity, monocytes and natural killer (NK) cells, and compare the signaling pathways involved in innate immunity. Additionally, we discuss COVID-19 trained immunity clinical trials, emphasizing the potential of trained immunity to fight SARS-CoV-2 infection. Understanding the mechanisms by which training agents activate innate immune cells to reprogram immune responses may prove beneficial in developing preventive and therapeutic targets against COVID-19.
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Platelet extracellular vesicles in COVID-19: Potential markers and makers.
Puhm, F, Flamand, L, Boilard, E
Journal of leukocyte biology. 2022;(1):63-74
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Abstract
Platelets and platelet extracellular vesicles (pEV) are at the crossroads of coagulation and immunity. Extracellular vesicles are messengers that not only transmit signals between cells, but also provide information about the status of their cell of origin. Thus, pEVs have potential as both biomarkers of platelet activation and contributors to pathology. Coronavirus Disease-19 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a complex disease affecting multiple organs and is characterized by a high degree of inflammation and risk of thrombosis in some patients. In this review, we introduce pEVs as valuable biomarkers in disease with a special focus on their potential as predictors of and contributors to COVID-19.
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Elucidating important structural features for the binding affinity of spike - SARS-CoV-2 neutralizing antibody complexes.
Sharma, D, Rawat, P, Janakiraman, V, Gromiha, MM
Proteins. 2022;(3):824-834
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Abstract
The coronavirus disease 2019 (COVID-19) has affected the lives of millions of people around the world. In an effort to develop therapeutic interventions and control the pandemic, scientists have isolated several neutralizing antibodies against SARS-CoV-2 from the vaccinated and convalescent individuals. These antibodies can be explored further to understand SARS-CoV-2 specific antigen-antibody interactions and biophysical parameters related to binding affinity, which can be utilized to engineer more potent antibodies for current and emerging SARS-CoV-2 variants. In the present study, we have analyzed the interface between spike protein of SARS-CoV-2 and neutralizing antibodies in terms of amino acid residue propensity, pair preference, and atomic interaction energy. We observed that Tyr residues containing contacts are highly preferred and energetically favorable at the interface of spike protein-antibody complexes. We have also developed a regression model to relate the experimental binding affinity for antibodies using structural features, which showed a correlation of 0.93. Moreover, several mutations at the spike protein-antibody interface were identified, which may lead to immune escape (epitope residues) and improved affinity (paratope residues) in current/emerging variants. Overall, the work provides insights into spike protein-antibody interactions, structural parameters related to binding affinity and mutational effects on binding affinity change, which can be helpful to develop better therapeutics against COVID-19.
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Targetting ferroptosis for blood cell-related diseases.
Chen, Z, Jiang, J, Fu, N, Chen, L
Journal of drug targeting. 2022;(3):244-258
Abstract
Ferroptosis is an iron-dependent cell death pathway and participates in various diseases. Current evidence suggests that ferroptosis can obviously affect the function of blood cells. This paper aims to elaborate the role of ferroptosis in blood cells and related diseases. First, abnormal ferroptosis damages the developing red blood cells by breaking systemic iron homeostasis, leading to erythropoiesis suppression and anaemia. Ferroptosis mediates neutrophils recruitment and neutrophil extracellular trap formation (NETosis). In T-cells, ferroptosis induces a novel point of synergy between immunotherapy and radiotherapy. Additionally, ferroptosis may mediate B cells differentiation, antibody responses and lymphoma. Nevertheless, increased ferroptosis can ameliorate acute myeloid leukaemia and T-cell leukaemia/lymphoma by inducing iron-dependent cancer cells death. Besides, ferroptosis activates platelets by increasing P-selectin, thus causing thromboembolism. Ferroptosis mediates virus infection and parasite infection by driving T-cell death and preventing T-cell immunity. Interestingly, ferroptosis is also considered as a critical player in COVID-19 infections, while targetting ferroptosis may also improve thromboembolism and prognosis in patients with COVID-19 infection. Overall, the crucial role of ferroptosis in blood cells will show a new therapeutic potential in blood cell-related diseases.HighlightsFerroptosis shows a new therapeutic potential for blood cell-related diseases.Ferroptosis damages erythropoiesis and thus induces anaemia.Ferroptosis induces platelet activation and leads to thromboembolism.Ferroptosis regulates T-cell and B-cell immunity, which participant in infectious diseases.Inversely, ferroptosis ameliorates acute myeloid leukaemia and T-cell leukaemia.
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The potential role of resveratrol as supportive antiviral in treating conditions such as COVID-19 - A formulator's perspective.
van Brummelen, R, van Brummelen, AC
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112767
Abstract
With an increased transmissibility but milder form of disease of the omicron variant of COVID-19 and the newer antivirals often still out of reach of many populations, a refocus of the current treatment regimens is required. Safe, affordable, and available adjuvant treatments should also be considered and known drugs and substances need to be repurposed and tested. Resveratrol, a well-known antioxidant of natural origin, shown to act as an antiviral as well as playing a role in immune stimulation, down regulation of the pro-inflammatory cytokine release and reducing lung injury by reducing oxidative stress, is such an option. New initiatives and collaborations will however need to be found to unleash resveratrol's full potential in the pharmaceutical market.
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Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity.
White, JH
Nutrients. 2022;(2)
Abstract
Vitamin D deficiency, characterized by low circulating levels of calcifediol (25-hydroxyvitamin D, 25D) has been linked to increased risk of infections of bacterial and viral origin. Innate immune cells produce hormonal calcitriol (1,25-dihydroxyvitamin D, 1,25D) locally from circulating calcifediol in response to pathogen threat and an immune-specific cytokine network. Calcitriol regulates gene expression through its binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. The hormone-bound VDR induces the transcription of genes integral to innate immunity including pattern recognition receptors, cytokines, and most importantly antimicrobial peptides (AMPs). Transcription of the human AMP genes β-defensin 2/defensin-β4 (HBD2/DEFB4) and cathelicidin antimicrobial peptide (CAMP) is stimulated by the VDR bound to promoter-proximal vitamin D response elements. HDB2/DEFB4 and the active form of CAMP, the peptide LL-37, which form amphipathic secondary structures, were initially characterized for their antibacterial actively. Notably, calcitriol signaling induces secretion of antibacterial activity in vitro and in vivo, and low circulating levels of calcifediol are associated with diverse indications characterized by impaired antibacterial immunity such as dental caries and urinary tract infections. However, recent work has also provided evidence that the same AMPs are components of 1,25D-induced antiviral responses, including those against the etiological agent of the COVID-19 pandemic, the SARS-CoV2 coronavirus. This review surveys the evidence for 1,25D-induced antimicrobial activity in vitro and in vivo in humans and presents our current understanding of the potential mechanisms by which CAMP and HBD2/DEFB4 contribute to antiviral immunity.
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Implications of the NADase CD38 in COVID pathophysiology.
Zeidler, JD, Kashyap, S, Hogan, KA, Chini, EN
Physiological reviews. 2022;(1):339-341
Abstract
During the COVID-19 pandemic, efforts have been made worldwide to develop effective therapies to address the devastating immune-mediated effects of SARS-CoV-2. With the exception of monoclonal antibody-mediated therapeutics and preventive approaches such as mass immunization, most experimental or repurposed drugs have failed in large randomized clinical trials (https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline). The worldwide spread of SARS-CoV-2 virus revealed specific susceptibilities to the virus among the elderly and individuals with age-related syndromes. These populations were more likely to experience a hyperimmune response characterized by a treatment-resistant acute lung pathology accompanied by multiple organ failure. These observations underscore the interplay between the virus, the biology of aging, and outcomes observed in the most severe cases of SARS-CoV-2 infection. The ectoenzyme CD38 has been implicated in the process of "inflammaging" in aged tissues. In a current publication, Horenstein et al. present evidence to support the hypothesis that CD38 plays a central role in altered immunometabolism resulting from COVID-19 infection. The authors discuss a critical but underappreciated trifecta of CD38-mediated NAD+ metabolism, aging, and COVID-19 immune response and speculate that the CD38/NAD+ axis is a promising therapeutic target for this disease.
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Epistatic models predict mutable sites in SARS-CoV-2 proteins and epitopes.
Rodriguez-Rivas, J, Croce, G, Muscat, M, Weigt, M
Proceedings of the National Academy of Sciences of the United States of America. 2022;(4)
Abstract
The emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major concern given their potential impact on the transmissibility and pathogenicity of the virus as well as the efficacy of therapeutic interventions. Here, we predict the mutability of all positions in SARS-CoV-2 protein domains to forecast the appearance of unseen variants. Using sequence data from other coronaviruses, preexisting to SARS-CoV-2, we build statistical models that not only capture amino acid conservation but also more complex patterns resulting from epistasis. We show that these models are notably superior to conservation profiles in estimating the already observable SARS-CoV-2 variability. In the receptor binding domain of the spike protein, we observe that the predicted mutability correlates well with experimental measures of protein stability and that both are reliable mutability predictors (receiver operating characteristic areas under the curve ∼0.8). Most interestingly, we observe an increasing agreement between our model and the observed variability as more data become available over time, proving the anticipatory capacity of our model. When combined with data concerning the immune response, our approach identifies positions where current variants of concern are highly overrepresented. These results could assist studies on viral evolution and future viral outbreaks and, in particular, guide the exploration and anticipation of potentially harmful future SARS-CoV-2 variants.
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SARS-CoV-2-specific B- and T-cell immunity in a population-based study of young Swedish adults.
Björkander, S, Du, L, Zuo, F, Ekström, S, Wang, Y, Wan, H, Sherina, N, Schoutens, L, Andréll, J, Andersson, N, et al
The Journal of allergy and clinical immunology. 2022;(1):65-75.e8
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Abstract
BACKGROUND Young adults are now considered major spreaders of coronavirus disease 2019 (COVID-19) disease. Although most young individuals experience mild to moderate disease, there are concerns of long-term adverse health effects. The impact of COVID-19 disease and to which extent population-level immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists in young adults remain unclear. OBJECTIVE We conducted a population-based study on humoral and cellular immunity to SARS-CoV-2 and explored COVID-19 disease characteristics in young adults. METHODS We invited participants from the Swedish BAMSE (Barn [Children], Allergy Milieu, Stockholm, Epidemiology) birth cohort (age 24-27 years) to take part in a COVID-19 follow-up. From 980 participants (October 2020 to June 2021), we here present data on SARS-CoV-2 receptor-binding domain-specific IgM, IgA, and IgG titers measured by ELISA and on symptoms and epidemiologic factors associated with seropositivity. Further, SARS-CoV-2-specific memory B- and T-cell responses were detected for a subpopulation (n = 108) by ELISpot and FluoroSpot. RESULTS A total of 28.4% of subjects were seropositive, of whom 18.4% were IgM single positive. One in 7 seropositive subjects was asymptomatic. Seropositivity was associated with use of public transport, but not with sex, asthma, rhinitis, IgE sensitization, smoking, or body mass index. In a subset of representative samples, 20.7% and 35.0% had detectable SARS-CoV-2 specific B- and T-cell responses, respectively. B- and T-cell memory responses were clearly associated with seropositivity, but T-cell responses were also detected in 17.2% of seronegative subjects. CONCLUSIONS Assessment of IgM and T-cell responses may improve population-based estimations of SARS-CoV-2 infection. The pronounced surge of both symptomatic and asymptomatic infections among young adults indicates that the large-scale vaccination campaign should be continued.
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Micronutrients and bioactive compounds in the immunological pathways related to SARS-CoV-2 (adults and elderly).
Arruda de Souza Monnerat, J, Ribeiro de Souza, P, Monteiro da Fonseca Cardoso, L, Dario Mattos, J, de Souza Rocha, G, Frauches Medeiros, R
European journal of nutrition. 2021;(2):559-579
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Abstract
The new coronavirus pandemic is affecting the entire world with more than 25 million confirmed cases in August 2020 according to the World Health Organization. It is known that the virus can affect several tissues and can progress to a respiratory failure in severe cases. To prevent the progression to this stage of the disease and minimize all the damage caused by coronavirus (SARS-CoV-2) the immune system must be in its integrity. A healthy nutritional status are fundamental to efficient immunological protection and consequently a good response to SARS-CoV-2. Micronutrients and bioactive compounds perform functions in immune cells that are extremely essential to stop SARS-CoV-2. Their adequate consumption is part of a non-pharmacological intervention to keep the immune system functioning. This review has as main objective to inform how micronutrients and bioactive compounds could act in the essential immunological pathways could stop SARS-CoV-2, focusing on the functions that have already established in the literature and transposing to this scenario.