Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells

ABSTRACTCoronavirus disease (COVID-19), caused by SARS-CoV-2, has affected over 65 million individuals and killed over 1.5 million persons (December 8, 2020; www.who.int)1. While fatality rates are higher among the elderly and those with underlying comorbidities2, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases.3–7 We report that the autoimmune PTPN2 risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry mediated by SARS-CoV-2 spike protein. Elevated ACE2 expression and viral entry were mediated by increased JAK-STAT signalling, and were reversed by the JAK inhibitor, tofacitinib. Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

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Neutrophils in respiratory viral infections

Mucosal Immunology ◽

10.1038/s41385-021-00397-4 ◽

2021 ◽

Author(s):

Cecilia Johansson ◽

Freja C. M. Kirsebom

Keyword(s):

Viral Infections ◽

Immune Cell ◽

Respiratory Infections ◽

Fungal Infections ◽

Severe Disease ◽

The Elderly ◽

Viral Control ◽

Immunological Mechanisms ◽

Respiratory Viral Infections ◽

Viral Respiratory Infections

AbstractViral respiratory infections are a common cause of severe disease, especially in infants, people who are immunocompromised, and in the elderly. Neutrophils, an important innate immune cell, infiltrate the lungs rapidly after an inflammatory insult. The most well-characterized effector mechanisms by which neutrophils contribute to host defense are largely extracellular and the involvement of neutrophils in protection from numerous bacterial and fungal infections is well established. However, the role of neutrophils in responses to viruses, which replicate intracellularly, has been less studied. It remains unclear whether and, by which underlying immunological mechanisms, neutrophils contribute to viral control or confer protection against an intracellular pathogen. Furthermore, neutrophils need to be tightly regulated to avoid bystander damage to host tissues. This is especially relevant in the lung where damage to delicate alveolar structures can compromise gas exchange with life-threatening consequences. It is inherently less clear how neutrophils can contribute to host immunity to viruses without causing immunopathology and/or exacerbating disease severity. In this review, we summarize and discuss the current understanding of how neutrophils in the lung direct immune responses to viruses, control viral replication and spread, and cause pathology during respiratory viral infections.

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Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients

10.1101/2020.03.30.20047852 ◽

2020 ◽

Cited By ~ 3

Author(s):

Amr H. Sawalha ◽

Ming Zhao ◽

Patrick Coit ◽

Qianjin Lu

Keyword(s):

Oxidative Stress ◽

Immune Response ◽

Viral Entry ◽

Viral Infections ◽

Severe Disease ◽

Disease Course ◽

Vicious Cycle ◽

Respiratory Complications ◽

Disease Remission ◽

Functional Receptor

SummaryInfection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specially, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

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Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19)

10.31219/osf.io/vaqz6 ◽

2020 ◽

Cited By ~ 1

Author(s):

Laurent Hiffler ◽

Benjamin Rakotoambinina

Keyword(s):

Viral Infections ◽

Rna Virus ◽

Severe Disease ◽

The Elderly ◽

Spectrum Management ◽

Common Finding ◽

Global Response ◽

Se Deficiency ◽

Virus Interactions ◽

Vulnerable Elderly

SARS-CoV-2 is an RNA virus responsible for the COVID-19 pandemic that already claimed more than 340,000 lives worldwide as of May 23, 2020, the majority of which are elderly. Selenium (Se), a natural trace element, has a key and complex role in the immune system. It is well-documented that Se deficiency is associated with higher susceptibility to RNA viral infections and more severe disease outcome. In this article, we firstly present evidence on how Se deficiency promotes mutations, replication and virulence of RNA viruses. Next, we review how Se might be beneficial via restoration of host antioxidant capacity, reduction of apoptosis and endothelial cell damages as well as platelet aggregation. It also appears that low Se status is a common finding in conditions considered at risk of severe COVID-19, especially in the elderly. Finally, we present a rationale for Se use at different stages of COVID-19. Se has been overlooked but may have a significant place in COVID-19 spectrum management, particularly in vulnerable elderly, and might represent a game changer in the global response to COVID-19.

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Acquired haemophilia in the elderly is a severe disease: report of five new cases

Haemophilia ◽

10.1046/j.1365-2516.2001.00531.x ◽

2001 ◽

Vol 7 (4) ◽

pp. 428-432 ◽

Cited By ~ 20

Author(s):

S. Godreuil ◽

R. Navarro ◽

P. Quittet ◽

L. Landreau ◽

J-F. Schved ◽

...

Keyword(s):

Severe Disease ◽

The Elderly ◽

Acquired Haemophilia

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Highlighting the Correlation Between Telomere Shortening and the Susceptibility to the Novel SARS-CoV-2 Virus (COVID-19)

10.31730/osf.io/k86p3 ◽

2020 ◽

Author(s):

Aml Ghanem

Keyword(s):

Telomere Length ◽

Stress Responses ◽

Viral Infections ◽

Deep Understanding ◽

The Elderly ◽

The Novel ◽

Telomere Shortening ◽

Infection Pathways ◽

And Gender ◽

Demographic Distribution

COVID-19 is a global crisis that requires a deep understanding of infection pathways to facilitate the development of effective treatments and vaccines. Telomere, which is regarded as a biomarker for other respiratory viral infections, might influence the demographic distribution of COVID-19 infection and fatality rates. Viral infection can induce many cellular remodeling events and stress responses, including telomere specific alterations, just as telomere shortening. In brief, this letter aims to highlight the connection between telomere shortening and susceptibility to COVID-19 infection, in addition to changes in telomeric length according to the variation of age and gender of confirmed cases with COVID-19 infection. To sum up, the correlation is revealed from the available data that connect telomere length and COVID-19 infection, demonstrated in the fact that the elderly patients and males are more susceptible to COVID-19 due to shortening in their telomere length.

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Polymyalgia Rheumatica - a Disease of the Elderly

Revista de Chimie ◽

10.37358/rc.18.1.6063 ◽

2018 ◽

Vol 69 (1) ◽

pp. 152-154

Author(s):

Vasilica Cristescu ◽

Aurelia Romila ◽

Luana Andreea Macovei

Keyword(s):

Giant Cell Arteritis ◽

Giant Cell ◽

Polymyalgia Rheumatica ◽

Temporal Arteritis ◽

Viral Infections ◽

Clinical Manifestations ◽

The Elderly ◽

Clinical Aspects ◽

Immune Disorder ◽

Markers Of Inflammation

Polymyalgia rheumatica is a disease that occurs mostly in the elderly and is rarely seen in patients less than 50 years of age. Polymyalgia rheumatica is a vasculitis, which manifests itself as an inflammatory disease of the vascular wall that can affect any type of blood vessel, regardless of its size. It has been considered a form of giant cell arteritis, involving primarily large and medium arteries and to a lesser extent the arterioles. Clinical manifestations are caused by the generic pathogenic process and depend on the characteristics of the damaged organ. PMR is a senescence-related immune disorder. It has been defined as a stand-alone condition and a syndrome referred to as rheumatic polyarteritis with manifestations of giant cell arteritis (especially in cases of Horton�s disease and temporal arteritis) which are commonly associated with polymyalgia. The clinical presentation is clearly dominated by the painful girdle syndrome, with a feeling of general discomfort. Polymyalgia and temporal arteritis may coexist or be consecutive to each other in the same patient, as in most of our patients. The present study describes 3 cases of polymyalgia rheumatica, admitted to the Clinic of Rheumatology of Sf. Apostol Andrei Hospital, Galati. The cases were compared with the literature. Two clinical aspects (polymyalgia rheumatica and/or Horton�s disease) and the relationship between them were also considered. Polymyalgia rheumatica is currently thought to have a multifactorial etiology, in which the following factors play a role: genetic factors or hereditary predisposition (some individuals are more prone to this disease), immune factors and viral infections (triggers of the disease). Other risk factors of polymyalgia rheumatica include age over 50 years and the association with giant cell arteritis. The characteristic feature of the disease is girdle pain, with intense stiffness of at least one hour�s duration. Markers of inflammation, erythrocyte sedimentation rate and C-reactive protein are almost always increased at the onset of the disease. Diseases that can mimic the clinical picture of polymyalgia rheumatica are neoplasia, infections, metabolic disorders of the bone and endocrine diseases.

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Human Coronaviruses: Counteracting the Damage by Storm

Viruses ◽

10.3390/v13081457 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1457

Author(s):

Dewald Schoeman ◽

Burtram C. Fielding

Keyword(s):

Immune Response ◽

Severe Disease ◽

Antiviral Agents ◽

The Elderly ◽

Highly Pathogenic ◽

Vaccine Responses ◽

Cell Mediated Immune Response ◽

Inhibition Antibody ◽

A Cell ◽

Human Coronaviruses

Over the past 18 years, three highly pathogenic human (h) coronaviruses (CoVs) have caused severe outbreaks, the most recent causative agent, SARS-CoV-2, being the first to cause a pandemic. Although much progress has been made since the COVID-19 pandemic started, much about SARS-CoV-2 and its disease, COVID-19, is still poorly understood. The highly pathogenic hCoVs differ in some respects, but also share some similarities in clinical presentation, the risk factors associated with severe disease, and the characteristic immunopathology associated with the progression to severe disease. This review aims to highlight these overlapping aspects of the highly pathogenic hCoVs—SARS-CoV, MERS-CoV, and SARS-CoV-2—briefly discussing the importance of an appropriately regulated immune response; how the immune response to these highly pathogenic hCoVs might be dysregulated through interferon (IFN) inhibition, antibody-dependent enhancement (ADE), and long non-coding RNA (lncRNA); and how these could link to the ensuing cytokine storm. The treatment approaches to highly pathogenic hCoV infections are discussed and it is suggested that a greater focus be placed on T-cell vaccines that elicit a cell-mediated immune response, using rapamycin as a potential agent to improve vaccine responses in the elderly and obese, and the potential of stapled peptides as antiviral agents.

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Trace Elements as Immunoregulators in SARS-CoV-2 and Other Viral Infections

Indian Journal of Clinical Biochemistry ◽

10.1007/s12291-021-00961-6 ◽

2021 ◽

Author(s):

Karthick Dharmalingam ◽

Amandeep Birdi ◽

Sojit Tomo ◽

Karli Sreenivasulu ◽

Jaykaran Charan ◽

...

Keyword(s):

Immune Response ◽

Trace Elements ◽

Viral Entry ◽

Viral Infections ◽

Inhibitory Effect ◽

Antioxidants Activity ◽

Host Immune Responses ◽

Complex Interactions ◽

Downstream Processes

AbstractNutritional deficiency is associated with impaired immunity and increased susceptibility to infections. The complex interactions of trace elements with the macromolecules trigger the effective immune response against the viral diseases. The outcome of various viral infections along with susceptibility is affected by trace elements such as zinc, selenium, iron, copper, etc. due to their immuno-modulatory effects. Available electronic databases have been comprehensively searched for articles published with full text available and with the key words “Trace elements”, “COVID-19”, “Viral Infections” and “Immune Response” (i.e. separately Zn, Se, Fe, Cu, Mn, Mo, Cr, Li, Ni, Co) appearing in the title and abstract. On the basis of available articles we have explored the role of trace elements in viral infections with special reference to COVID-19 and their interactions with the immune system. Zinc, selenium and other trace elements are vital to triggerTH1 cells and cytokine-mediated immune response for substantial production of proinflammatory cytokines. The antiviral activity of some trace elements is attributed to their inhibitory effect on viral entry, replication and other downstream processes. Trace elements having antioxidants activity not only regulate host immune responses, but also modify the viral genome. Adequate dietary intake of trace elements is essential for activation, development, differentiation and numerous functions.

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Nanobiocide Based-Silver Nanomaterials Upon Coronaviruses: Approaches for Preventing Viral Infections

Nanoscale Research Letters ◽

10.1186/s11671-021-03558-3 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Kamyar Khoshnevisan ◽

Hassan Maleki ◽

Hadi Baharifar

Keyword(s):

Viral Entry ◽

Viral Infections ◽

Respiratory Infections ◽

Antiviral Agents ◽

Long Term Stability ◽

Silver Nanomaterials ◽

Inhibitory Mechanisms ◽

Low Toxicity ◽

Nano Graphene

Abstract The effectiveness of silver nanomaterials (AgNMs), as antiviral agents, has been confirmed in humans against many different types of viruses. Nanobiocides-based AgNMs can be effectively applied to eliminate coronaviruses (CoVs), as the cause of various diseases in animals and humans, particularly the fatal human respiratory infections. Mostly, these NMs act effectively against CoVs, thanks to the NMs’ fundamental anti-viral structures like reactive oxygen species (ROS), and photo-dynamic and photo-thermal abilities. Particularly, the antiviral activity of AgNMs is clarified under three inhibitory mechanisms including viral entry limitation, attachment inhibition, and viral replication limitation. It is believed that nanobiocide with other possible materials such as TiO2, silica and, carbon NMs exclusively nano-graphene materials can emerge as a more effective disinfectant for long-term stability with low toxicity than common disinfectants. Nanobiocides also can be applied for the prevention and treatment of viral infections specifically against COVID-19. Graphic Abstract

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CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity

Infection ◽

10.1007/s15010-021-01606-9 ◽

2021 ◽

Author(s):

Jan-Moritz Doehn ◽

Christoph Tabeling ◽

Robert Biesen ◽

Jacopo Saccomanno ◽

Elena Madlung ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Disease Severity ◽

Clinical Studies ◽

Viral Infections ◽

Severe Disease ◽

Type I Interferons ◽

Type I ◽

Interferon Signaling ◽

Expression Levels

AbstractCoronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.

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