From bedside to bench: regulation of host factors in SARS-CoV-2 infection

AbstractThe zoonotic coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), which causes COVID-19 (coronavirus disease-2019), has resulted in a pandemic. This has led to an urgent need to understand the molecular determinants of SARS-CoV-2 infection, factors associated with COVID-19 heterogeneity and severity, and therapeutic options for these patients. In this review, we discuss the role of host factors in SARS-CoV-2 infection and describe variations in host factor expression as mechanisms underlying the symptoms and severity of COVID-19. We focus on two host factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), implicated in SARS-CoV-2 infection. We also discuss genetic variants associated with COVID-19 severity revealed in selected patients and based on genome-wide association studies (GWASs). Furthermore, we highlight important advances in cell and chromatin biology, such as single-cell RNA and chromatin sequencing and chromosomal conformation assays, as methods that may aid in the discovery of viral–host interactions in COVID-19. Understanding how regulation of host factor genes varies in physiological and pathological states might explain the heterogeneity observed in SARS-CoV-2 infection, help identify pathways for therapeutic development, and identify patients most likely to progress to severe COVID-19.

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Genetic and real-world clinical data, combined with empirical validation, nominate JAK-STAT signalling as a target for Alzheimer’s Disease therapeutic development

10.1101/179267 ◽

2017 ◽

Author(s):

Alejo J. Nevado-Holgado ◽

Elena Ribe ◽

Laura Thei ◽

Laura Furlong ◽

Miguel Angel-Mayer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Data ◽

Real World ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Therapeutic Development ◽

Stat Pathway

AbstractAs Genome Wide Association Studies (GWAS) have grown in size, the number of genetic variants that have been nominated for an increasing number of diseases has correspondingly increased. Despite this increase in the number of associated SNPs per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with an orthogonal source of evidence, namely real-world, routinely collected clinical data from more than 6 million patients in order to drive target nomination. First we show that when examined at a pathway level, analysis of all GWAS studies groups Alzheimer’s disease (AD) in a cluster with disorders of immunity and inflammation. Using clinical data we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the JAK-STAT pathway. Using four independent open-science datasets we then find evidence for altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of key drivers of this pathway, providing experimental evidence validating these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence potential target for therapeutic development, and moreover demonstrate a de-novo multi-modal approach to derive information from rapidly increasing genomic datasets.One Sentence SummaryCombining evidence from genome wide association studies, real-world clinical and cohort molecular data together with experimental studies in rodent model systems nominates JAK-STAT signaling as an aetiopathological event in Alzheimer’s disease

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Inconsistent trends regarding the association between ABO blood groups and susceptibility to SARS-CoV-2 infections

Journal of Undergraduate Life Sciences ◽

10.33137/juls.v15i1.36956 ◽

2021 ◽

Vol 15 (1) ◽

pp. 6

Author(s):

Jasmin Lee ◽

Carol Guo

Keyword(s):

Cohort Studies ◽

Viral Infections ◽

Association Studies ◽

Blood Type ◽

Host Susceptibility ◽

Genome Wide Association Studies ◽

Host Interactions ◽

Host Interaction ◽

Genome Wide ◽

Viral Particles

ABO antigens, produced from the ABO gene, are known to impact host interactions with various viruses. One characteristic is the host’s susceptibility to viral infections. Host interaction with viral particles is altered by the blood type-determined combination of ABO antigens on the cellular surface. SARS-CoV-2 is a novel strain of the coronavirus family known to have structural similarities with SARS-CoV. Considering ABO antigens’ association with SARS-CoV, studies have examined their relationship with SARS-CoV-2 as well. We reviewed current perspectives on the relationship between host susceptibility to SARS-CoV-2 infections and ABO antigens by examining cohort studies observing proportional differences between patients of varying blood types. While many studies indicated a higher risk of type A patients and a lower risk for type O patients, trends tended to vary per population. Consequently, we investigated the differences in study design between cohort studies that produced the variation in trends. Additionally, we examined genome-wide association studies that indicate a genetic association between the variables. We present the need for a standardized calculation method determining the significance of each blood group in its relationship with SARS-CoV-2 susceptibility per cohort.

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