Limited within-host diversity and tight transmission bottlenecks limit SARS-CoV-2 evolution in acutely infected individuals

Mapping Intimacies ◽

10.1101/2021.04.30.440988 ◽

2021 ◽

Author(s):

Katarina Braun ◽

Gage Kahl Moreno ◽

Cassia Wagner ◽

Molly A. Accola ◽

William M Rehrauer ◽

...

Keyword(s):

Immune Escape ◽

Acute Infection ◽

Host Diversity ◽

Recent Emergence ◽

Novel Variants ◽

Efficient Selection

The recent emergence of divergent SARS-CoV-2 lineages has raised concerns about the role of selection within individual hosts in propagating novel variants. Of particular concern are variants associated with immune escape and/or enhanced transmissibility. Though growing evidence suggests that novel variants can arise during prolonged infections, most infections are acute. Understanding the extent to which variants emerge and transmit among acutely infected hosts is therefore critical for predicting the pace at which variants resistant to vaccines or conferring increased transmissibility might emerge in the majority of SARS-CoV-2 infections. To characterize how within-host diversity is generated and propagated, we combine extensive laboratory and bioinformatic controls with metrics of within- and between-host diversity to 133 SARS-CoV-2 genomes from acutely infected individuals. We find that within-host diversity during acute infection is low and transmission bottlenecks are narrow, with very few viruses founding most infections. Within-host variants are rarely transmitted, even among individuals within the same household. Accordingly, we also find that within-host variants are rarely detected along phylogenetically linked infections in the broader community. Together, these findings suggest that efficient selection and transmission of novel SARS-CoV-2 variants is unlikely during typical, acute infection.

Download Full-text

Impact of the Double Mutants on Spike Protein of SARS-CoV-2 B.1.617 Lineage to the Human ACE2 Receptor Binding: A Structural Insight

Viruses ◽

10.3390/v13112295 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2295

Author(s):

Mohd Imran Khan ◽

Mohammad Hassan Baig ◽

Tanmoy Mondal ◽

Mohammed Alorabi ◽

Tanuj Sharma ◽

...

Keyword(s):

Binding Affinity ◽

Receptor Binding ◽

Immune Escape ◽

Principal Component ◽

Spike Protein ◽

Human Host ◽

Recent Emergence ◽

Novel Variants ◽

Structural Insight ◽

The Impact

The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these “variants of concern” has increased viral transmissibility or immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.1.617 lineage (Kappa and Delta) carry mutations within the receptor-binding domain of spike (S) protein (L452R + E484Q and L452R + T478K), the region binding to the host receptor. The double mutations carried by these novel variants are primarily responsible for an upsurge number of COVID-19 cases in India. In this study, we thoroughly investigated the impact of these double mutations on the binding capability to the human host receptor. We performed several structural analyses and found that the studied double mutations increase the binding affinity of the spike protein to the human host receptor (ACE2). Furthermore, our study showed that these double mutants might be a dominant contributor enhancing the receptor-binding affinity of SARS-CoV-2 and consequently making it more stable. We also investigated the impact of these mutations on the binding affinity of two monoclonal antibodies (Abs) (2-15 and LY-CoV555) and found that the presence of the double mutations also hinders its binding with the studied Abs. The principal component analysis, free energy landscape, intermolecular interaction, and other investigations provided a deeper structural insight to better understand the molecular mechanism responsible for increased viral transmissibility of these variants.

Download Full-text

Acute SARS-CoV-2 infections harbor limited within-host diversity and transmit via tight transmission bottlenecks

PLoS Pathogens ◽

10.1371/journal.ppat.1009849 ◽

2021 ◽

Vol 17 (8) ◽

pp. e1009849

Author(s):

Katarina M. Braun ◽

Gage K. Moreno ◽

Cassia Wagner ◽

Molly A. Accola ◽

William M. Rehrauer ◽

...

Keyword(s):

Immune Escape ◽

Host Diversity ◽

Novel Variants

The emergence of divergent SARS-CoV-2 lineages has raised concern that novel variants eliciting immune escape or the ability to displace circulating lineages could emerge within individual hosts. Though growing evidence suggests that novel variants arise during prolonged infections, most infections are acute. Understanding how efficiently variants emerge and transmit among acutely-infected hosts is therefore critical for predicting the pace of long-term SARS-CoV-2 evolution. To characterize how within-host diversity is generated and propagated, we combine extensive laboratory and bioinformatic controls with metrics of within- and between-host diversity to 133 SARS-CoV-2 genomes from acutely-infected individuals. We find that within-host diversity is low and transmission bottlenecks are narrow, with very few viruses founding most infections. Within-host variants are rarely transmitted, even among individuals within the same household, and are rarely detected along phylogenetically linked infections in the broader community. These findings suggest that most variation generated within-host is lost during transmission.

Download Full-text

The role of programmed cell death ligand-1/ programmed cell death-1 (PD-L1/PD-1) in HPV-induced cervical cancer and potential for their use in blockade therapy

Current Medicinal Chemistry ◽

10.2174/0929867327666200128105459 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Lifang Zhang ◽

Yu Zhao ◽

Quanmei Tu ◽

Xiangyang Xue ◽

Xueqiong Zhu ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Immune Escape ◽

Hypoxia Inducible Factor ◽

Hpv Infection ◽

Advanced Cervical Cancer ◽

Cervical Carcinogenesis ◽

Programmed Cell Death 1

Background: Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. Methods: We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. Results: One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signaling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and MicroRNAs, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in immune escape of cervical cancer through inhibition of host immune response. creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PD-L1/PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. Conclusion: Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body’s immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.

Download Full-text

SARS-CoV-2 within-host diversity and transmission

Science ◽

10.1126/science.abg0821 ◽

2021 ◽

Vol 372 (6539) ◽

pp. eabg0821 ◽

Cited By ~ 1

Author(s):

Katrina A. Lythgoe ◽

Matthew Hall ◽

Luca Ferretti ◽

Mariateresa de Cesare ◽

George MacIntyre-Cockett ◽

...

Keyword(s):

United Kingdom ◽

Severe Acute Respiratory Syndrome ◽

Phylogenetic Tree ◽

Immune Escape ◽

Clinical Samples ◽

Diversity Patterns ◽

Host Diversity ◽

Viral Loads ◽

The United Kingdom ◽

Low Levels

Extensive global sampling and sequencing of the pandemic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have enabled researchers to monitor its spread and to identify concerning new variants. Two important determinants of variant spread are how frequently they arise within individuals and how likely they are to be transmitted. To characterize within-host diversity and transmission, we deep-sequenced 1313 clinical samples from the United Kingdom. SARS-CoV-2 infections are characterized by low levels of within-host diversity when viral loads are high and by a narrow bottleneck at transmission. Most variants are either lost or occasionally fixed at the point of transmission, with minimal persistence of shared diversity, patterns that are readily observable on the phylogenetic tree. Our results suggest that transmission-enhancing and/or immune-escape SARS-CoV-2 variants are likely to arise infrequently but could spread rapidly if successfully transmitted.

Download Full-text

The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

Genes ◽

10.3390/genes12020300 ◽

2021 ◽

Vol 12 (2) ◽

pp. 300

Author(s):

Camilla Ceccatelli Berti ◽

Giulia di Punzio ◽

Cristina Dallabona ◽

Enrico Baruffini ◽

Paola Goffrini ◽

...

Keyword(s):

Molecular Mechanisms ◽

Mitochondrial Diseases ◽

Yeast Saccharomyces Cerevisiae ◽

Genome Data ◽

New Genes ◽

Eukaryotic Organism ◽

Novel Variants ◽

Therapeutic Molecules ◽

Nuclear Mutations

The increasing application of next generation sequencing approaches to the analysis of human exome and whole genome data has enabled the identification of novel variants and new genes involved in mitochondrial diseases. The ability of surviving in the absence of oxidative phosphorylation (OXPHOS) and mitochondrial genome makes the yeast Saccharomyces cerevisiae an excellent model system for investigating the role of these new variants in mitochondrial-related conditions and dissecting the molecular mechanisms associated with these diseases. The aim of this review was to highlight the main advantages offered by this model for the study of mitochondrial diseases, from the validation and characterisation of novel mutations to the dissection of the role played by genes in mitochondrial functionality and the discovery of potential therapeutic molecules. The review also provides a summary of the main contributions to the understanding of mitochondrial diseases emerged from the study of this simple eukaryotic organism.

Download Full-text

The role of the registered nurse first assistant within the perioperative setting

British Journal of Nursing ◽

10.12968/bjon.2021.30.3.148 ◽

2021 ◽

Vol 30 (3) ◽

pp. 148-153

Author(s):

Roland Pika ◽

Brid O'Brien ◽

Jill Murphy ◽

Kathleen Markey ◽

Claire O'Donnell

Keyword(s):

Registered Nurse ◽

Healthcare Sector ◽

Review Of The Literature ◽

Surgical Interventions ◽

Medical Practitioners ◽

Nursing Role ◽

Perioperative Nursing ◽

Recent Emergence ◽

Provision Of Care

Perioperative setting registered nurse first assistants (RNFAs) are described as non-medical practitioners who perform surgical interventions during surgery. They provide medical care to perioperative patients under the supervision of a consultant surgeon. First assistants in surgery can be an expanded perioperative nursing role. A review of the literature illuminates the need for continuous learning in developing skills in becoming competent RNFA practitioners and how they utilise acquired skills to assist, mentor and teach their colleagues within the perioperative setting. The RNFA is an advanced and expanded practice role. RNFAs contribute significantly to the provision of care within all phases of perioperative care (preoperative, intraoperative, postoperative). There is little literature on the role of the RNFA due to its relatively recent emergence in the healthcare sector and the small number of countries where it is implemented.

Download Full-text

First Survey of SNPs in TMEM154, TLR9, MYD88 and CCR5 Genes in Sheep Reared in Italy and their Association with Resistance to SRLVs Infection

Viruses ◽

10.3390/v13071290 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1290

Author(s):

Chiara Arcangeli ◽

Daniele Lucarelli ◽

Martina Torricelli ◽

Carla Sebastiani ◽

Marcella Ciullo ◽

...

Keyword(s):

Genetic Resistance ◽

Economic Losses ◽

Ccr5 Gene ◽

Innovative Strategy ◽

Visna Virus ◽

Starting Point ◽

Tlr9 Gene ◽

Novel Variants ◽

Serological Status

Maedi-visna virus (MVV) and caprine arthritis encephalitis virus (CAEV), referred to as small ruminant lentiviruses (SRLVs), belong to the genus Lentivirus of the Retroviridae family. SRLVs infect both sheep and goats, causing significant economic losses and animal welfare damage. Recent findings suggest an association between serological status and allelic variants of different genes such as TMEM154, TLR9, MYD88 and CCR5. The aim of this work was to investigate the role of specific polymorphisms of these genes in SRLVs infection in some sheep flocks in Italy. In addition to those already known, novel variants in the TMEM154 (P7H, I74V, I105V) gene were detected in this study. The risk of infection was determined finding an association between the serological status and polymorphisms P7H, E35K, N70I, I74V, I105V of TMEM154, R447Q, A462S and G520R in TLR9 gene, H176H* and K190K* in MYD88 genes, while no statistical association was observed for the 4-bp deletion of the CCR5 gene. Since no vaccines or treatments have been developed, a genetically based approach could be an innovative strategy to prevent and to control SRLVs infection. Our findings are an important starting point in order to define the genetic resistance profile towards SRLVs infection.

Download Full-text

Reduced Flow-Mediated Dilatation Is Not Related to COVID-19 Severity Three Months after Hospitalization for SARS-CoV-2 Infection

Journal of Clinical Medicine ◽

10.3390/jcm10061318 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1318

Author(s):

Marianne Riou ◽

Walid Oulehri ◽

Cedric Momas ◽

Olivier Rouyer ◽

Fabienne Lebourg ◽

...

Keyword(s):

Vascular Endothelium ◽

Matched Control ◽

Acute Infection ◽

Critical Role ◽

Lung Damage ◽

Vascular Effect ◽

Flow Mediated Dilatation ◽

Artery Flow

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide, with more than two million deaths. Evidence indicates the critical role of the vascular endothelium in its pathophysiology but, like potential changes in functional vasodilation, the vascular effect of SARS-CoV-2 at a given distance from the acute infection is largely unknown. We assessed brachial artery flow-mediated dilatation (FMD) in 27 COVID-19 patients needing conventional or intensive care unit hospitalization, three months after SARS-CoV-2 infection diagnosis and in nine age- and sex- matched control subjects. Interestingly, the FMD was lower in COVID-19 patients as compared to controls (8.2 (7.2–8.9) vs. 10.3 (9.1–11.7)); p = 0.002, and half of the hospitalized COVID-19 survivors presented with a reduced FMD < 8% at three months of COVID-19 onset. Impaired FMD was not associated with severe or critical SARS-CoV-2 infection, reflected by ICU hospitalization, total hospitalization duration, or severity of lung damage. In conclusion, reduced FMD is often observed even three months after hospitalization for SARS-CoV-2 infection, but such alteration predominantly appears to not be related to COVID-19 severity. Longer and larger follow-up studies will help to clarify the potential prognosis value of FMD among COVID-19 patients, as well as to further determine the mechanisms involved.

Download Full-text