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

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.

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

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.

scholarly journals SARS-CoV-2 within-host diversity and transmission

Science ◽  
2021 ◽  
Vol 372 (6539) ◽  
pp. eabg0821 ◽  
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.

scholarly journals Time-Programmed Delivery of Sorafenib and Anti-CD47 Antibody via a Double-Layer-Gel Matrix for Postsurgical Treatment of Breast Cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Liping Huang ◽  
Yiyi Zhang ◽  
Yanan Li ◽  
Fanling Meng ◽  
Hongyu Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Near Infrared ◽  
Immune Escape ◽  
Regulatory Protein ◽  
In Vivo Studies ◽  
Breast Cancer Patients ◽  
Thermally Responsive ◽  
Immunosuppressive Microenvironment

AbstractThe highly immunosuppressive microenvironment after surgery has a crucial impact on the recurrence and metastasis in breast cancer patients. Programmable delivery of immunotherapy-involving combinations through a single drug delivery system is highly promising, yet greatly challenging, to reverse postoperative immunosuppression. Here, an injectable hierarchical gel matrix, composed of dual lipid gel (DLG) layers with different soybean phosphatidylcholine/glycerol dioleate mass ratios, was developed to achieve the time-programmed sequential delivery of combined cancer immunotherapy. The outer layer of the DLG matrix was thermally responsive and loaded with sorafenib-adsorbed graphene oxide (GO) nanoparticles. GO under manually controlled near-infrared irradiation generated mild heat and provoked the release of sorafenib first to reeducate tumor-associated macrophages (TAMs) and promote an immunogenic tumor microenvironment. The inner layer, loaded with anti-CD47 antibody (aCD47), could maintain the gel state for a much longer time, enabling the sustained release of aCD47 afterward to block the CD47-signal regulatory protein α (SIRPα) pathway for a long-term antitumor effect. In vivo studies on 4T1 tumor-bearing mouse model demonstrated that the DLG-based strategy efficiently prevented tumor recurrence and metastasis by locally reversing the immunosuppression and synergistically blocking the CD47-dependent immune escape, thereby boosting the systemic immune responses.

The impact of Vaccination worldwide on SARS-CoV-2 infection: A Review on Vaccine Mechanisms, Results of Clinical Trials, Vaccinal Coverage and Interactions with Novel Variants

2021 ◽  
Vol 28 ◽  
Author(s):  
Douglas Henrique Pereira Damasceno ◽  
Arthur Aguiar Amaral ◽  
Cecília Andrade Silva ◽  
Ana Cristina Simões e Silva
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Placebo Group ◽  
Mechanisms Of Action ◽  
Novel Variants ◽  
The Impact ◽  
Positive Results ◽  
Epidemiological Information ◽  
Long Term Studies

Background: The COVID-19 pandemic demanded a global effort towards quickly developing safe and effective vaccines against SARS-CoV-2. Objective: This review aimed to discuss the main vaccines available, their mechanisms of action, results of clinical trials and epidemiological behavior. The implications of viral variants were also debated. Methods: A non-systematic literature review was performed between February and March 2021 by searching the Pubmed, Scopus, and SciELO databases, using different combinations of the following terms: "vaccines", "clinical trials" , "SARS-CoV-2", "Coronavirus", "COVID-19", "mechanisms of action". Data regarding clinical trials of SARS-CoV-2 vaccines and epidemiological information were also searched. Results: The mechanisms of action included vector-virus, mRNA and inactivated virus vaccines. The vaccines showed positive results in phases 2/3 clinical trials. The efficacy of the mRNA 1273 and of mRNA BNT 162b2 vaccines were 94.1% and 95%, respectively. The effectiveness of the ChAdOx1 nCoV-19 vaccine varied according to the scheme, with an overall value of 70.4%. The Gam-COVID-Vac vaccine had an efficacy of 91.6%. Regarding the Ad26.COV2.S vaccine, 99% or more of seroconversion was observed in all subgroups 29 days after vaccination. The CoronaVac vaccine induced an immune response in 92% of the volunteers receiving 3ug and in 98% with 6ug, in comparison to 3% in the placebo group. Conclusion: Global efforts have resulted in vaccines available in record time, with good safety and immunogenicity profile. However, only long-term studies can provide more information on duration of immunity and the need for additional doses.

scholarly journals Antibody Cocktail Exhibits Broad Neutralization against SARS-CoV-2 and SARS-CoV-2 variants

2021 ◽  
Author(s):  
Yuanyuan Qu ◽  
Xueyan Zhang ◽  
Meiyu Wang ◽  
Lina Sun ◽  
Yongzhong Jiang ◽  
...  
Keyword(s):  
Immune Escape ◽  
Conformational Epitope ◽  
Viral Escape ◽  
Angiotensin Converting Enzyme 2 ◽  
Neutralizing Activity ◽  
High Affinity ◽  
Phage Display Libraries ◽  
Novel Variants ◽  
Antibody Phage ◽  
Antibody Phage Display

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has precipitated multiple variants resistant to therapeutic antibodies. In this study, 12 high-affinity antibodies were generated from convalescent donors in early outbreaks using immune antibody phage display libraries. Of them, two RBD-binding antibodies (F61 and H121) showed high affinity neutralization against SARS-CoV-2, whereas three S2-target antibodies failed to neutralize SARS-CoV-2. Following structure analysis, F61 identified a linear epitope located in residues G446 - S494, which overlapped with angiotensin-converting enzyme 2 (ACE2) binding sites, while H121 recognized a conformational epitope located on the side face of RBD, outside from ACE2 binding domain. Hence the cocktail of the two antibodies achieved better performance of neutralization to SARS-CoV-2. Importantly, F61 and H121 exhibited efficient neutralizing activity against variants B.1.1.7 and B.1.351, those showed immune escape. Efficient neutralization of F61 and H121 against multiple mutations within RBD revealed a broad neutralizing activity against SARS-CoV-2 variants, which mitigated the risk of viral escape. Our findings defined the basis of therapeutic cocktails of F61 and H121 with broad neutralization and delivered a guideline for the current and future vaccine design, therapeutic antibody development, and antigen diagnosis of SARS-CoV-2 and its novel variants.

scholarly journals Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

2015 ◽  
Vol 112 (21) ◽  
pp. 6653-6658 ◽  
Author(s):  
Pavel Skums ◽  
Leonid Bunimovich ◽  
Yury Khudyakov
Keyword(s):  
Immune Escape ◽  
Complex Dynamics ◽  
Viral Evolution ◽  
Hcv Infection ◽  
Viral Population ◽  
Viral Adaptation ◽  
Chronic Hcv Infection ◽  
Potential Strategy ◽  
Chronic Hcv

Hepatitis C virus (HCV) has the propensity to cause chronic infection. Continuous immune escape has been proposed as a mechanism of intrahost viral evolution contributing to HCV persistence. Although the pronounced genetic diversity of intrahost HCV populations supports this hypothesis, recent observations of long-term persistence of individual HCV variants, negative selection increase, and complex dynamics of viral subpopulations during infection as well as broad cross-immunoreactivity (CR) among variants are inconsistent with the immune-escape hypothesis. Here, we present a mathematical model of intrahost viral population dynamics under the condition of a complex CR network (CRN) of viral variants and examine the contribution of CR to establishing persistent HCV infection. The model suggests a mechanism of viral adaptation by antigenic cooperation (AC), with immune responses against one variant protecting other variants. AC reduces the capacity of the host’s immune system to neutralize certain viral variants. CRN structure determines specific roles for each viral variant in host adaptation, with variants eliciting broad-CR antibodies facilitating persistence of other variants immunoreacting with these antibodies. The proposed mechanism is supported by empirical observations of intrahost HCV evolution. Interference with AC is a potential strategy for interruption and prevention of chronic HCV infection.

Heterogeneous Interactions of Leukemic and Control Bone Marrow Stroma Cells with an AML Cell Line and AML Leukemic Blasts.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1047-1047
Author(s):  
Ulrike Buttkereit ◽  
Sana Mohamad ◽  
Monika Lindemann ◽  
Joachim R. Goethert ◽  
Bertram Opalka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Line ◽  
Immune Escape ◽  
Conflicts Of Interest ◽  
Expression Patterns ◽  
Tumor Stroma ◽  
Malignant Cell ◽  
Cell Counting ◽  
Set Up

Abstract Abstract 1047 Tumor-stroma interaction plays a pivotal role for malignant cell survival, proliferation, immune escape, and drug resistance. We had previously shown that bone marrow (BM) stroma from leukemia patients had different gene expression patterns and support of normal CD34+ cells compared to controls (Ctr). Aim of this study was to evaluate growth, survival, and colony-forming potential issues of M-07e AML cells and AML blasts as indicator cells (IC) upon contact with non-leukemic and leukemic stroma. Plastic-adherent BM cells from leukemic or Ctr non-leukemic donors were cultured for several weeks. Polyclonal as well as isolated single fibroblast colony (F-CFU) cultures were set up. Short-term and long-term co-cultures of BM stroma used M-07e AML cells and AML blasts as IC. After long-term co-culture colony forming units (CFU) were determined in the adherent and non-adherent fraction of the IC. Proliferation of IC was determined by cell counting and 3H-TdR incorporation assays. The human HS-5 stroma cell line was used in selected experiments. The F-CFU frequency was determined from 39 Ctr samples, 6 MDS samples, 59 leukemic samples, and 12 lymphoma samples with BM infiltration. Succession of F-CFU numbers in respective samples was AML / MDS < Ctr < MM / FL II << 2°AML. Polyclonal stroma cells from AML BM supported M-07e IC survival slightly but not significantly better than Ctr stroma. No noteworthy support for primary AML blasts was observed with either stroma. Stroma from both AML and Ctr donors stimulated colony formation of M-07e IC without marked differences in the frequency of compact and diffuse colonies. In 3H-TdR assays M-07e IC were stimulated by IL-3 and certain but not all stroma samples tested. Notably, IL-3-induced proliferation of M-07e IC was decreased in the presence of stroma and almost completely suppressed by HS-5 cells. When single F-CFU were isolated, expanded, and tested for their capacity to support M-07e IC stimulating as well as non-stimulating F-CFU were found. Support competence of stroma cells decreased with passage number. Primary BM polyclonal stroma cells and single F-CFU from leukemic and non-leukemic donors showed a broad heterogeneity with respect to support of cell growth or colony-forming potential in favour of the AML M-07e IC line. Thus, the interaction of stroma and normal or leukemic hematopoietic cells seems to be a complex system awaiting further investigations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical Significance of Fusobacterium nucleatum Infection and Regulatory T Cell Enrichment in Esophageal Squamous Cell Carcinoma

2021 ◽  
Vol 27 ◽  
Author(s):  
Ning Zhang ◽  
Yiwen Liu ◽  
Hong Yang ◽  
Mengxia Liang ◽  
Xiaopeng Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Immune Escape ◽  
Clinical Stage ◽  
Fusobacterium Nucleatum ◽  
Malignant Progression ◽  
Pathogenic Microorganisms ◽  
Degree Of Differentiation ◽  
Favorable Conditions

A variety of pathogenic microorganisms promote tumor occurrence and development through long-term colonization in the body. Fusobacterium nucleatum (F. nucleatum) is abundant in precancerous esophageal lesions and is closely related to the malignant progression of esophageal squamous cell carcinoma (ESCC). The invasion of exogenous microorganisms can reshape the immune microenvironment, make the immune system incapacitated, and assist tumor cells in immune escape. A variety of pathogenic microorganisms induce the recruitment of regulatory T cell (Tregs) to allow tumor cells to escape immune surveillance and provide favorable conditions for their own long-term colonization. Tregs are one of the major obstacles to tumor immunotherapy and have a significant positive correlation with the occurrence and development of many kinds of tumors. Because F. nucleatum can instantly enter cells and colonize for a long time, we speculated that F. nucleatum infection could facilitate the immune escape of tumor cells through enrichment of Tregs and promote the malignant progression of ESCC. In this study, we found a significant concordance between F. nucleatum infection and Tregs infiltration. Therefore, we propose the view that chronic infection of F. nucleatum may provide favorable conditions for long-term colonization of itself by recruiting Tregs and suppressing the immune response. At the same time, the massive enrichment of Treg may also weaken the immune response and assist in the long-term colonization of F. nucleatum. We analyzed the correlation between F. nucleatum infection with the clinicopathological characteristics and survival prognosis of the patients. F. nucleatum infection was found to be closely related to sex, smoking, drinking, degree of differentiation, depth of invasion, lymph node metastasis, and clinical stage. The degree of differentiation, depth of infiltration, lymph node metastasis, clinical stage, and F. nucleatum infection are independent risk factors affecting ESCC prognosis. Additionally, the survival rate and median survival time were significantly shortened in the F. nucleatum infection positive group. Therefore, we propose that long-term smoking and alcohol consumption cause poor oral and esophageal environments, thereby significantly increasing the risk of F. nucleatum infection. In turn, F. nucleatum infection and colonization may weaken the antitumor immune response through Treg enrichment and further assist in self-colonization, promoting the malignant progression of ESCC.

scholarly journals A Third Dose of SARS-CoV-2 Vaccine Increases Neutralizing Antibodies Against Variants of Concern in Solid Organ Transplant Recipients

2021 ◽  
Author(s):  
Andrew H Karaba ◽  
Xianming Zhu ◽  
Tao Liang ◽  
Kristy H Wang ◽  
Alex G Rittenhouse ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Organ Transplant Recipients ◽  
Novel Variants ◽  
Antibody Titers ◽  
Solid Organ Transplant Recipients

Immunocompromised populations are at high risk for severe COVID-19. Vaccine-induced SARS-CoV-2 antibody responses are attenuated in solid organ transplant recipients (SOTRs), and breakthrough infections are more common. Additional SARS-CoV-2 vaccine doses may increase anti-spike antibody titers in some SOTRs, but whether this results in enhanced neutralizing capability, especially versus novel variants of concern (VOCs) that exhibit immune escape and higher infectivity (e.g., the Delta variant), is unclear. Here, we report that a third dose of a SARS-CoV-2 vaccine increases anti-SARS-CoV-2 spike and RBD IgG levels as well as plasma neutralizing capability versus VOCs, including Delta, in some SOTRs. However, anti-spike IgG and neutralizing capability remained significantly reduced compared to fully vaccinated healthy controls. These findings highlight the need for continued study of strategies to improve protection from COVID-19 in immunosuppressed populations as more SARS-CoV-2 VOCs emerge.

scholarly journals A novel biomimetic nanomedicine system with anti-inflammatory and anti-osteoporosis effects improves the therapy efficacy of steroid-resistant nephrotic syndrome

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jian Li ◽  
Mingyi Zhao ◽  
Xinying Xiang ◽  
Qingnan He ◽  
Rong Gui
Keyword(s):  
Nephrotic Syndrome ◽  
Glycyrrhizic Acid ◽  
Immune Escape ◽  
Platelet Membrane ◽  
Steroid Resistance ◽  
Inflammatory Factors ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Anti Inflammatory

AbstractClinically, steroid-resistant nephrotic syndrome (SRNS) is always prolonged and difficult to treat and easily develops into end-stage renal disease, resulting in a low survival rate. Strategies to reverse steroid resistance and reduce the long-term use of high doses of steroid medicines are urgently needed. In this study, a novel nanoparticle drug system (Pm-GCH) with a core–shell structure was designed. Metal–organic frameworks, synthesized by glycyrrhizic acid (G) and calcium ions (Ca2+) loaded with hydrocortisone (H) were the core of the nanoparticles. Platelet membrane vesicles were the shells. The natural platelet membrane endows Pm-GCH with good biocompatibility and the ability to promote immune escape. In addition, under the chemotaxis of inflammatory factors, platelet membranes assist Pm-GCH in nonspecific targeting of the inflammatory sites of the kidney. Under an inflammatory acid environment, GCH slowly degrades and releases glycyrrhizic acid and hydrocortisone. Glycyrrhizic acid inhibits the inactivation of hydrocortisone, jointly inhibits the activity of phospholipase A2 (PLA2) and the classic activation pathway of complement C2, blocks the production of inflammatory factors, plays an anti-inflammatory role, and enhances the efficacy of hydrocortisone in the treatment of SRNS. Moreover, glycyrrhizic acid alleviates osteoporosis induced by long-term use of glucocorticoids. These results indicate that Pm-GCH is a promising treatment strategy for SRNS. Graphical Abstract

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