scholarly journals A general solution to broad-spectrum vaccine design for rapidly mutating viruses

2020 ◽  
Author(s):  
Jacob Glanville ◽  
Sarah Ives ◽  
Jean-Philippe Bürckert ◽  
Christina Pettus ◽  
Karina Reyna Peñate ◽  
...  
Keyword(s):  
B Cells ◽  
General Solution ◽  
Broad Spectrum ◽  
Vaccine Design ◽  
Past Century ◽  
Coat Proteins ◽  
Vaccine Responses ◽  
Viral Coat ◽  
Pandemic Strains ◽  
Multiple Strains

Abstract Rapidly evolving pathogens pose a challenge to vaccine design, as their mutations render previous vaccine responses obsolete. For influenza, conserved epitopes on the viral coat proteins have been identified, but mysteriously they are missed by the antibodies elicited by most vaccine recipients [1, 2]. In simulated immunizations using 263 million antibody-hemagglutinin (HA) structural docking solutions, non-conserved epitopes were immunodominant when HAs were immunized at standard concentrations. However, by vaccinating with a pool of 30 diverse and dilute HA variants, B-cells that recognize broadly-conserved epitopes across HA receive up to 30-fold higher antigen dose, with concentration being linearly correlated to conservation on a per epitope basis. If individual variants are at concentrations below the minimum threshold of immune activation, then cross-reactive B-cells will be preferentially elicited. In pig immunizations, the approach induced a broad-spectrum antibody response against a panel of 36 strains from 1918-2014, including all pandemic strains from the past century and multiple strains not in the vaccine. In further swine studies with a vaccine containing HAs from 1918-2008, we observe broad-spectrum neutralizing responses against 6 future heterologous strains, including pandemic strains, spanning H1N1 2009-2017 and H3N2 2009-2014. Our results support a greater understanding of why non-conserved epitopes are immunodominant, as well as indicate a general solution to overcome this in broad-spectrum vaccine design.

scholarly journals Metabolic defects in splenic B cell compartments from patients with liver cirrhosis

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Man Huang ◽  
Xiaoju Liu ◽  
Haocheng Ye ◽  
Xin Zhao ◽  
Juanjuan Zhao ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
B Cells ◽  
B Cell ◽  
Memory B Cells ◽  
Rna Seq ◽  
Vaccine Responses ◽  
Cell Functions ◽  
Metabolic Defects ◽  
Cell Compartments ◽  
Cirrhotic Patients

Abstract Liver cirrhosis is associated with defective vaccine responses and increased infections. Dysregulated B cell compartments in cirrhotic patients have been noticed but not well characterized, especially in the spleen. Here, we comprehensively investigated B cell perturbations from the spleens and peripheral blood of cirrhotic patients. We found that liver cirrhosis significantly depleted both switched and nonswitched splenic memory B cells, which was further confirmed histologically. Bulk RNA-seq revealed significant metabolic defects as the potential mechanism for the impaired splenic B cell functions. Functionally, the splenic memory B cells from cirrhotic patients showed strong metabolic defects and reduced proliferation compared with those from healthy controls. Thus, liver cirrhosis extensively disturbs the splenic and peripheral B cell compartments, which may contribute to defective humoral immunity during liver cirrhosis.

scholarly journals Preexisting Immunity, More Than Aging, Influences Influenza Vaccine Responses

2015 ◽  
Vol 2 (2) ◽  
Author(s):  
Adrian J. Reber ◽  
Jin Hyang Kim ◽  
Renata Biber ◽  
H. Keipp Talbot ◽  
Laura A. Coleman ◽  
...  
Keyword(s):  
Older Adults ◽  
B Cells ◽  
Immune Responses ◽  
Influenza Vaccine ◽  
Hemagglutination Inhibition ◽  
Negative Impact ◽  
Memory B Cells ◽  
Vaccine Response ◽  
Vaccine Responses ◽  
Antibody Levels

Abstract Background.  Influenza disproportionately impacts older adults while current vaccines have reduced effectiveness in the older population. Methods.  We conducted a comprehensive evaluation of cellular and humoral immune responses of adults aged 50 years and older to the 2008–2009 seasonal trivalent inactivated influenza vaccine and assessed factors influencing vaccine response. Results.  Vaccination increased hemagglutination inhibition and neutralizing antibody; however, 66.3% of subjects did not reach hemagglutination inhibition titers ≥ 40 for H1N1, compared with 22.5% for H3N2. Increasing age had a minor negative impact on antibody responses, whereas prevaccination titers were the best predictors of postvaccination antibody levels. Preexisting memory B cells declined with age, especially for H3N2. However, older adults still demonstrated a significant increase in antigen-specific IgG+ and IgA+ memory B cells postvaccination. Despite reduced frequency of preexisting memory B cells associated with advanced age, fold-rise in memory B cell frequency in subjects 60+ was comparable to subjects age 50–59. Conclusions.  Older adults mounted statistically significant humoral and cell-mediated immune responses, but many failed to reach hemagglutination inhibition titers ≥40, especially for H1N1. Although age had a modest negative effect on vaccine responses, prevaccination titers were the best predictor of postvaccination antibody levels, irrespective of age.

A Broad Spectrum of Functional HIV-Specific Memory B Cells in the Blood of Infected Individuals With High CD4+ T-Cell Counts

2011 ◽  
Vol 57 (3) ◽  
pp. e56-e58 ◽  
Author(s):  
Kevin Kunz ◽  
Sven Reiche ◽  
Yamen Dwai ◽  
Christiane Cordes ◽  
Ivanka Krznaric ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Broad Spectrum ◽  
Memory B Cells ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
Specific Memory

Interaction of plant viruses and viral coat proteins with mixed model membranes

Biochemistry ◽  
1987 ◽  
Vol 26 (19) ◽  
pp. 6217-6223 ◽  
Author(s):  
Klaas P. Datema ◽  
Ruud B. Spruijt ◽  
Benedictus J. M. Verduin ◽  
Marcus A. Hemminga
Keyword(s):  
Mixed Model ◽  
Plant Viruses ◽  
Model Membranes ◽  
Coat Proteins ◽  
Viral Coat ◽  
Viral Coat Proteins

scholarly journals The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment

2010 ◽  
Vol 428 (3) ◽  
pp. 325-346 ◽  
Author(s):  
Toni M. Antalis ◽  
Marguerite S. Buzza ◽  
Kathryn M. Hodge ◽  
John D. Hooper ◽  
Sarah Netzel-Arnett
Keyword(s):  
Serine Protease ◽  
Serine Proteases ◽  
Catalytic Domain ◽  
Proteolytic Processing ◽  
Coat Proteins ◽  
Vital Functions ◽  
Human Pathology ◽  
Functional Consequences ◽  
Viral Coat ◽  
Precursor Molecules

The serine proteases of the trypsin-like (S1) family play critical roles in many key biological processes including digestion, blood coagulation, and immunity. Members of this family contain N- or C-terminal domains that serve to tether the serine protease catalytic domain directly to the plasma membrane. These membrane-anchored serine proteases are proving to be key components of the cell machinery for activation of precursor molecules in the pericellular microenvironment, playing vital functions in the maintenance of homoeostasis. Substrates activated by membrane-anchored serine proteases include peptide hormones, growth and differentiation factors, receptors, enzymes, adhesion molecules and viral coat proteins. In addition, new insights into our understanding of the physiological functions of these proteases and their involvement in human pathology have come from animal models and patient studies. The present review discusses emerging evidence for the diversity of this fascinating group of membrane serine proteases as potent modifiers of the pericellular microenvironment through proteolytic processing of diverse substrates. We also discuss the functional consequences of the activities of these proteases on mammalian physiology and disease.

scholarly journals NAD+-consuming enzymes in immune defense against viral infection

2021 ◽  
Vol 478 (23) ◽  
pp. 4071-4092
Author(s):  
Jialin Shang ◽  
Michael R. Smith ◽  
Ananya Anmangandla ◽  
Hening Lin
Keyword(s):  
Immune Responses ◽  
Broad Spectrum ◽  
Defense Mechanisms ◽  
Viral Infections ◽  
Antiviral Agents ◽  
Scientific Progress ◽  
Immune Defense ◽  
Past Century ◽  
Antiviral Immune Response ◽  
Antiviral Function

The COVID-19 pandemic reminds us that in spite of the scientific progress in the past century, there is a lack of general antiviral strategies. In analogy to broad-spectrum antibiotics as antibacterial agents, developing broad spectrum antiviral agents would buy us time for the development of vaccines and treatments for future viral infections. In addition to targeting viral factors, a possible strategy is to understand host immune defense mechanisms and develop methods to boost the antiviral immune response. Here we summarize the role of NAD+-consuming enzymes in the immune defense against viral infections, with the hope that a better understanding of this process could help to develop better antiviral therapeutics targeting these enzymes. These NAD+-consuming enzymes include PARPs, sirtuins, CD38, and SARM1. Among these, the antiviral function of PARPs is particularly important and will be a focus of this review. Interestingly, NAD+ biosynthetic enzymes are also implicated in immune responses. In addition, many viruses, including SARS-CoV-2 contain a macrodomain-containing protein (NSP3 in SARS-CoV-2), which serves to counteract the antiviral function of host PARPs. Therefore, NAD+ and NAD+-consuming enzymes play crucial roles in immune responses against viral infections and detailed mechanistic understandings in the future will likely facilitate the development of general antiviral strategies.

scholarly journals Front Cover: Template‐Free Self‐Assembly of Artificial De Novo Viral Coat Proteins into Nanorods: Effects of Sequence, Concentration, and Temperature (Chem. Eur. J. 47/2019)

2019 ◽  
Vol 25 (47) ◽  
pp. 10971-10971
Author(s):  
Ernesto Cazares Vargas ◽  
Martien A. Cohen Stuart ◽  
Renko de Vries ◽  
Armando Hernandez‐Garcia
Keyword(s):  
Self Assembly ◽  
De Novo ◽  
Coat Proteins ◽  
Front Cover ◽  
Viral Coat ◽  
Template Free ◽  
Viral Coat Proteins

Golgi processed foot-and-mouth disease virus proteins

1983 ◽  
Vol 41 ◽  
pp. 642-643
Author(s):  
S. H. Wool ◽  
J. Polatnick
Keyword(s):  
Guinea Pig ◽  
Rna Polymerase ◽  
Nonstructural Protein ◽  
Foot And Mouth Disease ◽  
Viral Rna ◽  
Coat Proteins ◽  
Mouth Disease Virus ◽  
Viral Coat ◽  
Membrane Bound

The Golgi apparatus was isolated from infected baby hamster kidney cells by centrifugation through discontinuous sucrose gradients. Tritium-labeled protein samples were analyzed by polyacrylamide gel electrophoretic autoradiograms. Pulse-chase studies showed that the viral-induced RNA polymerase passed through the Golgi as infection progressed. Some viral coat proteins were also associated with the Golgi as were other as yet unidentified viral proteins (Fig. 1). Immune labeling of isolated and in situ Golgi confirmed the presence of viral RNA polymerase. The isolated (Fig. 2) and in situ Golgi were labeled with guinea pig antipolymerase antibody and ferritin-labeled goat anti-guinea pig sera to show the presence of viral RNA polymerase.Earlier work in this laboratory established that the RNA polymerase was bound to membranes of newly formed smooth vacuoles during infection with FMDV. The smaller protein on the gel in Fig. 1 (arrow) corresponds in size to VPg (a nonstructural protein bound to the 5' end of viral RNA) has also been shown to be membrane bound.

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