scholarly journals Influenza Hemagglutinin and Neuraminidase: Yin–Yang Proteins Coevolving to Thwart Immunity

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 346 ◽  
Author(s):  
Ivan Kosik ◽  
Jonathan W. Yewdell
Keyword(s):  
Influenza A ◽  
Antigenic Variation ◽  
Innate Immune ◽  
Viral Fitness ◽  
Adaptive Immune ◽  
Influenza Hemagglutinin ◽  
Immune Pressure ◽  
Virion Release ◽  
Infectious Cycle

Influenza A virions possess two surface glycoproteins—the hemagglutinin (HA) and neuraminidase (NA)—which exert opposite functions. HA attaches virions to cells by binding to terminal sialic acid residues on glycoproteins/glycolipids to initiate the infectious cycle, while NA cleaves terminal sialic acids, releasing virions to complete the infectious cycle. Antibodies specific for HA or NA can protect experimental animals from IAV pathogenesis and drive antigenic variation in their target epitopes that impairs vaccine effectiveness in humans. Here, we review progress in understanding HA/NA co-evolution as each acquires epistatic mutations to restore viral fitness to mutants selected in the other protein by host innate or adaptive immune pressure. We also discuss recent exciting findings that antibodies to HA can function in vivo by blocking NA enzyme activity to prevent nascent virion release and enhance Fc receptor-based activation of innate immune cells.

scholarly journals TprK Sequence Diversity Accumulates during Infection of Rabbits with Treponema pallidum subsp. pallidum Nichols Strain

2006 ◽  
Vol 74 (3) ◽  
pp. 1896-1906 ◽  
Author(s):  
Rebecca E. LaFond ◽  
Arturo Centurion-Lara ◽  
Charmie Godornes ◽  
Wesley C. Van Voorhis ◽  
Sheila A. Lukehart
Keyword(s):  
Antigenic Variation ◽  
Treponema Pallidum ◽  
Adaptive Immune Response ◽  
Serial Passage ◽  
Sequence Diversity ◽  
Adaptive Immune ◽  
Immune Pressure ◽  
V Region ◽  
Slow Passage

ABSTRACT The tprK gene in Treponema pallidum undergoes antigenic variation. In all T. pallidum isolates examined to date, except the Nichols type strain, heterogeneous tprK sequences have been identified. This heterogeneity is localized to seven variable (V) regions, and tprK sequence diversity accumulates with serial passage in naïve rabbits. The T. pallidum Nichols genome described a single tprK sequence, and after decades of independent passage, only minor tprK sequence diversity is seen among the Nichols strains from different laboratories. We hypothesized that T. pallidum Nichols is capable of only limited tprK diversification. To address this hypothesis, we passaged the T. pallidum Nichols strain in naïve rabbits at the peak of infection (rapid passage) or after the adaptive immune response had cleared most organisms in vivo (slow passage). After 22 rapid passages (9- to 10-day intervals), no tprK V region sequence changes were observed. In contrast, after two slow passages (30- to 35-day intervals), three V regions had sequences that were completely different from that of the original inoculum. New sequences were observed in all seven V regions by the fifth slow passage. In contrast to the rapid-passaged Nichols strain, rapid-passaged Chicago C, a clonal strain isolated from the highly diverse parent Chicago strain, developed significant tprK diversification. These findings suggest that tprK variation can occur, but at a lower rate, in Nichols and that immune pressure may be required for accumulation of bacteria with diverse tprK sequences. Adaptation to growth in rabbits may explain the limited repertoire of V region sequences seen in the Nichols strain.

scholarly journals Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Christopher S. Anderson ◽  
Sandra Ortega ◽  
Francisco A. Chaves ◽  
Amelia M. Clark ◽  
Hongmei Yang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Fitness ◽  
Antigenic Drift ◽  
Virus Infections ◽  
Head Region ◽  
Immune Pressure ◽  
Stalk Domain ◽  
Ha Protein

Abstract The induction of antibodies specific for the influenza HA protein stalk domain is being pursued as a universal strategy against influenza virus infections. However, little work has been done looking at natural or induced antigenic variability in this domain and the effects on viral fitness. We analyzed human H1 HA head and stalk domain sequences and found substantial variability in both, although variability was highest in the head region. Furthermore, using human immune sera from pandemic A/California/04/2009 immune subjects and mAbs specific for the stalk domain, viruses were selected in vitro containing mutations in both domains that partially contributed to immune evasion. Recombinant viruses encoding amino acid changes in the HA stalk domain replicated well in vitro, and viruses incorporating two of the stalk mutations retained pathogenicity in vivo. These findings demonstrate that the HA protein stalk domain can undergo limited drift under immune pressure and the viruses can retain fitness and virulence in vivo, findings which are important to consider in the context of vaccination targeting this domain.

scholarly journals Differential Viral-Host Immune Interactions Associated with Oseltamivir-Resistant H275Y and Wild-Type H1N1 A(pdm09) Influenza Virus Pathogenicity

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 794
Author(s):  
Beatriz Vidaña ◽  
Pamela Martínez-Orellana ◽  
Jaime Martorell ◽  
Massimiliano Baratelli ◽  
Jorge Martínez ◽  
...  
Keyword(s):  
Influenza A ◽  
Clinical Signs ◽  
Viral Fitness ◽  
Type I ◽  
Lung Pathology ◽  
Wild Type ◽  
Viral Kinetics ◽  
Influenza A H1n1

Oseltamivir is a common therapy against influenza A virus (IAV) infections. The acquisition of oseltamivir resistance (OR) mutations, such as H275Y, hampers viral fitness. However, OR H1N1 viruses have demonstrated the ability to spread throughout different populations. The objective of this work was to compare the fitness of two strains of OR (R6 and R7) containing the H275Y mutation, and a wild-type (F) pandemic influenza A (H1N1) 2009 (pdm09) virus both in vitro and in vivo in mice and to select one OR strain for a comparison with F in ferrets. R6 showed faster replication and pathogenicity than R7 in vitro and in mice. Subsequently, R6 was selected for the fitness comparison with the F strain in ferrets. Ferrets infected with the F virus showed more severe clinical signs, histopathological lung lesions, and viral quantification when compared to OR R6-infected animals. More importantly, differential viral kinetics correlated with differential pro-inflammatory host immune responses in the lungs of infected ferrets, where OR-infected animals developed a protective higher expression of type I IFN and Retinoid acid Inducible Gene I (RIG-I) genes early after infection, resulting in the development of milder disease. These results suggest the presence of early specific viral-host immune interactions relevant in the development of influenza-associated lung pathology.

scholarly journals A modular approach toward producing nanotherapeutics targeting the innate immune system

2021 ◽  
Vol 7 (10) ◽  
pp. eabe7853
Author(s):  
Mandy M. T. van Leent ◽  
Anu E. Meerwaldt ◽  
Alexandre Berchouchi ◽  
Yohana C. Toner ◽  
Marianne E. Burnett ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Apolipoprotein A1 ◽  
Modular Approach ◽  
Allograft Survival ◽  
Adaptive Immune ◽  
Broad Variety

Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less explored. The intrinsic interactions between nanoparticles and phagocytic myeloid cells make these materials especially suited for engaging the innate immune system. However, developing nanotherapeutics is an elaborate process. Here, we demonstrate a modular approach that facilitates efficiently incorporating a broad variety of drugs in a nanobiologic platform. Using a microfluidic formulation strategy, we produced apolipoprotein A1–based nanobiologics with favorable innate immune system–engaging properties as evaluated by in vivo screening. Subsequently, rapamycin and three small-molecule inhibitors were derivatized with lipophilic promoieties, ensuring their seamless incorporation and efficient retention in nanobiologics. A short regimen of intravenously administered rapamycin-loaded nanobiologics (mTORi-NBs) significantly prolonged allograft survival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation.

scholarly journals Influenza H3 and H1 hemagglutinins have different genetic barriers for resistance to broadly neutralizing stem antibodies

2019 ◽  
Author(s):  
Nicholas C. Wu ◽  
Andrew J. Thompson ◽  
Juhye M. Lee ◽  
Wen Su ◽  
Britni M. Arlian ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Viral Fitness ◽  
Resistance Mutations ◽  
Genetic Barrier ◽  
Influenza Hemagglutinin ◽  
Genetic Barriers ◽  
Universal Influenza Vaccine

ABSTRACTIn the past decade, the discovery and characterization of broadly neutralizing antibodies (bnAbs) to the highly conserved stem region of influenza hemagglutinin (HA) have provided valuable insights for development of a universal influenza vaccine. However, the genetic barrier for resistance to stem bnAbs has not been thoroughly evaluated. Here, we performed a series of deep mutational scanning experiments to probe for resistance mutations. We found that the genetic barrier to resistance to stem bnAbs is generally very low for the H3 subtype but substantially higher for the H1 subtype. Several resistance mutations in H3 cannot be neutralized by stem bnAbs at the highest concentration tested, do not reduce in vitro viral fitness and in vivo pathogenicity, and are often present in circulating strains as minor variants. Thus, H3 HAs have a higher propensity than H1 HAs to escape major stem bnAbs and creates a potential challenge in the development of a bona fide universal influenza vaccine.ONE SENTENCE SUMMARYAcquisition of resistance by influenza virus to broadly neutralizing hemagglutinin stem antibodies varies tremendously depending on subtype.

Hepcidin regulation by innate immune and infectious stimuli

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4129-4139 ◽  
Author(s):  
Andrew E. Armitage ◽  
Lucy A. Eddowes ◽  
Uzi Gileadi ◽  
Suzanne Cole ◽  
Natasha Spottiswoode ◽  
...  
Keyword(s):  
Influenza A ◽  
Acute Infection ◽  
Transferrin Saturation ◽  
Hepatoma Cells ◽  
Innate Immune ◽  
Dependent Manner ◽  
Human Hepatoma Cells ◽  
Hepcidin Expression

Abstract Hepcidin controls the levels and distribution of iron, an element whose availability can influence the outcome of infections. We investigated hepcidin regulation by infection-associated cytokines, pathogen-derived molecules, and whole pathogens in vitro and in vivo. We found that IL-22, an effector cytokine implicated in responses to extracellular infections, caused IL-6–independent hepcidin up-regulation in human hepatoma cells, suggesting it might represent an additional inflammatory hepcidin agonist. Like IL-6, IL-22 caused phosphorylation of STAT3 and synergized with BMP6 potentiating hepcidin induction. In human leukocytes, IL-6 caused potent, transient hepcidin up-regulation that was augmented by TGF-β1. Pathogen-derived TLR agonists also stimulated hepcidin, most notably the TLR5 agonist flagellin in an IL-6–dependent manner. In contrast, leukocyte hepcidin induction by heat-killed Candida albicans hyphae was IL-6–independent, but partially TGF-β–dependent. In a murine acute systemic candidiasis model, C albicans strongly stimulated hepcidin, accompanied by a major reduction in transferrin saturation. Similarly, hepcidin was up-regulated with concomitant lowering of serum iron during acute murine Influenza A/PR/8/34 virus (H1N1) infection. This intracellular pathogen also stimulated hepcidin expression in leukocytes and hepatoma cells. Together, these results indicate that hepcidin induction represents a component of the innate immune response to acute infection, with the potential to affect disease pathogenesis.

scholarly journals Different genetic barriers for resistance to HA stem antibodies in influenza H3 and H1 viruses

Science ◽  
2020 ◽  
Vol 368 (6497) ◽  
pp. 1335-1340 ◽  
Author(s):  
Nicholas C. Wu ◽  
Andrew J. Thompson ◽  
Juhye M. Lee ◽  
Wen Su ◽  
Britni M. Arlian ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Viral Fitness ◽  
Resistance Mutations ◽  
Genetic Barrier ◽  
Influenza Hemagglutinin ◽  
Genetic Barriers ◽  
Universal Influenza Vaccine

The discovery and characterization of broadly neutralizing human antibodies (bnAbs) to the highly conserved stem region of influenza hemagglutinin (HA) have contributed to considerations of a universal influenza vaccine. However, the potential for resistance to stem bnAbs also needs to be more thoroughly evaluated. Using deep mutational scanning, with a focus on epitope residues, we found that the genetic barrier to resistance to stem bnAbs is low for the H3 subtype but substantially higher for the H1 subtype owing to structural differences in the HA stem. Several strong resistance mutations in H3 can be observed in naturally circulating strains and do not reduce in vitro viral fitness and in vivo pathogenicity. This study highlights a potential challenge for development of a truly universal influenza vaccine.

scholarly journals The Micro-Immunotherapy Medicine 2LEID Exhibits an Immunostimulant Effect by Boosting Both Innate and Adaptive Immune Responses

2021 ◽  
Vol 23 (1) ◽  
pp. 110
Author(s):  
Camille Jacques ◽  
Mathias Chatelais ◽  
Karim Fekir ◽  
Louis Fauconnier ◽  
Manon Mellier ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Immune System ◽  
Influenza A ◽  
Respiratory Infections ◽  
Umbilical Vein ◽  
Antigen Specificity ◽  
Activation Markers ◽  
Adaptive Immune

This study aimed at evaluating the effects of the micro-immunotherapy medicine (MIM) 2LEID, both in vitro and in vivo, on several components of the innate and adaptive immune system. MIM increased the phagocytic activity of macrophages, and it augmented the expression of the activation markers CD69 and HLA-DR in NK cells and monocytes/macrophages, respectively. The effect of MIM was evaluated in a model of respiratory infection induced by influenza A virus administration to immunocompetent mice in which it was able to improve neutrophil recruitment within the lungs (p = 0.1051) and slightly increased the circulating levels of IgM (p = 0.1655). Furthermore, MIM stimulated the proliferation of CD3-primed T lymphocytes and decreased the secretion of the immunosuppressive cytokine IL-10 in CD14+-derived macrophages. Human umbilical vein endothelial cells were finally used to explore the effect of MIM on endothelial cells, in which it slightly increased the expression of immune-related markers such as HLA-I, CD137L, GITRL, PD-L1 and ICAM-1. In conclusion, the present study suggests that MIM might be a promising nonspecific (without antigen specificity) immunostimulant drug in preventing and early treating respiratory infections, but not only exclusively, as it would gently support several facets of the immune system and host defenses.

scholarly journals Quantifying memory CD8 T cell-mediated immune pressure on influenza A virus infection in vivo

2020 ◽  
Author(s):  
Zheng-Rong Tiger Li ◽  
Veronika I. Zarnitsyna ◽  
Anice C. Lowen ◽  
Rustom Antia ◽  
Jacob E. Kohlmeier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Selection Pressure ◽  
Influenza A ◽  
Cd8 T Cell ◽  
T Cell Epitopes ◽  
Memory Cd8 T Cells ◽  
Immune Pressure

AbstractThe conservation of T cell epitopes in human influenza A virus has prompted the development of T cell-inducing influenza vaccines. However, the selection pressure mediated by memory CD8 T cells upon influenza virus has not been directly measured. Using a droplet digital PCR technique to distinguish wild-type and an epitope-mutant PR8 influenza viruses in vivo, this study quantifies the viral replicative fitness of a CD8 T cell-escaping mutation in the immunodominant influenza NP366-374 epitope in C57BL/6 (B6) mice under different settings of cellular immunity. Although this mutation does not result in a viral fitness defect in vitro or during the early stages of in vivo infection in naïve B6 mice, it does confer a moderate but consistent advantage to the mutant virus following heterosubtypic challenge of HKx31-immunized mice. In addition, this advantage was maintained under increased MHC diversity but became more substantial when the breadth of epitope recognition is limited. Finally, we showed that lung-resident, but not circulating, memory CD8 T cells are the primary source of cellular immune pressure early during infection, prior to the induction of a secondary effector T cell response. Integrating the data with an established modeling framework, we show that the relatively modest immune pressure mediated by memory CD8 T cells is one of the important factors responsible for the conservation of CD8 T cell epitopes in influenza A viruses that circulate among humans. Thus, a T cell-inducing vaccine that generates lung-resident memory CD8 T cells covering a sufficient breadth of epitopes may transiently protect against severe pathology without driving the virus to rapidly evolve and escape.Author SummarySince the historic Spanish flu in 1918, influenza has caused several pandemics and become an important public health concern. The inactivated vaccines routinely used attempt to boost antibodies, which may not be as effective when antigenic mismatch happens and could drive the virus to evolve and escape due to their high immune pressure. In contrast, the ability of influenza-specific T cells to reduce pathology and the conservation of T-cell epitopes across subtypes have shed light on the development of universal vaccines. In this study, we assessed the CD8 T cell-mediated selection pressure on influenza virus in mouse using a digital PCR technique. Within mice that have influenza-specific systemic and lung-resident memory CD8 T cells established, we found the advantage conferred by an escaping mutation in one of the immunodominant epitopes is around 25%. This advantage becomes much greater when the cellular immunity focuses on the focal epitope, while it is delayed when only systemic cellular immunity is established. Combining the data with our previous modeling work, we conclude that the small selection pressure imposed by CD8 T cells can explain the overall conservation of CD8 T cell epitopes of influenza A virus in addition to functional constraint.

scholarly journals Incomplete influenza A virus genomes are abundant but readily complemented during spatially structured viral spread

2019 ◽  
Author(s):  
Nathan T. Jacobs ◽  
Nina O. Onuoha ◽  
Alice Antia ◽  
Rustom Antia ◽  
John Steel ◽  
...  
Keyword(s):  
Influenza A ◽  
Mutant Virus ◽  
Viral Fitness ◽  
H3n2 Virus ◽  
Multiple Infection ◽  
Mixed System ◽  
Viral Genomes ◽  
Viral Spread ◽  
A Cell

AbstractViral genomes comprising multiple distinct RNA segments can undergo genetic exchange through reassortment, a process that facilitates viral evolution and can have major epidemiological consequences. Segmentation also allows the replication of incomplete viral genomes (IVGs), however, and evidence suggests that IVGs occur frequently for influenza A viruses. Here we quantified the frequency of IVGs using a novel single cell assay and then examined their implications for viral fitness. We found that each segment of influenza A/Panama/2007/99 (H3N2) virus has only a 58% probability of being present in a cell infected with a single virion. These observed frequencies accurately account for the abundant reassortment seen in co-infection, and suggest that an average of 3.7 particles are required for replication of a full viral genome in a cell. This dependence on multiple infection is predicted to decrease infectivity and to slow viral propagation in a well-mixed system. Importantly, however, modeling of spatially structured viral growth predicted that the need for complementation is met more readily when secondary spread occurs locally. This expectation was supported by experimental infections in which the level spatial structure was manipulated. Furthermore, a virus engineered to be entirely dependent on co-infection to replicate in vivo was found to grow robustly in guinea pigs, suggesting that coinfection is sufficiently common in vivo to support propagation of IVGs. The infectivity of this mutant virus was, however, reduced 815-fold relative wild-type and the mutant virus did not transmit to contacts. Thus, while incomplete genomes augment reassortment and contribute to within-host spread, the existence of rare complete IAV genomes may be critical for transmission to new hosts.

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