Antigenic drift refers to the evolutionary accumulation of amino acid substitutions in viral proteins selected by host adaptive immune systems as the virus circulates in a population. Antigenic drift ...can substantially limit the duration of immunity conferred by infection and vaccination. Here, I explain the factors contributing to the rapid antigenic drift of the SARS-CoV-2 spike protein and receptor proteins of other viruses and discuss the implications for SARS-CoV-2 evolution and immunity.
Antigenic drift refers to the evolutionary accumulation of amino acid substitutions in viral proteins selected by host adaptive immune systems as the virus circulates in a population. Antigenic drift can substantially limit the duration of immunity conferred by infection and vaccination. Here, I explain the factors contributing to the rapid antigenic drift of the SARS-CoV-2 spike protein and receptor proteins of other viruses and discuss the implications for SARS-CoV-2 evolution and immunity.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." Antiviral antibodies are present at relatively high concentrations in ...blood and lymph, where they can function directly by neutralizing viral infectivity and indirectly via Fc-mediated viral clearance by phagocytic cells and natural killer (NK) cell killing. ...the immune system may have evolved to permit viral mucosal infections. If mucosal infection was a significant threat to host reproduction, wouldn’t innate antiviral mechanisms (e.g., type I interferon (IFN)-stimulated genes) be employed constitutively in mucosae rather than conditionally?
In the 35 years since the revelation that short peptides bound to major histocompatibility complex class I and II molecules are the secret of the major histocompatibility complex–restricted nature of ...T-cell recognition, there has been enormous progress in characterizing the immunopeptidome, the repertoire of peptide presented for immunosurveillance. Here, the major milestones in the journey are marked, the contribution of proteasome-mediated splicing to the immunopeptidome is discussed, and exciting recent findings relating the immunopeptidome to the translatome revealed by ribosome profiling (RiboSeq) is detailed. Finally, what is needed for continued progress is opined about, which includes the infusion of talented young scientists into the antigen-processing field, currently undergoing a renaissance; thanks in part to the astounding success of T-cell–based cancer immunotherapy.
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•Concise history of the discoveries leading to the molecular explanation for the phenomenon of the MHC class I–restricted nature of T-cell recognition.•Historical review of how MS became a critical technique for defining MHC class I–associated peptides and understanding how peptides are generated from proteins biosynthesized by the antigen-presenting cell.•Critical review of recent findings linking the translatome to the MHC class I immunopeptidome and the controversy regarding contribution of proteasome-mediated peptide splicing to the immunopeptidome.•Speculative discussion of the future contributions of MS to understanding the generation of the MHC class I immunopeptidome.
A pioneer in studying CD8+ T-cell immunosurveillance of viruses and tumors reviews the critical contributions of MS-based studies to early, current, and future understanding of how cells generate the MHC class I immunopeptidome: the repertoire of foreign and self-peptides presented by MHC class I molecules for T-cell recognition.
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.
The remarkable success of immune checkpoint inhibitors demonstrates the potential of tumour-specific CD8
T cells to prevent and treat cancer. Although the number of lives saved by immunotherapy ...mounts, only a relatively small fraction of patients are cured. Here, we review two of the factors that limit the application of CD8
T cell immunotherapies: difficulties in identifying tumour-specific peptides presented by MHC class I molecules and the ability of tumour cells to impair antigen presentation as they evolve under T cell selection. We describe recent advances in understanding how peptides are generated from non-canonical translation of defective ribosomal products, relate this to the dysregulated translation that is a feature of carcinogenesis and propose dysregulated translation as an important new source of tumour-specific peptides. We discuss how the synthesis and function of components of the antigen-processing and presentation pathway, including the recently described immunoribosome, are manipulated by tumours for immunoevasion and point to common druggable targets that may enhance immunotherapy.
A major obstacle to vaccination against antigenically variable viruses is skewing of antibody responses to variable immunodominant epitopes. For influenza virus hemagglutinin (HA), the ...immunodominance of the variable head impairs responses to the highly conserved stem. Here, we show that head immunodominance depends on the physical attachment of head to stem. Stem immunogenicity is enhanced by immunizing with stem-only constructs or by increasing local HA concentration in the draining lymph node. Surprisingly, coimmunization of full-length HA and stem alters stem-antibody class switching. Our findings delineate strategies for overcoming immunodominance, with important implications for human vaccination.
Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major ...factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals.
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•Wild mice from Maryland are close relatives to standard laboratory mouse strains•Gut microbiota of wild mice and laboratory mice differ significantly•Wild mouse gut microbiota can be banked and maintained in a laboratory mouse colony•Natural gut microbiota improves outcome in viral infection and tumorigenesis models
Characterization of a wild mice reference microbiome opens a window of opportunity to understand how the gut microbiota affects aspects of host physiology that are important in the natural world outside the laboratory.
Adaptive immune responses against antigenically variable viruses and cellular pathogens are efficient in many cases, but largely limited to the infecting or immunizing strain. A major factor that ...limits immunity is immunodominance (ID), the hierarchical focusing of adaptive immune responses on a subset of antigenic determinants. While CD8+ T cell ID has been extensively studied, studies of basic mechanisms of B cell ID are limited, despite the importance of antibodies (Abs) for durable protection against pathogens. Here, we review recent progress in understanding the basic rules and mechanisms of B cell ID, compare B and CD8+ T cell ID, and outline challenges to overcoming ID to develop Ab-based ‘universal’ vaccines for influenza A and other highly variable viruses.
ID, a central feature of adaptive immunity, is poorly understood for B cells.
The focus of Ab responses on immunodominant antigenic sites drives the selection of viral escape mutants, undermining vaccination for influenza and other highly variable viruses.
Similar immunogen- and immune system-dependent factors contribute to B and T cell ID.
Understanding the bases of ID is key to manipulating the immune response and targeting vaccines to conserved, cross-reactive antigenic sites.
Defective ribosomal products (DRiPs) are a subset of rapidly degraded polypeptides that provide peptide ligands for major histocompatibility complex (MHC) class I molecules. Here, recent progress in ...understanding DRiP biogenesis is reviewed. These findings place DRiPs at the center of the MHC class I antigen processing pathway, linking immunosurveillance of viruses and tumors to mechanisms of specialized translation and cellular compartmentalization. DRiPs enable the immune system to rapidly detect alterations in cellular gene expression with great sensitivity.
CD8+ T cells play a critical role in limiting peripheral virus replication, yet how they locate virus-infected cells within tissues is unknown. Here, we have examined the environmental signals that ...CD8+ T cells use to localize and eliminate virus-infected skin cells. Epicutaneous vaccinia virus (VV) infection, mimicking human smallpox vaccination, greatly increased expression of the CXCR3 chemokine receptor ligands CXCL9 and CXCL10 in VV-infected skin. Despite normal T cell numbers in the skin, Cxcr3−/− mice exhibited dramatically impaired CD8+-T-cell-dependent virus clearance. Intravital microscopy revealed that Cxcr3−/− T cells were markedly deficient in locating, engaging, and killing virus-infected cells. Further, transfer of wild-type CD8+ T cells restored viral clearance in Cxcr3−/− animals. These findings demonstrate a function for CXCR3 in enhancing the ability of tissue-localized CD8+ T cells to locate virus-infected cells and thereby exert anti-viral effector functions.
•CXCR3 ligands are upregulated in VV-infected skin•Cxcr3−/− mice have normal T cell numbers in infected skin but enhanced infection•Cxcr3−/− T cells are defective in locating virus-infected cells for killing in situ•Transfer of wild-type CD8+ T cells restores viral control in Cxcr3−/− animals
The factors that guide antiviral cytotoxic T cells migrating within tissues to their virus-infected targets are unclear. Hickman and colleagues show that CXCR3 expression on CD8+ T cells enhances their ability to locate infected cells in the skin and thus maximizes viral clearance.
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