scholarly journals The size of the immune repertoire of bacteria

2019 ◽  
Author(s):  
Serena Bradde ◽  
Armita Nourmohammad ◽  
Sidhartha Goyal ◽  
Vijay Balasubramanian
Keyword(s):  
Immune System ◽  
Adaptive Immunity ◽  
Adaptive Immune System ◽  
Optimal Size ◽  
Immune Repertoire ◽  
Viral Dna ◽  
Trade Off ◽  
Adaptive Immune ◽  
Dna Elements ◽  
Large Genomes

Some bacteria and archaea possess an immune system, based on the CRISPR-Cas mechanism, that confers adaptive immunity against phage. In such species, individual bacteria maintain a “cassette” of viral DNA elements called spacers as a memory of past infections. The typical cassette contains a few dozen spacers. Given that bacteria can have very large genomes, and since having more spacers should confer a better memory, it is puzzling that so little genetic space would be devoted by bacteria to their adaptive immune system. Here, we identify a fundamental trade-off between the size of the bacterial immune repertoire and effectiveness of response to a given threat, and show how this tradeoff imposes a limit on the optimal size of the CRISPR cassette.

scholarly journals The size of the immune repertoire of bacteria

2020 ◽  
Vol 117 (10) ◽  
pp. 5144-5151 ◽  
Author(s):  
Serena Bradde ◽  
Armita Nourmohammad ◽  
Sidhartha Goyal ◽  
Vijay Balasubramanian
Keyword(s):  
Immune Memory ◽  
Long Term Memory ◽  
Optimal Size ◽  
Immune Repertoire ◽  
Viral Dna ◽  
Term Memory ◽  
Adaptive Immune ◽  
Dna Elements ◽  
Adaptive Immune Systems

Some bacteria and archaea possess an immune system, based on the CRISPR-Cas mechanism, that confers adaptive immunity against viruses. In such species, individual prokaryotes maintain cassettes of viral DNA elements called spacers as a memory of past infections. Typically, the cassettes contain several dozen expressed spacers. Given that bacteria can have very large genomes and since having more spacers should confer a better memory, it is puzzling that so little genetic space would be devoted by prokaryotes to their adaptive immune systems. Here, assuming that CRISPR functions as a long-term memory-based defense against a diverse landscape of viral species, we identify a fundamental tradeoff between the amount of immune memory and effectiveness of response to a given threat. This tradeoff implies an optimal size for the prokaryotic immune repertoire in the observational range.

scholarly journals Snippets of virus integrated into human genome suggests possibility of CRISPR-like adaptive immune system in human cells

2019 ◽  
Author(s):  
Wenfa Ng
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Human Genome ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Human Cells ◽  
Rna Seq ◽  
Viral Dna ◽  
Adaptive Immune ◽  
Foreign Dna

Snippets of virus that infect humans have been shown to be incorporated into the human genome. Could such virus snippets provide a form of adaptive immunity similar to that offered by CRISPR to bacterial cells? To answer the question, RNA-seq could be used to provide a broad view of the RNA transcribed from DNA in the genome. Using known genome sequence of viruses that infect humans as template, reads obtained from RNA-seq would be profiled for virus snippets integrated into human genome and subsequently transcribed as part of an adaptive immune system. Subsequently, viruses corresponding to the virus snippets in human genome would be used to infect human cell lines to obtain direct evidence of how virus snippets mediate an adaptive immune response at the cellular level. Specifically, successful defence of the cell by virus snippets triggering an adaptive immune response would manifest as viable cells compared to lysed cells unable to mount an immune response. Following demonstration of cell viability under viral challenge, in vitro biochemical assays using cell lysate would interrogate the specific proteins and enzymes that mediate possible cutting of the foreign DNA or RNA. To this end, beads immobilized with virus snippets would serve as bait for binding to complementary viral DNA or RNA as well as potential endogenous endonuclease protein. Following precipitation and recovery of beads, possible endonuclease that bind to both viral DNA or RNA and virus snippets immobilized on beads would be isolated through gel electrophoresis and subsequently purified. Purified endonuclease would be assayed for activity against a variety of nucleic acids (both DNA and RNA) from various sources with and without added virus snippets. This provides important information on substrate range and specificity of the potential endonuclease. Amino acid sequencing of the purified endonuclease would help downstream bioinformatic search for candidate protein in the human genome. Finally, cryo-electron microscopy could help determine the structure of the endonuclease in complex with viral nucleic acids and virus snippets. Such structural information would provide more insights into mechanistic details describing the binding and cleavage of viral DNA or RNA in a CRISPR-like adaptive immune response in human cells. Overall, tantalizing clues have emerged that a CRISPR-like adaptive immune response may exist in human cells for defending against viral attack. Combination of cell biological, biochemical and structural tools could lend insights into the potential endonuclease that mediate double strand break of foreign DNA or RNA using virus snippets transcribed from the human genome as guide RNA. If demonstrated to be true for a variety of human viruses across different cell lines, the newly discovered viral defence mechanism in human cells hold important implications for understanding the adoption and evolution of CRISPR in eukaryotic cells.

scholarly journals Augmenting adaptive immunity: progress and challenges in the quantitative engineering and analysis of adaptive immune receptor repertoires

2019 ◽  
Vol 4 (4) ◽  
pp. 701-736 ◽  
Author(s):  
Alex J. Brown ◽  
Igor Snapkov ◽  
Rahmad Akbar ◽  
Milena Pavlović ◽  
Enkelejda Miho ◽  
...  
Keyword(s):  
Immune System ◽  
Adaptive Immunity ◽  
Adaptive Immune System ◽  
Immune Receptor ◽  
Adaptive Immune

The adaptive immune system is a natural diagnostic sensor and therapeutic.

Reduction Of Immune Repertoire Diversity Through DNA Sequence Constraints At VDJ Junctions

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4944-4944
Author(s):  
Bryan Howie ◽  
Harlan Robins ◽  
Christopher S Carlson
Keyword(s):  
Immune System ◽  
T Cell ◽  
T Cell Receptor ◽  
Adaptive Immune System ◽  
Cell Receptor ◽  
Immune Repertoire ◽  
Adaptive Immune ◽  
Repertoire Diversity ◽  
Equity Ownership ◽  
Junctional Diversity

Abstract B and T lymphocytes are effector cells of the adaptive immune system. These cells express surface receptors that bind a huge variety of antigens, and together they comprise a person’s immune repertoire. A diverse repertoire is essential for mounting robust immune responses against a wide range of pathogens, and repertoire diversity affects the probability that DNA sequencing can uniquely tag a clonally expanded population of cells for the detection of minimum residual disease (MRD) during cancer treatment. Immune repertoire diversity arises partly through the combinatorial splicing of gene segments from the variable (V), diversity (D), and joining (J) regions of a B or T cell receptor locus. Much additional diversity is created through the stochastic insertion and deletion of nucleotides at the splice junctions, and by somatic hypermutation (SHM) in maturing lymphocytes. The generation of junctional diversity is an important part of this process, but it may be constrained by the underlying biological mechanisms. To explore the landscape of junctional diversity among immune receptor loci, we developed a likelihood model that can annotate VDJ junctions in the presence of SHM and compute the probability that a given receptor sequence was generated only once in a person’s repertoire, which is essential for tracking MRD. Using high-throughput sequencing data from several individuals and a range of receptor loci, we identify mechanistic constraints that limit B and T cell receptor diversity. For example, we show that the usual variability in CDR3 length is reduced at the immunoglobulin kappa (IgK) locus, and we connect this finding to sequence motifs that constrain nucleotide deletion at the ends of IgK gene segments. Our findings will inform future genetic studies of the adaptive immune system, and they provide quantitative guidance for deciding which cancer clones can be tracked for reliable MRD detection. Disclosures: Howie: Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Carlson:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties.

3. Adaptive immunity: a voyage of (non-)self-discovery

2017 ◽  
pp. 30-41
Author(s):  
Paul Klenerman
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Lymphocytes ◽  
Adaptive Immunity ◽  
Single Unit ◽  
Adaptive Immune System ◽  
Adaptive Immune ◽  
System A ◽  
Self Discovery ◽  
B And T Lymphocytes

How does the immune system respond to such diverse threats, including viruses never encountered previously by us as a species? The inherent diversity in the immune system can be explained by examining how the adaptive immune system is built, in particular the receptors on B and T lymphocytes. ‘The adaptive immune system: a voyage of (non-)self-discovery’ describes B and T cells, receptors, and the creation of antibodies. Antibody genes are not created as a single unit but are made up from smaller parts, generating many more possible combinations. The antibodies that are created from the genetic template are further honed, becoming highly specific to their target.

scholarly journals Understanding Early-Life Adaptive Immunity to Guide Interventions for Pediatric Health

2021 ◽  
Vol 11 ◽  
Author(s):  
Eleanor C. Semmes ◽  
Jui-Lin Chen ◽  
Ria Goswami ◽  
Trevor D. Burt ◽  
Sallie R. Permar ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
B Cell ◽  
Adaptive Immunity ◽  
Early Life ◽  
Adaptive Immune System ◽  
Vaccine Adjuvants ◽  
Adaptive Immune Responses ◽  
Pediatric Health ◽  
Adaptive Immune

Infants are capable of mounting adaptive immune responses, but their ability to develop long-lasting immunity is limited. Understanding the particularities of the neonatal adaptive immune system is therefore critical to guide the design of immune-based interventions, including vaccines, in early life. In this review, we present a thorough summary of T cell, B cell, and humoral immunity in early life and discuss infant adaptive immune responses to pathogens and vaccines. We focus on the differences between T and B cell responses in early life and adulthood, which hinder the generation of long-lasting adaptive immune responses in infancy. We discuss how knowledge of early life adaptive immunity can be applied when developing vaccine strategies for this unique period of immune development. In particular, we emphasize the use of novel vaccine adjuvants and optimization of infant vaccine schedules. We also propose integrating maternal and infant immunization strategies to ensure optimal neonatal protection through passive maternal antibody transfer while avoiding hindering infant vaccine responses. Our review highlights that the infant adaptive immune system is functionally distinct and uniquely regulated compared to later life and that these particularities should be considered when designing interventions to promote pediatric health.

scholarly journals The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

2016 ◽  
Vol 113 (9) ◽  
pp. E1316-E1325 ◽  
Author(s):  
Samuel E. Marsh ◽  
Edsel M. Abud ◽  
Anita Lakatos ◽  
Alborz Karimzadeh ◽  
Stephen T. Yeung ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
B Cells ◽  
Adaptive Immunity ◽  
Immune Cell ◽  
Adaptive Immune System ◽  
Phagocytic Capacity ◽  
Adaptive Immune ◽  
5Xfad Mice

The innate immune system is strongly implicated in the pathogenesis of Alzheimer’s disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting “Rag-5xfAD” mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive–innate immunity cross talk and accelerated disease progression.

scholarly journals Merits of constant expression of CRISPR loci in adaptive immunity of bacteria

2019 ◽  
Author(s):  
Wenfa Ng
Keyword(s):  
Immune System ◽  
Adaptive Immunity ◽  
Adaptive Immune System ◽  
Energetic Cost ◽  
Sequence Information ◽  
Molecular Memory ◽  
Base Pairing ◽  
Evolutionary Forces ◽  
Adaptive Immune ◽  
Phage Dna

Bacteria fend off attack of bacteriophage through a variety of systems such as restriction-modification as well as clustered regularly interspersed short palindromic repeats (CRISPR). CRISPR is an adaptive immune system that provides a molecular memory of past attacks of bacteriophages on the bacterial strain in a vertically inheritable fashion. More importantly, such molecular memory of past phage infection is utilized in guiding a precision attack on the nucleic acids of invading bacteriophages. To do this, snippets of DNA from invading phages that have been neutralized are inserted into CRISPR-loci in the bacterial genome. Transcription of the CRISPR loci provides active RNA variants of the DNA snippets from phages useful for guiding the Cas9 endonuclease to invading phage DNA through complementary base pairing defined by a spacer region. While the system provides real-time surveillance of the bacterial cytoplasm for phage DNA resembling those from past infections, energetic cost of constantly transcribing the CRISPR loci might be high. Specifically, as currently understood, the CRISPR system would express phage DNA snippets catalogued in the CRISPR loci irrespective of environmental and nutritional conditions to help fend off possible infections by the same phages. However, phages responsible for past infections may not be present in the vicinity of the bacterial cell’s environment, which meant that expression of the CRISPR loci might be a waste of cellular energy and resources without any gain in fitness advantage to the bacterial cell compared to those from another species in the same environment. Hence, the evolutionary forces that shape the retention of the extant form of CRISPR remains to be understood in the context of how cellular energetics of adaptive immunity connects with bacterial fitness. Theoretically, a better system would involve the selective expression of specific CRISPR loci targeting the DNA or RNA of particular bacteriophage invading the cell. Such a system would incur less energy and resources to maintain, but would require another layer of intracellular surveillance able to identify the type and species of invading bacteriophage. Doing so would return us to the same problem as a molecular surveillance system requires key elements of recognition and actuation where recognition requires a molecular template of sequence information characteristic of particular bacteriophage. Given that DNA is a more stable format for storing sequence information compared to RNA, and that complementary base pairing as recognition mechanism require single stranded nucleic acid, current incarnation of CRISPR loci might be close to optimal in device architecture and functional logic. Hence, could we do better in redesigning bacterial adaptive immune system able to recognize a diversity of phages involved in past infection of a species or strain at reduced energetic and material cost?

scholarly journals Periphery and brain, innate and adaptive immunity in Parkinson’s disease

2021 ◽  
Vol 141 (4) ◽  
pp. 527-545 ◽  
Author(s):  
Ashley S. Harms ◽  
Sara A. Ferreira ◽  
Marina Romero-Ramos
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Immune System ◽  
Adaptive Immunity ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Adaptive Immune System ◽  
Alpha Synuclein ◽  
Adaptive Immune

AbstractParkinson’s disease (PD) is a neurodegenerative disorder where alpha-synuclein plays a central role in the death and dysfunction of neurons, both, in central, as well as in the peripheral nervous system. Besides the neuronal events observed in patients, PD also includes a significant immune component. It is suggested that the PD-associated immune response will have consequences on neuronal health, thus opening immunomodulation as a potential therapeutic strategy in PD. The immune changes during the disease occur in the brain, involving microglia, but also in the periphery with changes in cells of the innate immune system, particularly monocytes, as well as those of adaptive immunity, such as T-cells. This realization arises from multiple patient studies, but also from data in animal models of the disease, providing strong evidence for innate and adaptive immune system crosstalk in the central nervous system and periphery in PD. Here we review the data showing that alpha-synuclein plays a crucial role in the activation of the innate and adaptive immune system. We will also describe the studies suggesting that inflammation in PD includes early changes in innate and adaptive immune cells that develop dynamically through time during disease, contributing to neuronal degeneration and symptomatology in patients. This novel finding has contributed to the definition of PD as a multisystem disease that should be approached in a more integratory manner rather than a brain-focused classical approach.

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