Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges

Piasecka, Barbara; Duffy, Darragh; Urrutia, Alejandra; Quach, Hélène; Patin, Étienne; Posseme, Céline; Bergstedt, Jacob; Charbit, Bruno; Rouilly, Vincent; MacPherson, Cameron Ross; Hasan, Milena; Albaud, Benoit; Gentien, David; Fellay, Jacques; Albert, Matthew L.; Quintana-Murci, Lluı́s

doi:10.1073/pnas.1714765115

Cited by 194 publications

(246 citation statements)

References 65 publications

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“…127,128 This could help in designing vaccines or vaccine adjuvants that can circumvent restrictions due to immunological differences arising from varying genetic compositions. 129,130 Personalized vaccines stem from our understanding of how, within the human leukocyte antigen (HLA) systemalso referred to as the major histocompatibility complex (MHC), the T cells are able to recognize peptides of pathogenic origin. 131,132 HLA molecules enjoy the double advantages of having stable polymorphisms and being fully characterized.…”

Section: The Subpopulation Levelmentioning

confidence: 99%

<p>Immunoinformatics and Vaccine Development: An Overview</p>

Oli

Obialor

Ifeanyichukwu

et al. 2020

ITT

161

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The use of vaccines have resulted in a remarkable improvement in global health. It has saved several lives, reduced treatment costs and raised the quality of animal and human lives. Current traditional vaccines came empirically with either vague or completely no knowledge of how they modulate our immune system. Even at the face of potential vaccine design advance, immune-related concerns (as seen with specific vulnerable populations, cases of emerging/reemerging infectious disease, pathogens with complex lifecycle and antigenic variability, need for personalized vaccinations, and concerns for vaccines' immunological safety -specifically vaccine likelihood to trigger non-antigen-specific responses that may cause autoimmunity and vaccine allergy) are being raised. And these concerns have driven immunologists toward research for a better approach to vaccine design that will consider these challenges. Currently, immunoinformatics has paved the way for a better understanding of some infectious disease pathogenesis, diagnosis, immune system response and computational vaccinology. The importance of this immunoinformatics in the study of infectious diseases is diverse in terms of computational approaches used, but is united by common qualities related to host-pathogen relationship. Bioinformatics methods are also used to assign functions to uncharacterized genes which can be targeted as a candidate in vaccine design and can be a better approach toward the inclusion of women that are pregnant into vaccine trials and programs. The essence of this review is to give insight into the need to focus on novel computational, experimental and computation-driven experimental approaches for studying of host-pathogen interactions and thus making a case for its use in vaccine development.

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Section: The Subpopulation Levelmentioning

confidence: 99%

<p>Immunoinformatics and Vaccine Development: An Overview</p>

Oli

Obialor

Ifeanyichukwu

et al. 2020

ITT

161

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“…where each sequence is associated to a specific, random barcode (1). The barcoded sequence is then introduced in a reporter plasmid, where it is ligated to the 3 0 of a green fluorescent protein (GFP) associated with a basic promoter sequence (2). The plasmid library is then transfected into a cell line representative of the tissue of interest (3).…”

Section: Concluding Remarks: a Strategy For The Futurementioning

confidence: 99%

“…The host immune response to stress exhibits considerable variation, both at the individual and population levels . While many nonheritable factors contribute to this variability, including age, gender, or past exposures to pathogens (see Reference for a review on these aspects). There is also widespread evidence that genetics plays a significant role in determining the efficacy of the human immune response, in particular in the context of innate immunity .…”

Section: Introductionmentioning

confidence: 99%

Characterising the genetic basis of immune response variation to identify causal mechanisms underlying disease susceptibility

Rotival

2019

HLA

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Over the last 10 years, genome‐wide association studies (GWAS) have identified hundreds of susceptibility loci for autoimmune diseases. However, despite increasing power for the detection of both common and rare coding variants affecting disease susceptibility, a large fraction of disease heritability has remained unexplained. In addition, a majority of the identified loci are located in noncoding regions, and translation of disease‐associated loci into new biological insights on the etiology of immune disorders has been lagging. This highlights the need for a better understanding of noncoding variation and new strategies to identify causal genes at disease loci. In this review, I will first detail the molecular basis of gene expression and review the various mechanisms that contribute to alter gene activity at the transcriptional and post‐transcriptional level. I will then review the findings from 10 years of functional genomics studies regarding the genetics on gene expression, in particular in the context of infection. Finally, I will discuss the extent to which genetic variants that modulate gene expression at transcriptional and post‐transcriptional level contribute to disease susceptibility and present strategies to leverage this information for the identification of causal mechanisms at disease loci in the era of whole genome sequencing.

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“…We recently utilized the 1,000 donor cohort of Milieu Interieur to dissect the relative contributions of age, sex, cellular composition and genetics to induced immune responses to microbial stimulation. 14 Of particular interest for vaccine responses was the age-specific association with IFN-γ, a commonly used correlate of protection in vaccine clinical studies given its key role in adaptive immunity. 15 Notably, IFN-γ gene expression showed a strong and significant decline with age for bacterial, fungal, and viral responses (Fig.…”

Section: Integrating Non-genetic Differences In Vaccine Responsesmentioning

confidence: 99%

“…Towards this goal, we recently described within Milieu Interieur a master genetic regulator of bacteria-induced immune responses. Variability in the TLR 1/6/10 gene locus regulated 105 genes after stimulation with E. coli, 80 genes after stimulation with BCG, 7 genes after stimulation with S. aureus, and 13 genes after stimulation with SEB 14 (measurement of 560 immune related genes). Individuals with the homozygous dominant, TT genotype, of the most differential single nucleotide polymorphism (SNP) (rs4833095, T-allele frequency = 0.79) displayed lower expression for many inflammatory response genes (e.g., IL1B, IL6, IL12B) and higher expression for regulatory response genes (e.g., TGFB1, TGFBI, IL1RAP).…”

Section: Integrating Genetic Differences In Vaccine Responsesmentioning

confidence: 99%

Milieu intérieur: Defining the boundaries of a healthy immune response for improved vaccination strategies

Duffy

2018

Human Vaccines & Immunotherapeutics

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Immune responses in human populations are highly variable, with this variability presenting challenges for vaccine design. As such a better understanding of the factors that determine this variability will help in the development of precision vaccination strategies. The Milieu Interieur consortium was established to address this challenge through a definition of the normal boundaries of a healthy immune response, and the characterization of their genetic and environmental determinants. To do this we have implemented standardized tools for monitoring functional immune responses at the proteomic and transcriptional level, which have been applied to a 1,000 healthy donor cohort. This approach has recently allowed us to quantify the extent of genetic control of cellular variability and transcriptional responses to infection. Initial findings on the influence of age, sex, and genetics may already be included in considerations for improved vaccine development, and ongoing analysis will further define the factors behind inter-individual variability in diverse immune responses. This approach will help to guide the development of the next generation of vaccines that will take into account differences in populations and eventually individuals.

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Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges

Cited by 194 publications

References 65 publications

<p>Immunoinformatics and Vaccine Development: An Overview</p>

<p>Immunoinformatics and Vaccine Development: An Overview</p>

Characterising the genetic basis of immune response variation to identify causal mechanisms underlying disease susceptibility

Milieu intérieur: Defining the boundaries of a healthy immune response for improved vaccination strategies

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