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How Pathogen Exposure Order Influences Innate Immune International Journal of Molecular Sciences Review Exposome and Immunity Training: How Pathogen Exposure Order Influences Innate Immune Cell Lineage Commitment and Function , , Kevin Adams, K. Scott Weber * y and Steven M. Johnson * y Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; [email protected] * Correspondence: [email protected] (K.S.W.); [email protected] (S.M.J.) Authors contributed equally to this work. y Received: 2 October 2020; Accepted: 9 November 2020; Published: 11 November 2020 Abstract: Immune memory is a defining characteristic of adaptive immunity, but recent work has shown that the activation of innate immunity can also improve responsiveness in subsequent exposures. This has been coined “trained immunity” and diverges with the perception that the innate immune system is primitive, non-specific, and reacts to novel and recurrent antigen exposures similarly. The “exposome” is the cumulative exposures (diet, exercise, environmental exposure, vaccination, genetics, etc.) an individual has experienced and provides a mechanism for the establishment of immune training or immunotolerance. It is becoming increasingly clear that trained immunity constitutes a delicate balance between the dose, duration, and order of exposures. Upon innate stimuli, trained immunity or tolerance is shaped by epigenetic and metabolic changes that alter hematopoietic stem cell lineage commitment and responses to infection. Due to the immunomodulatory role of the exposome, understanding innate immune training is critical for understanding why some individuals exhibit protective phenotypes while closely related individuals may experience immunotolerant effects (e.g., the order of exposure can result in completely divergent immune responses). Research on the exposome and trained immunity may be leveraged to identify key factors for improving vaccination development, altering inflammatory disease development, and introducing potential new prophylactic treatments, especially for diseases such as COVID-19, which is currently a major health issue for the world. Furthermore, continued exposome research may prevent many deleterious effects caused by immunotolerance that frequently result in host morbidity or mortality. Keywords: exposome; trained immunity; epigenetics; NK cells; monocytes; macrophages; dendritic cells; histone modification; DNA methylation; COVID-19; SARS-CoV-2 1. Introduction Innate immunity is the first line of host defense against external exposures. While traditionally viewed as primitive and nonspecific, a growing body of clinical and experimental evidence argues the innate immune system develops memory as a result of previous exposures, allowing the innate system to respond with enhanced and broad immunological protection upon exposure to a secondary stimulus [1,2]. This biological process of enhanced innate immunity response on secondary pathogen exposure has been termed “trained immunity” [2,3]. Trained immunity shares many phenotypic and epigenetic characteristics with adaptive immune memory; however, one of the starkest distinctions is the propensity for trained immunity to develop against heterologous stimuli (Figure1). Innate memory is not antigen specific and is often protective against unrelated organisms, such as when vaccination Int. J. Mol. Sci. 2020, 21, 8462; doi:10.3390/ijms21228462 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 8462 2 of 26 Int. J. Mol.Int. J.Sci. Mol. 2019 Sci., 2019 20, x, 20 FOR, x FOR PEER PEER REVIEW REVIEW 2 of 25 2 of 25 for tuberculosis with Bacillus Calmette–Guerin (BCG) also affords protection against fungal or even viral infectionsvaccinationvaccination suchfor tuberculosisfor as tuberculosis SARS-CoV-2 with with [Bacillus4 Bacillus–6]. CalmeCalmette–Guerintte–Guerin (BCG) (BCG) also also affords affords protection protection against against fungalfungal or even or even viral viral infectio infections nssuch such as as SARS-CoV-2 SARS-CoV-2 [4–6].[4–6]. Figure 1. Innate immunity can result in broad immunological protection, whereas adaptive immunity Figure 1. Innate immunity can result in broad immunological protection, whereas adaptive immunity provides antigen-specific protection. (A) For innate immunity, trained immunity can provide providesFigure antigen-specificprotection 1. Innate against immunity heterologous protection. can result stimul (A in) For broadi, whereas innate immunological with immunity, adaptive protection,immunity trained immunity(B whereas), memory adaptivecan is elicited provide immunitywith protection againstprovides heterologousprimary antigen-specific exposure stimuli, to a specific whereasprotection. antigen, with (A and) adaptiveFor then innate, a secondary immunity immunity, exposure (B ),trai memory andned subsequent immunity is elicited protection can withprovide primary exposureprotection torequires a specificagainst exposure heterologous antigen, with the andsame stimulthen, antigen.i, whereas a secondary with adaptive exposure immunity and subsequent (B), memory protection is elicited with requires primary exposure to a specific antigen, and then, a secondary exposure and subsequent protection exposure withThe exposome the same is antigen. the compilation of everything an individual has encountered throughout their requires exposure with the same antigen. life [7]. Research into the exposome examines the combination of all exposures an individual has The exposomeencountered isduring the compilationa set period of their of everything life and the subsequent an individual effects on has that encountered individual (Figure throughout 2A) their life [7]. ResearchThe[7]. exposomeThe exposome into theis the exposomevaries compilation spatiotemporally, examines of everything theis highly combinationan individual dynamic hasand of all encountereddiverse, exposures and throughoutprovides an individual a their has encounteredlife [7].mechanism Research during aby into set which period the trainedexposome of their immunity lifeexamines and or theimmunotolerance th subsequente combination eisff ofectsestablished all on exposures that [8]. individual This an occursindividual (Figure via has2A) [ 7]. encountereddistinct duringchanges ain set leukocyte period of epigenetics their life and and the metabolism subsequent (Figure effects 2B) on that that initiate individual changes (Figure in 2A) The exposome varies spatiotemporally, is highly dynamic and diverse, and provides a mechanism by [7]. Theleukocyte exposome lineage variescommitment spatiotemporally, and the strength is ofhighly the immune dynamic response and (Figurediverse, 2C), and eventually provides a whichmechanism trainedresulting immunity by in whichdivergent ortrained levels immunotolerance ofimmunity infection survival,or immunotolerance is established inflammation, [ 8and ].is Thisdiseaseestablished occurs (Figure [8]. via 2D). This distinct Studies occurs of changes via in leukocytedistinct epigeneticsthe exposomechanges andinare leukocyterelatively metabolism sparse, epigenetics (Figure yet the effects2andB) that onmetabolism initiatehuman health changes (Figure are dramatic. in 2B) leukocyte that Two initiate major lineage projects changes commitment in and theleukocyte strengthaimed lineage at unraveling of the commitment immune the exposome responseand theare strengthThe (Figure Huma ofn2C), Earlythe eventuallyimmune Life Exposome response resulting (HELIX) (Figure inproject divergent 2C), and eventually the levels of EXPOsOMICS project. The HELIX project is a study aimed at measuring and correlating the effects infectionresulting survival, in divergent inflammation, levels of and infection disease survival, (Figure inflammation,2D). Studies ofand the disease exposome (Figure are 2D). relatively Studies sparse,of of early-life exposures on human health [9]. The EXPOsOMICS project utilizes high-throughput yet thethe e ffexposomeectssequencing on human are and relatively “omics” health sparse, areexperiment dramatic. yet sthe to effectsbuild Two majormodels on human projectsof lifetime health aimed exposures are dramatic. at unraveling and theirTwo effectsmajor the exposome onprojects are The Humanaimedhuman at Early unraveling health Life [10,11]. Exposome the exposome (HELIX) are The project Huma andn Early the EXPOsOMICS Life Exposome project. (HELIX) The project HELIX and project the is a studyEXPOsOMICS aimed at measuring project. The and HELIX correlating project is thea study effects aimed of early-lifeat measuring exposures and correlating on human the effects health [9]. of early-life exposures on human health [9]. The EXPOsOMICS project utilizes high-throughput The EXPOsOMICS project utilizes high-throughput sequencing and “omics” experiments to build sequencing and “omics” experiments to build models of lifetime exposures and their effects on models of lifetime exposures and their effects on human health [10,11]. human health [10,11]. Figure 2. The effect of the exposome on innate immunity. (A) The order of exposure to external stimuli can have an important effect on innate immunity. (B) These stimuli elicit various epigenetic and metabolic changes that in turn dictate (C) lineage commitment and the strength of the innate immune response, which ultimately determine (D) the health outcome of the affected individual. The blue and orange lines in (C) denote innate immunity activation (blue line) versus tolerization (orange line). Figure 2. The effect of the exposome on innate immunity. (A) The order of exposure to external stimuli
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