Trends in Immunology
Volume 43, Issue 9, September 2022, Pages 696-705
Journal home page for Trends in Immunology

Opinion
Innate antiviral immunity: how prior exposures can guide future responses

https://doi.org/10.1016/j.it.2022.07.001Get rights and content

Highlights

  • Host and microbial metabolites are key regulators of immune function, positively and negatively regulating signaling cascades in innate and adaptive immunity.

  • Every individual has their own unique history of exposure to environmental and microbial stimuli. We argue that these distinct exposure combinations guide the nature and magnitude of future immune responses.

  • Immune responses to infection and vaccination are heterogeneous, with some individuals showing limited efficacy in controlling infections or producing protective immune responses to vaccination. This cannot be explained solely by genetics but is regulated in part by prior exposure history.

  • Next-generation, high-dimensional assays combined with systems immunology are enabling us to investigate the causes of heterogeneous immune responses, and may help identify potential therapeutic interventions to overcome poor responses to infection and/or vaccination.

Innate immunity is an intrinsic baseline defense in cells, with its earliest origins in bacteria, and with key roles in defense against pathogens and in the activation of B and T cell responses. In mammals, the efficacy of innate immunity in initiating the cascades that lead to pathogen control results from the interplay of transcriptomic, epigenomic, and proteomic responses regulating immune activation and long-lived pathogen-specific memory responses. Recent studies suggest that intrinsic innate immunity is modulated by individual exposure histories – prior infections, vaccinations, and metabolites of microbial origin – and this promotes, or impairs, the development of efficacious innate immune responses. Understanding how environmental factors regulate innate immunity and boost protection from infection or response to vaccination could be a valuable tool for pandemic preparedness.

Section snippets

Intrinsic innate antiviral immunity: a baseline defense against viral infections

Several cellular components of the innate immune system play a primary role in shaping protective and/or deleterious immune responses to infections and vaccination. Innate immune cells have traditionally included monocytes/macrophages, dendritic cells (DCs), natural killer (NK) cells, neutrophils, and granulocytes, although several cell types (including epithelial cells) can mount innate antiviral responses [1]. During an acute tissue infection, neutrophils followed by monocytes/macrophages and

Trained immunity and IIAVI: linking the future to the past

Linked with the concept of IIAVI is the recently described state of trained immunity (TI), or the acquisition of epigenetic modifications that induce a state of hyper- or hypo-responsiveness to future infection. TI was first described in monocytes/macrophages and considered ‘innate memory’ analogous to the adaptive memory seen in T and B cells (Figure 1) [16., 17., 18.]. The most well characterized example of TI involves Toll-like receptor 4 (TLR4) activation and Bacillus–Calmette–Guerin (BCG)

Daily exposure: how our history of environmental and microbial exposure shapes immunity

Exposure to a myriad of environmental agents can potentially impact antiviral immune responses (Figure 2, Key figure). Among the most important of these agents are metabolites derived from the diet and/or the microbiome. Many biological and cellular processes rely on metabolites derived from the activity of microbes on mucosal surfaces, mainly in the gastrointestinal (GI) tract. These microbes (e.g., bacteria) take breakdown products of the diet and digestion and convert them into bioactive

From metabolite to mechanism: metabolite regulation of innate immunity in response to infection or vaccination

Gut microbiota can release several metabolites, including short-chain fatty acids (SCFAs), polyamines, indoles, bile acids (BAs), and lipid-associated metabolites [24]. These metabolites bind to receptors on mammalian immune cells: NOD-like receptors [25], TLRs [26], the aryl hydrocarbon receptor (AHR) [27], and G-protein-coupled receptors (GPCRs) [28] including GPR43 [29] and GPR41 [30]. SCFAs can promote cytokine and chemokine secretion leading to migration and activation of cells such as

AHR can integrate host, microbial, and xenobiotic metabolites to modulate innate and adaptive immune responses

One of the major signaling cascades linking metabolites to immune function is the AHR [48] (Figure 3 and Box 1). AHR signaling can regulate the differentiation and function of mouse and human myeloid and plasmacytoid DCs, which are central components in generating effective immune responses to viral infection and vaccination [49,50]. However, there are conflicting reports showing that AHR can increase or decrease expression of MHC-II (which presents antigen to T cells) and CD86 which binds to

Concluding remarks and future perspectives

The emergence of epigenetics as a long-term regulator of gene expression profiles, and the capacity for metabolites derived from microbial products to impact epigenetic pathways in both innate and adaptive immune cells, suggest that differences in the microbiome/metabolome among individuals can have durable impacts on host immune responses to infection and vaccination [17]. In this opinion article we argue that new evidence suggests that the metabolome/metabotype may directly control innate

Acknowledgments

R.P.S. and J.A.T. were supported by funds from the National Cancer Institute (NCI)/National Institutes of Health (NIH) U54CA260563 and the National Institute of Allergy and Infectious Diseases (NIAID)/NIH R01AI125202, U19AI128910, and 75N93019C00046 (NIAID Adjuvant Discovery Program). M.S.S. was supported with funds from NIAID/NIH R56AI147623, U19AI057266, U19AI090023, U54CA260563, and 75N93021C00017 (NIAID Centers of Excellence for Influenza Research and Surveillance). M.S.D. was supported by

Author contributions

J.A.T. and R.P.S. conceptually developed, wrote, and edited the article. M.S.S. and M.S.D. assisted with writing and editing.

Declaration of interests

The authors declare no conflicts of interest.

Glossary

Aryl hydrocarbon receptor (AHR)
a cellular receptor for multiple classes of host- and microbe-derived metabolites. Activated AHR can function as a transcription factor, binding individually or cooperatively with other immune transcription factors such as NF-κB and STATs to target DNA sequences and modulate gene expression.
Breadth
refers to the degree of diversity in antigenic recognition of the antibody repertoire of an individual. The greater the breadth to a pathogen, the more pathogenic

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