Systems Biology of Seasonal Influenza Vaccination in Humans

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Abstract

We used a systems biological approach to study innate and adaptive responses to influenza vaccination in humans, during 3 consecutive influenza seasons. Healthy adults were vaccinated with inactivated (TIV) or live attenuated (LAIV) influenza vaccines. TIV induced greater antibody titers and enhanced numbers of plasmablasts than LAIV. In TIV vaccinees, early molecular signatures correlated with, and accurately predicted, later antibody titers in two independent trials. Interestingly, the expression of Calcium/calmodulin-dependent kinase IV (CamkIV) at day 3 was inversely correlated with later antibody titers. Vaccination of CamkIV ^−/− mice with TIV induced enhanced antigen-specific antibody titers, demonstrating an unappreciated role for CaMKIV in the regulation of antibody responses. Thus systems approaches can predict immunogenicity, and reveal new mechanistic insights about vaccines.

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In silico prediction of protein-protein interactions in human macrophages

Oussema Souiai, Fatma Zahra Guerfali, Slimane Miled … (2015)

Background: Protein-protein interaction (PPI) network analyses are highly valuable in deciphering and understanding the intricate organisation of cellular functions. Nevertheless, the majority of available protein-protein interaction networks are context-less, i.e. without any reference to the spatial, temporal or physiological conditions in which the interactions may occur. In this work, we are proposing a protocol to infer the most likely protein-protein interaction (PPI) network in human macrophages. Results: We integrated the PPI dataset from the Agile Protein Interaction DataAnalyzer (APID) with different meta-data to infer a contextualized macrophage-specific interactome using a combination of statistical methods. The obtained interactome is enriched in experimentally verified interactions and in proteins involved in macrophage-related biological processes (i.e. immune response activation, regulation of apoptosis). As a case study, we used the contextualized interactome to highlight the cellular processes induced upon Mycobacterium tuberculosis infection. Conclusion: Our work confirms that contextualizing interactomes improves the biological significance of bioinformatic analyses. More specifically, studying such inferred network rather than focusing at the gene expression level only, is informative on the processes involved in the host response. Indeed, important immune features such as apoptosis are solely highlighted when the spotlight is on the protein interaction level.

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Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans.

Troy Querec, Rama Akondy, Eva K. Lee … (2009)

A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.

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Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity

Troy David Querec, Soumaya Bennouna, Sefik S Alkan … (2006)

The live attenuated yellow fever vaccine 17D (YF-17D) is one of the most effective vaccines available, with a 65-yr history of use in >400 million people globally. Despite this efficacy, there is presently no information about the immunological mechanisms by which YF-17D acts. Here, we present data that suggest that YF-17D activates multiple Toll-like receptors (TLRs) on dendritic cells (DCs) to elicit a broad spectrum of innate and adaptive immune responses. Specifically, YF-17D activates multiple DC subsets via TLRs 2, 7, 8, and 9 to elicit the proinflammatory cytokines interleukin (IL)-12p40, IL-6, and interferon-α. Interestingly, the resulting adaptive immune responses are characterized by a mixed T helper cell (Th)1/Th2 cytokine profile and antigen-specific CD8+ T cells. Furthermore, distinct TLRs appear to differentially control the Th1/Th2 balance; thus, whilst MyD88-deficient mice show a profound impairment of Th1 cytokines, TLR2-deficient mice show greatly enhanced Th1 and Tc1 responses to YF-17D. Together, these data enhance our understanding of the molecular mechanism of action of YF-17D, and highlight the potential of vaccination strategies that use combinations of different TLR ligands to stimulate polyvalent immune responses.

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Author and article information

Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 7 June 2011

Publication date (Electronic): 10 July 2011

Publication date PMC-release: 1 February 2012

Volume: 12

Issue: 8

Pages: 786-795

Affiliations

[1 ] Emory Vaccine Center, Emory University, Atlanta, GA 30329

[2 ] Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329

[3 ] Department of Microbiology and Immunology, Emory University, Atlanta, GA 30329

[4 ] Center for Operations Research in Medicine & Healthcare, School of Industrial & Systems Engineering, Georgia Institute of Technology, Atlanta, GA 30332

[5 ] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27705

[6 ] Department of Cellular and Molecular Biology and Pathology, University of Naples “Federico II”, Naples, Italy 80131

[7 ] Dana-Farber Cancer Institute, Boston, MA 02115

[8 ] Department of Medicine, Division of Nephrology, Emory University School of Medicine, Atlanta, GA 30329

[9 ] Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322

[10 ] Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103

[11 ] Laboratory of Infectious Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

[12 ] Department of Pathology, Emory University School of Medicine, Atlanta, GA 30329

Author notes

[* ]Corresponding Author: Bali Pulendran, Ph.D., Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA, Tel: 404 727 8945, Fax: 404 727 8199, bpulend@ 123456emory.edu

Article

Manuscript ID: nihpa301940

DOI: 10.1038/ni.2067

PMC ID: 3140559

PubMed ID: 21743478

SO-VID: 9b7e50fb-7e0c-4b00-8f2f-35d9868b2b46

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