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Email Address: Kaja Murali-Krishna :murali.kaja@emory.edu Suryaprakash Sambhara: ssambhara@cdc.gov

We thank Rafi Ahmed, Emory Vaccine Center, for his critical and insightful discussions and suggestions throughout the course of this work;

We thank Robert Karaffa at the Emory University Flow Cytometry Core Facility for help in flow cytometry support; and Alicia Johnson for technical help.

The findings and conclusions in this report are ours and do not necessarily represent the views of the Centers for Disease Control and Prevention or the funding agencies.

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Research Funding:

This work was supported by National Institutes of Health (NIH) grants R01AI086133 and U19AI083019 to K.M.-K

Activation of the RIG-I Pathway during Influenza Vaccination Enhances the Germinal Center Reaction, Promotes T Follicular Helper Cell Induction, and Provides a Dose-Sparing Effect and Protective Immunity

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Journal Title:

Journal of Virology

Volume:

Volume 88, Number 24

Publisher:

, Pages 13990-14001

Type of Work:

Article | Final Publisher PDF

Abstract:

Pattern recognition receptors (PRR) sense certain molecular patterns uniquely expressed by pathogens. Retinoic-acid-inducible gene I (RIG-I) is a cytosolic PRR that senses viral nucleic acids and induces innate immune activation and secretion of type I interferons (IFNs). Here, using influenza vaccine antigens, we investigated the consequences of activating the RIG-I pathway for antigen-specific adaptive immune responses. We found that mice immunized with influenza vaccine antigens coadministered with 5'ppp-double-stranded RNA (dsRNA), a RIG-I ligand, developed robust levels of hemagglutination-inhibiting antibodies, enhanced germinal center reaction, and T follicular helper cell responses. In addition, RIG-I activation enhanced antibody affinity maturation and plasma cell responses in the draining lymph nodes, spleen, and bone marrow and conferred protective immunity against virus challenge. Importantly, activation of the RIG-I pathway was able to reduce the antigen requirement by 10- to 100-fold in inducing optimal influenza-specific cellular and humoral responses, including protective immunity. The effects induced by 5'ppp-dsRNA were significantly dependent on type I IFN and IPS-1 (an adapter protein downstream of the RIG-I pathway) signaling but were independent of the MyD88- and TLR3-mediated pathways. Our results show that activation of the RIG-I-like receptor pathway programs the innate immunity to achieve qualitatively and quantitatively enhanced protective cellular adaptive immune responses even at low antigen doses, and this indicates the potential utility of RIG-I ligands as molecular adjuvants for viral vaccines.

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© 2014, American Society for Microbiology

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits distribution of derivative works, making multiple copies, distribution, public display, and publicly performance, provided the original work is properly cited. This license requires copyright and license notices be kept intact, credit be given to copyright holder and/or author. This license prohibits exercising rights for commercial purposes.

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