Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 108 (13): 5354-5359

Copyright © 2011 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / IMMUNOLOGY

Microbiota regulates immune defense against respiratory tract influenza A virus infection

Takeshi Ichinohea,b,1, Iris K. Panga,1, Yosuke Kumamotoa, David R. Peaperc, John H. Hoa, Thomas S. Murrayc,d, and Akiko Iwasakia,2

aDepartment of Immunobiology, dDepartment of Pediatrics, and cLaboratory Medicine, Yale University School of Medicine, New Haven, CT 06520; and bDepartment of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan

Edited by Dan R. Littman, New York University Medical Center, New York, NY, and approved February 7, 2011 (received for review December 23, 2010)

Abstract: Although commensal bacteria are crucial in maintaining immune homeostasis of the intestine, the role of commensal bacteria in immune responses at other mucosal surfaces remains less clear. Here, we show that commensal microbiota composition critically regulates the generation of virus-specific CD4 and CD8 T cells and antibody responses following respiratory influenza virus infection. By using various antibiotic treatments, we found that neomycin-sensitive bacteria are associated with the induction of productive immune responses in the lung. Local or distal injection of Toll-like receptor (TLR) ligands could rescue the immune impairment in the antibiotic-treated mice. Intact microbiota provided signals leading to the expression of mRNA for pro–IL-1β and pro–IL-18 at steady state. Following influenza virus infection, inflammasome activation led to migration of dendritic cells (DCs) from the lung to the draining lymph node and T-cell priming. Our results reveal the importance of commensal microbiota in regulating immunity in the respiratory mucosa through the proper activation of inflammasomes.

Key Words: mucosal immunity • NLRP3 • caspase-1 • adaptive immunity


Author contributions: T.I., I.K.P., Y.K., D.R.P., T.S.M., and A.I. designed research; T.I., I.K.P., Y.K., D.R.P., J.H.H., and T.S.M. performed research; T.I., I.K.P., Y.K., D.R.P., J.H.H., T.S.M., and A.I. analyzed data; and T.I., I.K.P., D.R.P., T.S.M., and A.I. wrote the paper.

1T.I. and I.K.P. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1019378108/-/DCSupplemental.

2To whom correspondence should be addressed. E-mail: akiko.iwasaki{at}yale.edu.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Antibiotic Treatment Suppresses Rotavirus Infection and Enhances Specific Humoral Immunity.
R. Uchiyama, B. Chassaing, B. Zhang, and A. T. Gewirtz (2014)
The Journal of Infectious Disease
   Abstract »    Full Text »    PDF »
Antibiotics Help Control Rotavirus Infections and Enhance Antirotaviral Immunity: Are You Serious?.
L. A. Bartelt and R. L. Guerrant (2014)
The Journal of Infectious Disease
   Full Text »    PDF »
An Attenuated Duck Plague Virus (DPV) Vaccine Induces both Systemic and Mucosal Immune Responses To Protect Ducks against Virulent DPV Infection.
J. Huang, R. Jia, M. Wang, B. Shu, X. Yu, D. Zhu, S. Chen, Z. Yin, X. Chen, and A. Cheng (2014)
Clin. Vaccine Immunol. 21, 457-462
   Abstract »    Full Text »    PDF »
Common and Emerging Infectious Diseases in the Animal Shelter.
P. A. Pesavento and B. G. Murphy (2014)
Veterinary Pathology 51, 478-491
   Abstract »    Full Text »    PDF »
Mechanisms and Biological Roles of Contact-Dependent Growth Inhibition Systems.
C. S. Hayes, S. Koskiniemi, Z. C. Ruhe, S. J. Poole, and D. A. Low (2014)
Cold Spring Harb Perspect Med 4, a010025
   Abstract »    Full Text »    PDF »
House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection.
K. E. Fujimura, T. Demoor, M. Rauch, A. A. Faruqi, S. Jang, C. C. Johnson, H. A. Boushey, E. Zoratti, D. Ownby, N. W. Lukacs, et al. (2014)
PNAS 111, 805-810
   Abstract »    Full Text »    PDF »
Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment.
N. Iida, A. Dzutsev, C. A. Stewart, L. Smith, N. Bouladoux, R. A. Weingarten, D. A. Molina, R. Salcedo, T. Back, S. Cramer, et al. (2013)
Science 342, 967-970
   Abstract »    Full Text »    PDF »
The amazing innate immune response to influenza A virus infection.
S. Tripathi, M. R. White, and K. L. Hartshorn (2013)
Innate Immunity
   Abstract »    Full Text »    PDF »
Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection.
T. Ichinohe, T. Yamazaki, T. Koshiba, and Y. Yanagi (2013)
PNAS 110, 17963-17968
   Abstract »    Full Text »    PDF »
Increased Susceptibility of IgA-Deficient Mice to Pulmonary Francisella tularensis Live Vaccine Strain Infection.
Y. Furuya, G. S. Kirimanjeswara, S. Roberts, and D. W. Metzger (2013)
Infect. Immun. 81, 3434-3441
   Abstract »    Full Text »    PDF »
Clinical Effects of Probiotic Bifidobacterium longum BB536 on Immune Function and Intestinal Microbiota in Elderly Patients Receiving Enteral Tube Feeding.
H. Akatsu, N. Iwabuchi, J.-z. Xiao, Z. Matsuyama, R. Kurihara, K. Okuda, T. Yamamoto, and M. Maruyama (2013)
JPEN J Parenter Enteral Nutr 37, 631-640
   Abstract »    Full Text »    PDF »
Network-based drug discovery by integrating systems biology and computational technologies.
E. L. Leung, Z.-W. Cao, Z.-H. Jiang, H. Zhou, and L. Liu (2013)
Brief Bioinform 14, 491-505
   Abstract »    Full Text »    PDF »
Sequencing, Annotation, and Characterization of the Influenza Ferret Infectome.
A. J. Leon, D. Banner, L. Xu, L. Ran, Z. Peng, K. Yi, C. Chen, F. Xu, J. Huang, Z. Zhao, et al. (2013)
J. Virol. 87, 1957-1966
   Abstract »    Full Text »    PDF »
Nonalloreactive T Cells Prevent Donor Lymphocyte Infusion-Induced Graft-versus-Host Disease by Controlling Microbial Stimuli.
H. W. Li, J. Sachs, C. Pichardo, R. Bronson, G. Zhao, and M. Sykes (2012)
J. Immunol. 189, 5572-5581
   Abstract »    Full Text »    PDF »
Specific Dietary Oligosaccharides Increase Th1 Responses in a Mouse Respiratory Syncytial Virus Infection Model.
M. A. Schijf, D. Kruijsen, J. Bastiaans, F. E. J. Coenjaerts, J. Garssen, G. M. van Bleek, and B. van't Land (2012)
J. Virol. 86, 11472-11482
   Abstract »    Full Text »    PDF »
Predicting the Outcome of Infectious Diseases: Variability among Inbred Mice as a New and Powerful Tool for Biomarker Discovery.
M. E. Martin, J. A. Dieter, Z. Luo, N. Baumgarth, and J. V. Solnick (2012)
mBio 3, e00199-12
   Abstract »    Full Text »    PDF »
Prevention of Virus-Induced Type 1 Diabetes with Antibiotic Therapy.
N. Hara, A. K. Alkanani, D. Ir, C. E. Robertson, B. D. Wagner, D. N. Frank, and D. Zipris (2012)
J. Immunol. 189, 3805-3814
   Abstract »    Full Text »    PDF »
Inflammasomes and viruses: cellular defence versus viral offence.
A. M. Gram, J. Frenkel, and M. E. Ressing (2012)
J. Gen. Virol. 93, 2063-2075
   Abstract »    Full Text »    PDF »
Upper Respiratory Tract Microbial Communities, Acute Otitis Media Pathogens, and Antibiotic Use in Healthy and Sick Children.
M. M. Pettigrew, A. S. Laufer, J. F. Gent, Y. Kong, K. P. Fennie, and J. P. Metlay (2012)
Appl. Envir. Microbiol. 78, 6262-6270
   Abstract »    Full Text »    PDF »
Compartmentalized Control of Skin Immunity by Resident Commensals.
S. Naik, N. Bouladoux, C. Wilhelm, M. J. Molloy, R. Salcedo, W. Kastenmuller, C. Deming, M. Quinones, L. Koo, S. Conlan, et al. (2012)
Science 337, 1115-1119
   Abstract »    Full Text »    PDF »
Microbiota, Disease, and Back to Health: A Metastable Journey.
R. Blumberg and F. Powrie (2012)
Science Translational Medicine 4, 137rv7
   Full Text »    PDF »
Impaired NLRP3 Inflammasome Function in Elderly Mice during Influenza Infection Is Rescued by Treatment with Nigericin.
H. W. Stout-Delgado, S. E. Vaughan, A. C. Shirali, R. J. Jaramillo, and K. S. Harrod (2012)
J. Immunol. 188, 2815-2824
   Abstract »    Full Text »    PDF »
Measles Virus V Protein Inhibits NLRP3 Inflammasome-Mediated Interleukin-1{beta} Secretion.
N. Komune, T. Ichinohe, M. Ito, and Y. Yanagi (2011)
J. Virol. 85, 13019-13026
   Abstract »    Full Text »    PDF »
Antibiotics in Feed Induce Prophages in Swine Fecal Microbiomes.
H. K. Allen, T. Looft, D. O. Bayles, S. Humphrey, U. Y. Levine, D. Alt, and T. B. Stanton (2011)
mBio 2, e00260-11
   Abstract »    Full Text »    PDF »
Lung dendritic cells at the innate-adaptive immune interface.
T. V. Condon, R. T. Sawyer, M. J. Fenton, and D. W. H. Riches (2011)
J. Leukoc. Biol. 90, 883-895
   Abstract »    Full Text »    PDF »
Successful Transmission of a Retrovirus Depends on the Commensal Microbiota.
M. Kane, L. K. Case, K. Kopaskie, A. Kozlova, C. MacDearmid, A. V. Chervonsky, and T. V. Golovkina (2011)
Science 334, 245-249
   Abstract »    Full Text »    PDF »
Our microbial selves: what ecology can teach us.
A. Gonzalez, J. C. Clemente, A. Shade, J. L. Metcalf, S. Song, B. Prithiviraj, B. E. Palmer, and R. Knight (2011)
EMBO Rep. 12, 775-784
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882