Giuseppe
Emeritus
Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59 (PNAS, abstract, edited)
[Source: Proc Natl Acad Sci USA, full text: <cite cite="http://www.pnas.org/content/108/7/2927.short?rss=1">Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59 ? PNAS</cite>. Abstract, edited.]
Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59
1. Ali H. Ellebedy a, 2. Christopher Lupfer b, 3. Hazem E. Ghoneim a, 4. Jennifer DeBeauchamp a, 5. Thirumala-Devi Kanneganti b,1,2, and 6. Richard J. Webby a,1,2
Author Affiliations
1. Departments of (a) Infectious Diseases and 2. (b) Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
1. Edited* by Robert G. Webster, St. Jude Children's Research Hospital, Memphis, TN, and approved December 21, 2010 (received for review August 23, 2010)
2. 1T.-D.K. and R.J.W. contributed equally to this work.
Abstract
Clinical studies have indicated that subvirion inactivated vaccines against avian influenza viruses, particularly H5N1, are poorly immunogenic in humans. As a consequence, the use of adjuvants has been championed for the efficient vaccination of a na?ve population against avian influenza. Aluminum salts (alum) and the oil-in-water emulsion MF59 are safe and effective adjuvants that are being used with influenza vaccines, but the mechanism underlying their stimulation of the immune system remains poorly understood. It was shown recently that activation of a cytosolic innate immune-sensing complex known as ?NLR-Pyrin domain containing 3? (NLRP3) inflammasome, also known as ?cryopyrin,? ?cold-induced autoinflammatory syndrome 1? (CIAS1), or nacht domain-, leucine-rich repeat-, and PYD-containing protein 3 (Nalp3), is essential for the adjuvant effect of alum. Here we show that the inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adapter protein within the NLRP3 inflammasome, is a crucial element in the adjuvant effect of MF59 when combined with H5N1 subunit vaccines. In the absence of ASC, H5-specific IgG antibody responses are significantly reduced, whereas the responses are intact in NLRP3−/− and caspase-1−/− mice. This defect is caused mainly by the failure of antigen-specific B cells to switch from IgM to IgG production. We conclude that ASC plays an inflammasome-independent role in the induction of antigen-specific humoral immunity after vaccination with MF59-adjuvanted influenza vaccines. These findings have important implications for the rational design of next-generation adjuvants.
Footnotes
* 2 To whom correspondence may be addressed. E-mail: Thirumala-Devi.Kanneganti@StJude.org or richard.webby@stjude.org.
* Author contributions: A.H.E., T.-D.K., and R.J.W. designed research; A.H.E., C.L., H.E.G., and J.D. performed research; A.H.E., T.-D.K., and R.J.W. analyzed data; and A.H.E., T.-D.K., and R.J.W. wrote the paper.
* The authors declare no conflict of interest.
* ↵*This Direct Submission article had a prearranged editor.
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1012455108/-/DCSupplemental.
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[Source: Proc Natl Acad Sci USA, full text: <cite cite="http://www.pnas.org/content/108/7/2927.short?rss=1">Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59 ? PNAS</cite>. Abstract, edited.]
Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59
1. Ali H. Ellebedy a, 2. Christopher Lupfer b, 3. Hazem E. Ghoneim a, 4. Jennifer DeBeauchamp a, 5. Thirumala-Devi Kanneganti b,1,2, and 6. Richard J. Webby a,1,2
Author Affiliations
1. Departments of (a) Infectious Diseases and 2. (b) Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
1. Edited* by Robert G. Webster, St. Jude Children's Research Hospital, Memphis, TN, and approved December 21, 2010 (received for review August 23, 2010)
2. 1T.-D.K. and R.J.W. contributed equally to this work.
Abstract
Clinical studies have indicated that subvirion inactivated vaccines against avian influenza viruses, particularly H5N1, are poorly immunogenic in humans. As a consequence, the use of adjuvants has been championed for the efficient vaccination of a na?ve population against avian influenza. Aluminum salts (alum) and the oil-in-water emulsion MF59 are safe and effective adjuvants that are being used with influenza vaccines, but the mechanism underlying their stimulation of the immune system remains poorly understood. It was shown recently that activation of a cytosolic innate immune-sensing complex known as ?NLR-Pyrin domain containing 3? (NLRP3) inflammasome, also known as ?cryopyrin,? ?cold-induced autoinflammatory syndrome 1? (CIAS1), or nacht domain-, leucine-rich repeat-, and PYD-containing protein 3 (Nalp3), is essential for the adjuvant effect of alum. Here we show that the inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adapter protein within the NLRP3 inflammasome, is a crucial element in the adjuvant effect of MF59 when combined with H5N1 subunit vaccines. In the absence of ASC, H5-specific IgG antibody responses are significantly reduced, whereas the responses are intact in NLRP3−/− and caspase-1−/− mice. This defect is caused mainly by the failure of antigen-specific B cells to switch from IgM to IgG production. We conclude that ASC plays an inflammasome-independent role in the induction of antigen-specific humoral immunity after vaccination with MF59-adjuvanted influenza vaccines. These findings have important implications for the rational design of next-generation adjuvants.
Footnotes
* 2 To whom correspondence may be addressed. E-mail: Thirumala-Devi.Kanneganti@StJude.org or richard.webby@stjude.org.
* Author contributions: A.H.E., T.-D.K., and R.J.W. designed research; A.H.E., C.L., H.E.G., and J.D. performed research; A.H.E., T.-D.K., and R.J.W. analyzed data; and A.H.E., T.-D.K., and R.J.W. wrote the paper.
* The authors declare no conflict of interest.
* ↵*This Direct Submission article had a prearranged editor.
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1012455108/-/DCSupplemental.
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