Quantifying the early immune response and adaptive immune response kinetics in mice infected with influenza A virus.
Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is approximately 1.2 days, and the half-life of free infectious IAV is approximately 4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is approximately 0.5 days, and the average half-life of free infectious virus is approximately 1.8 min. During the adaptive phase, model fitting confirms that CD8(+) CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity.
Miao
Hongyu
H
Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York 146421, USA.
Hollenbaugh
Joseph A
JA
Zand
Martin S
MS
Holden-Wiltse
Jeanne
J
Mosmann
Tim R
TR
Perelson
Alan S
AS
Wu
Hulin
H
Topham
David J
DJ
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D004847:Epithelial Cells / Q000502:physiology / Q000821:virology; D006207:Half-Life; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008962:Models, Theoretical; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013997:Time Factors
D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007075:Immunoglobulin M
J Immunol. 1997 Dec 1;159(11):5197-200
9548456
PLoS Comput Biol. 2007 Dec;3(12):e240
18069885
Infect Immun. 1979 Sep;25(3):992-7
500197
Nature. 1995 Jan 12;373(6510):123-6
7816094
J Immunol. 1992 Aug 15;149(4):1319-25
1354233
J Theor Biol. 2007 May 7;246(1):70-86
17266989
J Exp Med. 2005 Apr 4;201(7):1101-12
15795235
J Virol. 2004 Apr;78(7):3572-7
15016880
SIAM Rev Soc Ind Appl Math. 2011 Jan 1;53(1):3-39
21785515
Semin Immunol. 2004 Jun;16(3):171-7
15130501
Am J Pathol. 2001 Dec;159(6):2055-69
11733356
PLoS One. 2007 Dec 12;2(12):e1301
18074025
J Exp Med. 2003 Oct 6;198(7):1011-21
14517272
J Virol. 2009 Jul;83(14):7151-65
19439465
J Theor Biol. 1994 Apr 21;167(4):323-60
7516024
Biotechnol Bioeng. 2005 Apr 5;90(1):46-58
15736163
Am J Pathol. 2006 Apr;168(4):1169-78; quiz 1404-5
16565492
Virology. 1997 Dec 8;239(1):217-25
9426461
Ann Appl Stat. 2010 Mar 1;4(1):460-483
20556240
Immunol Rev. 1997 Oct;159:105-17
9416506
J Immunol. 2004 Mar 1;172(5):2731-8
14978070
J Virol. 1996 Feb;70(2):1288-91
8551597
J Virol. 1995 Apr;69(4):2075-81
7884853
J Theor Biol. 2000 Apr 7;203(3):285-301
10716909
Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L231-4
18487354
J Immunol. 1994 Aug 1;153(3):1246-53
8027552
J Immunol. 1996 Oct 1;157(7):2947-52
8816401
J Virol. 1995 Mar;69(3):1429-34
7853474
J Immunol. 1990 May 15;144(10):3980-6
1692070
Nature. 1995 Jan 12;373(6510):117-22
7529365
J Exp Med. 2002 Oct 7;196(7):957-68
12370257
J Immunol. 2009 Sep 1;183(5):3177-87
19675172
Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1599-603
17242364
Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11029-33
8248207
Immunol Cell Biol. 2007 Jun;85(4):274-9
17420769
Nature. 1997 May 8;387(6629):188-91
9144290
Science. 1996 Mar 15;271(5255):1582-6
8599114
Virus Res. 2001 Sep;77(1):3-17
11451482
J Exp Med. 2000 Jul 17;192(2):271-80
10899913
J R Soc Interface. 2009 May 6;6(34):447-54
18708323
Nat Rev Immunol. 2002 Jan;2(1):28-36
11905835
BMC Bioinformatics. 2006 Nov 02;7:483
17081289
J Immunol. 2000 Mar 1;164(5):2635-43
10679103
Ann Stat. 2010 Jan 1;38(4):2351-2387
21132064
J Am Stat Assoc. 2008 Dec 1;103(484):1570-1583
19956350
Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8091-6
18523003
J Exp Med. 1997 Dec 15;186(12):2063-8
9396777
J Virol. 2006 Aug;80(15):7590-9
16840338
J Virol. 2008 Dec;82(23):11749-57
18815293
J Immunol. 2005 Nov 1;175(9):5827-38
16237075
Am J Physiol. 1993 Feb;264(2 Pt 1):L183-92
8447430
J Theor Biol. 2005 Jan 21;232(2):223-34
15530492
J Immunol. 1952 Aug;69(2):155-81
14946411
J Immunol. 1995 Sep 15;155(6):2955-9
7673713
J Math Biol. 2010 May;60(5):711-26
19633852
J Exp Med. 1991 Oct 1;174(4):875-80
1919440