Attenuated Bordetella pertussis protects against highly pathogenic influenza A viruses by dampening the cytokine storm.
The threat of a pandemic spread of highly virulent influenza A viruses currently represents a top global public health problem. Mass vaccination remains the most effective way to combat influenza virus. However, current vaccination strategies face the challenge to meet the demands in a pandemic situation. In a mouse model of severe influenza virus-induced pneumonitis, we observed that prior nasal administration of an attenuated strain of Bordetella pertussis (BPZE1) provided effective and sustained protection against lethal challenge with two different influenza A virus subtypes. In contrast to most cross-protective effects reported so far, the protective window offered upon nasal treatment with BPZE1 lasted up to at least 12 weeks, suggesting a unique mechanism(s) involved in the protection. No significant differences in viral loads were observed between BPZE1-treated and control mice, indicating that the cross-protective mechanism(s) does not directly target the viral particles and/or infected cells. This was further confirmed by the absence of cross-reactive antibodies and T cells in serum transfer and in vitro restimulation experiments, respectively. Instead, compared to infected control mice, BPZE1-treated animals displayed markedly reduced lung inflammation and tissue damage, decreased neutrophil infiltration, and strong suppression of the production of major proinflammatory mediators in their bronchoalveolar fluids (BALFs). Our findings thus indicate that protection against influenza virus-induced severe pneumonitis can be achieved through attenuation of exaggerated cytokine-mediated inflammation. Furthermore, nasal treatment with live attenuated B. pertussis offers a potential alternative to conventional approaches in the fight against one of the most frightening current global public health threats.
Li
Rui
R
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, CeLS Building no. 03-05, 28 Medical Drive, Singapore 117597, Singapore.
Lim
Annabelle
A
Phoon
Meng Chee
MC
Narasaraju
Teluguakula
T
Ng
Jowin K W
JK
Poh
Wee Peng
WP
Sim
Meng Kwoon
MK
Chow
Vincent T
VT
Locht
Camille
C
Alonso
Sylvie
S
D056704:Adaptive Immunity; D000281:Administration, Intranasal; D000818:Animals; D001886:Bordetella pertussis / Q000276:immunology* / Q000472:pathogenicity; D018925:Chemokines / Q000276:immunology; D056738:Cross Protection; D016207:Cytokines / Q000276:immunology*; D004196:Disease Outbreaks / Q000517:prevention & control; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections; D011014:Pneumonia / Q000517:prevention & control / Q000821:virology; D015996:Survival Rate
D018925:Chemokines; D016207:Cytokines; D007252:Influenza Vaccines
Immunology. 1995 Nov;86(3):372-8
8550073
J Immunol. 2006 Mar 15;176(6):3578-84
16517726
Ann Acad Med Singap. 2008 Jun;37(6):451-3
18618054
Am J Pathol. 2000 Jun;156(6):1951-9
10854218
Chest. 1997 May;111(5):1306-21
9149588
Lancet. 2004 Feb 21;363(9409):617-9
14987888
J Immunol. 2003 Aug 1;171(3):1133-9
12874198
Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1560-5
19164548
J Immunol. 2003 Sep 15;171(6):3119-27
12960338
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7944-9
8755582
Microbes Infect. 2009 Jan;11(1):2-11
18983930
J Virol. 1999 Jul;73(7):5903-11
10364342
N Engl J Med. 2005 Sep 29;353(13):1374-85
16192482
Immunol Rev. 2008 Oct;225:68-84
18837776
Infect Immun. 2005 Jul;73(7):4295-301
15972522
Science. 2005 Oct 7;310(5745):77-80
16210530
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5158-63
11309507
J Exp Med. 1993 Jun 1;177(6):1773-7
8496690
Immunology. 2004 May;112(1):2-12
15096178
Infect Immun. 1997 Feb;65(2):544-50
9009311
Am Rev Respir Dis. 1992 Feb;145(2 Pt 1):332-6
1736737
N Engl J Med. 2005 Dec 22;353(25):2667-72
16371632
Immunol Cell Biol. 2007 Feb-Mar;85(2):85-92
17213831
Science. 2004 Jul 16;305(5682):371-6
15218094
J Virol. 1994 Jun;68(6):3667-73
8189504
J Med Virol. 2007 Jun;79(6):811-9
17457919
Infect Immun. 2001 Sep;69(9):5440-6
11500415
Nat Med. 2006 Oct;12(10):1203-7
16964257
Am J Respir Crit Care Med. 2007 Sep 1;176(5):431-8
17556716
Science. 1995 Sep 15;269(5230):1583-5
7667639
Infect Immun. 2008 Jan;76(1):111-9
17954727
Vaccine. 2007 Sep 28;25(39-40):6852-62
17719149
PLoS Pathog. 2006 Jul;2(7):e65
16839199
Infect Immun. 1991 Nov;59(11):3982-8
1937757
Curr Opin Pharmacol. 2007 Jun;7(3):272-8
17418639
Immunology. 1993 Oct;80(2):266-72
7903277
Emerg Infect Dis. 2010 Apr;16(4):595-603
20350372
Emerg Infect Dis. 2007 May;13(5):708-12
17553248
Nature. 2007 Jan 18;445(7125):319-23
17230189
J Exp Med. 2002 Jan 21;195(2):221-31
11805149
Vaccine. 2001 Dec 12;20(5-6):926-33
11738759
J Immunol. 2001 Nov 1;167(9):5099-105
11673520
Annu Rev Immunol. 1993;11:571-611
8476573
Nature. 2006 Oct 5;443(7111):578-81
17006449
J Exp Med. 1993 Feb 1;177(2):397-407
8426110