title: Attenuated Bordetella pertussis protects against highly pathogenic influenza A viruses by dampening the cytokine storm.
abstract: 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.
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, CeLS Building no. 03-05, 28 Medical Drive, Singapore 117597, Singapore.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lim
authors.forename: Meng Chee
authors.initials: MC
authors.lastname: Phoon
authors.forename: Teluguakula
authors.initials: T
authors.lastname: Narasaraju
authors.forename: Jowin K W
authors.initials: JK
authors.lastname: Ng
authors.forename: Wee Peng
authors.initials: WP
authors.lastname: Poh
authors.forename: Meng Kwoon
authors.initials: MK
authors.lastname: Sim
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Chow
authors.forename: Camille
authors.initials: C
authors.lastname: Locht
authors.forename: Sylvie
authors.initials: S
authors.lastname: Alonso
mesh_terms: 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
chemical_list: D018925:Chemokines; D016207:Cytokines; D007252:Influenza Vaccines
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