The administration of intranasal live attenuated influenza vaccine induces changes in the nasal microbiota and nasal epithelium gene expression profiles

Abstract

BackgroundViral infections such as influenza have been shown to predispose hosts to increased colonization of the respiratory tract by pathogenic bacteria and secondary bacterial pneumonia. To examine how viral infections and host antiviral immune responses alter the upper respiratory microbiota, we analyzed nasal bacterial composition by 16S ribosomal RNA (rRNA) gene sequencing in healthy adults at baseline and at 1 to 2 weeks and 4 to 6 weeks following instillation of live attenuated influenza vaccine or intranasal sterile saline. A subset of these samples was submitted for microarray host gene expression profiling.ResultsWe found that live attenuated influenza vaccination led to significant changes in microbial community structure, diversity, and core taxonomic membership as well as increases in the relative abundances of Staphylococcus and Bacteroides genera (both p < 0.05). Hypergeometric testing for the enrichment of gene ontology terms in the vaccinated group reflected a robust up-regulation of type I and type II interferon-stimulated genes in the vaccinated group relative to controls. Translational murine studies showed that poly I:C administration did in fact permit greater nasal Staphylococcus aureus persistence, a response absent in interferon alpha/beta receptor deficient mice.ConclusionsCollectively, our findings demonstrate that although the human nasal bacterial community is heterogeneous and typically individually robust, activation of a type I interferon (IFN)-mediated antiviral response may foster the disproportionate emergence of potentially pathogenic species such as S. aureus.Trial registrationThis study was registered with Clinicaltrials.gov on 11/3/15, NCT02597647.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-015-0133-2) contains supplementary material, which is available to authorized users.

Interaction between the nasal microbiota and S. pneumoniae in the context of live-attenuated influenza vaccine

“…Characterization of microbiota changes related to LAIV/ influenza virus was challenging, given the relatively large pneumococcus-induced ecological perturbations observed in both volunteers who became high-dense and non-carriers. Our data suggest that LAIV only modestly modulates microbiota-mediated receptiveness, and in addition, impacts pneumococcal acquisition and density by the induced mucosal inflammation 13,14 .…”

“…The role of influenza in acquisition and blooming of pneumococci is demonstrated in a controlled experimental infection model using wild-type influenza virus 9 , and in studies testing live-attenuated influenza vaccine (LAIV) in mice 10 and humans 11,12 . Mechanistic pathways have been partly delineated 11,12 ; however, less is known on the effects of viral infection on the resident respiratory microbiota and vice versa 13,14 .…”

Viral–bacterial interactions in the respiratory tract

“…Indeed, several studies point to distinct mechanisms of copathogenesis depending on the order of infection (Lee et al, 2010;McCullers & Rehg, 2002). In the host, however, the impact of sequential infections most likely does not stop there, as acute exposures to pathogens have been shown to trigger alterations in the local bacterial microbiome (Molyneaux et al, 2013;Tarabichi et al, 2015), which may impact on subsequent 'rounds' of infection. Moreover, the pulmonary microbiome encompasses not only bacteria, but also fungi and viruses (Marsland & Gollwitzer, 2014).…”

“…Although a causal relationship between nasopharyngeal colonization and the response to viral infection cannot be deduced from these studies, they suggest that microbiological phenotyping might be predictive of the risk and response to viral infection. If a causality exists, a shift in the nasopharyngeal microbiota caused by vaccinations against respiratory pathogens would have implications for unrelated infections as well (Biesbroek et al, 2014;Tarabichi et al, 2015).…”

Interactions of Respiratory Viruses and the Nasal Microbiota during the First Year of Life in Healthy Infants

“…Furthermore, respiratory viral infections play an important role in morbidity and early immune development during the first year of life in otherwise healthy infants (12)(13)(14)(15)(16). Despite recent data on the association between viral infections and changes in the microbiota in adults, data for young children are scarce (17)(18)(19)(20)(21)(22). Due to several risk factors triggering both viral and bacterial infections, it is difficult to draw causal associations between those early infections and later disease development.…”