The respiratory microbiome and susceptibility to influenza virus infection

Abstract

Influenza is a major cause of morbidity and mortality worldwide. However, vaccine effectiveness has been low to moderate in recent years and vaccine coverage remains low, especially in low- and middle-income countries. Supplementary methods of prevention should be explored to reduce the high burden of influenza. A potential target is the respiratory tract microbiome, complex microbial communities which envelop the respiratory epithelium and play an important role in shaping host immunity. Using a household transmission study, we examined whether the nose/throat microbiota was associated with influenza susceptibility among participants exposed to influenza virus in the household. Further, we characterized changes in the nose/throat microbiota to explore whether community stability was influenced by influenza virus infection. Using a generalized linear mixed effects model, we found a nasal/oropharyngeal community state type (CST) associated with decreased susceptibility to influenza. The CST was rare and transitory among young children but a prevalent and stable CST among adults. Using boosting and linear mixed effects models, we found associations between the nose/throat microbiota and influenza also existed at the taxa level, specifically with the relative abundance of Alloprevotella, Prevotella, and Bacteroides oligotypes. We found high rates of change between bacterial community states among both secondary cases and household contacts who were not infected during follow up. Further work is needed to separate the effect of influenza virus infection from the considerable short-term changes that occur even in the absence of virus. Lastly, age was strongly associated with susceptibility to influenza and the nose/throat bacterial community structure. Although additional studies are needed to determine causality, our results suggest the nose/throat microbiome may be a potential target for reducing the burden of influenza.

Fig 1. Graphical abstract.

Fig 2. Relative abundance of 15 oligotypes, by nasal/oropharyngeal community state type (CST).

Oligotypes included in the figure attributed >50% of the difference between the single-CST model and the five-CST model. Bars represent the mean relative abundance of each oligotype (±1 standard error). 1,405 samples from 717 study participants residing in 144 households in Managua, Nicaragua, 2012–2014.

Fig 3. Secondary attack rates by nasal/oropharyngeal community state type at enrollment and age.

533 household contacts of influenza cases with defined community state type at enrollment, residing in 144 households in Managua, Nicaragua, 2012–2014. Numbers represent sample size of each group.

Fig 4. Generalized linear mixed effects model estimating odds of influenza virus infection.

Model adjusting for nasal/oropharyngeal community state type (relative to community state type 1), age (relative to adults), a smoker in the household, household crowding (average of >3 persons per bedroom), and clustering by household. 468 household contacts of influenza cases with complete data, residing in 132 households in Managua, Nicaragua, 2012–2014.

Fig 5. Stability of nasal/oropharyngeal community state type (CST) over follow up.

513 household contacts with microbiota data both at enrollment and follow up, residing in 144 households in Managua, Nicaragua, 2012–2014. (A) By influenza case status. (B) By age, among 443 household contacts who remained negative for influenza virus infection during follow up. (C) By age, among 70 secondary cases. Circles represent nasal/oropharyngeal community state types (CST) and circle size is proportional to prevalence of CSTs at enrollment. CST u corresponds to samples with an undefined CST. Transition rates between CSTs were estimated as Markov chain probabilities and are shown numerically. Transitions rates <0.10 were removed for simplicity. Complete data are available in S2 Appendix.

Fig 6. Generalized linear mixed effects model estimating odds of change in nasal/oropharyngeal community state type (CST) during follow up.

Model adjusting for influenza virus infection, nasal/oropharyngeal community state type at enrollment (relative to CST 1), age (relative to adults), a smoker in the household, household crowding (average of >3 persons per bedroom), and clustering by household. 443 household contacts with defined CST at enrollment and follow up and complete data, residing in 130 households in Managua, Nicaragua, 2012–2014. Household contacts with an undefined CST were excluded from analysis.