The microbiota of the respiratory tract: gatekeeper to respiratory health (original) (raw)

• Lloyd-Price, J., Abu-Ali, G. & Huttenhower, C. The healthy human microbiome. Genome Med. 8, 51 (2016).
  Article PubMed PubMed Central Google Scholar
• Weibel, E. R. Morphometry of the Human Lung (Springer Berlin Heidelberg, 1963).
  Book Google Scholar
• Bogaert, D., De Groot, R. & Hermans, P. W. M. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect. Dis. 4, 144–154 (2004). This review discusses how nasopharyngeal colonization with S. pneumoniae can be an important prerequisite to respiratory and invasive pneumococcal disease.
  Article CAS PubMed Google Scholar
• Bäumler, A. J. & Sperandio, V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535, 85–93 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• Yun, Y. et al. Environmentally determined differences in the murine lung microbiota and their relation to alveolar architecture. PLoS ONE 9, e113466 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012). This study in mice highlights that the early presence of microbiota can lead to host epigenetic changes, decreased accumulation of pro-inflammatory cells and development towards an asthmatic phenotype later in life.
  Article CAS PubMed PubMed Central Google Scholar
• Gollwitzer, E. S. et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat. Med. 20, 642–647 (2014). This paper comprehensively presents mechanistic evidence that the presence of the lung microbiota early in life promotes the healthy maturation of the neonatal immune system within a postnatal window of opportunity.
  Article CAS PubMed Google Scholar
• Som, P. M. & Naidich, T. P. Illustrated review of the embryology and development of the facial region, part 1: early face and lateral nasal cavities. Am. J. Neuroradiol. 34, 2233–2240 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Herriges, M. & Morrisey, E. E. Lung development: orchestrating the generation and regeneration of a complex organ. Development 141, 502–513 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• German, R. Z. & Palmer, J. B. Anatomy and development of oral cavity and pharynx. GI Motil. Online http://www.nature.com/gimo/contents/pt1/full/gimo5.html (2006).
• Burri, P. H. Fetal and postnatal development of the lung. Annu. Rev. Physiol. 46, 617–628 (1984).
  Article CAS PubMed Google Scholar
• Wostmann, B. S. The germfree animal in nutritional studies. Annu. Rev. Nutr. 1, 257–279 (1981).
  Article CAS PubMed Google Scholar
• Fukuyama, S. et al. Initiation of NALT organogenesis is independent of the IL-7R, LTβR, and NIK signaling pathways but requires the Id2 gene and CD3−CD4+CD45+ cells. Immunity 17, 31–40 (2002).
  Article CAS PubMed Google Scholar
• Aagaard, K. et al. The placenta harbors a unique microbiome. Sci. Transl Med. 6, 237ra65 (2014).
  PubMed PubMed Central Google Scholar
• Collado, M. C., Rautava, S., Aakko, J., Isolauri, E. & Salminen, S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci. Rep. 6, 23129 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Lauder, A. P. et al. Comparison of placenta samples with contamination controls does not provide evidence for a distinct placenta microbiota. Microbiome 4, 29 (2016).
  Article PubMed PubMed Central Google Scholar
• Gomez de Agüero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016).
  Article CAS PubMed Google Scholar
• Koch, M. A. et al. Maternal IgG and IgA antibodies dampen mucosal T helper cell responses in early life. Cell 165, 827–841 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).
  Article PubMed PubMed Central Google Scholar
• Bosch, A. A. et al. Development of upper respiratory tract microbiota in infancy is affected by mode of delivery. EBioMedicine 9, 336–345 (2016).
  Article PubMed PubMed Central Google Scholar
• Biesbroek, G. et al. Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children. Am. J. Respir. Crit. Care Med. 190, 1283–1292 (2014). This is a longitudinal study on the nasopharyngeal microbiota in children up to 2 years of age that links microbiome stability over time to environmental drivers, such as breastfeeding, specific bacterial community members and consecutive decreased rates of respiratory tract infections.
  Article PubMed Google Scholar
• Teo, S. M. et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 17, 704–715 (2015). This study in infants links nasopharyngeal colonization with Streptococcus spp., Moraxella spp. and Haemophilus spp. early in life to the development of LRT infections, consecutive atopic disease and future asthma.
  Article CAS PubMed PubMed Central Google Scholar
• Biesbroek, G. et al. The impact of breastfeeding on nasopharyngeal microbial communities in infants. Am. J. Respir. Crit. Care Med. 190, 298–308 (2014).
  Article PubMed Google Scholar
• Duijts, L., Jaddoe, V. W. V., Hofman, A. & Moll, H. A. Prolonged and exclusive breastfeeding reduces the risk of infectious diseases in infancy. Pediatrics 126, e18–e25 (2010).
  Article PubMed Google Scholar
• Schanche, M. et al. High-resolution analyses of overlap in the microbiota between mothers and their children. Curr. Microbiol. 71, 283–290 (2015).
  Article CAS PubMed Google Scholar
• Jeurink, P. V. et al. Human milk: a source of more life than we imagine. Benef. Microbes 4, 17–30 (2013).
  Article CAS PubMed Google Scholar
• Hicks, L. A., Taylor, T. H. & Hunkler, R. J. U.S. outpatient antibiotic prescribing, 2010. N. Engl. J. Med. 368, 1461–1462 (2013).
  Article CAS PubMed Google Scholar
• Prevaes, S. M. et al. Development of the nasopharyngeal microbiota in infants with cystic fibrosis. Am. J. Respir. Crit. Care Med. 193, 504–515 (2016).
  Article CAS PubMed Google Scholar
• Pettigrew, M. M. et al. Upper respiratory tract microbial communities, acute otitis media pathogens, and antibiotic use in healthy and sick children. Appl. Environ. Microbiol. 78, 6262–6270 (2012). This cohort study indicates that specific commensal nasopharyngeal bacteria, including Corynebacterium spp. and Dolosigranulum spp., are associated with the exclusion of pathogens that are known to cause acute otitis media (AOM) and the risk of AOM.
  Article CAS PubMed PubMed Central Google Scholar
• Leibovitz, E. et al. Recurrent acute otitis media occurring within one month from completion of antibiotic therapy: relationship to the original pathogen. Pediatr. Infect. Dis. J. 22, 209–216 (2003).
  PubMed Google Scholar
• Bogaert, D. et al. Variability and diversity of nasopharyngeal microbiota in children: a metagenomic analysis. PLoS ONE 6, e17035 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Bogaert, D. et al. Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. Lancet 363, 1871–1872 (2004).
  Article CAS PubMed Google Scholar
• Mika, M. et al. Dynamics of the nasal microbiota in infancy: a prospective cohort study. J. Allergy Clin. Immunol. 135, 905–912.e11 (2015).
  Article PubMed Google Scholar
• Spijkerman, J. et al. Long-term effects of pneumococcal conjugate vaccine on nasopharyngeal carriage of S. pneumoniae, S. aureus, H. influenzae and M. catarrhalis. PLoS ONE 7, e39730 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Greenberg, D. et al. The contribution of smoking and exposure to tobacco smoke to Streptococcus pneumoniae and Haemophilus influenzae carriage in children and their mothers. Clin. Infect. Dis. 42, 897–903 (2006).
  Article PubMed Google Scholar
• Liu, C. M. et al. Staphylococcus aureus and the ecology of the nasal microbiome. Sci. Adv. 1, e1400216 (2015).
  Article PubMed PubMed Central Google Scholar
• Lim, M. Y. et al. Analysis of the association between host genetics, smoking, and sputum microbiota in healthy humans. Sci. Rep. 6, 23745 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Stearns, J. C. et al. Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age. ISME J. 9, 1246–1259 (2015).
  Article PubMed PubMed Central Google Scholar
• Jakobsson, H. E. et al. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS ONE 5, e9836 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Charlson, E. S. et al. Disordered microbial communities in the upper respiratory tract of cigarette smokers. PLoS ONE 5, e15216 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Morris, A. et al. Comparison of the respiratory microbiome in healthy nonsmokers and smokers. Am. J. Respir. Crit. Care Med. 187, 1067–1075 (2013).
  Article PubMed PubMed Central Google Scholar
• Whelan, F. J. et al. The loss of topography in the microbial communities of the upper respiratory tract in the elderly. Ann. Am. Thorac. Soc. 11, 513–521 (2014).
  Article PubMed Google Scholar
• Vissing, N. H., Chawes, B. L. K. & Bisgaard, H. Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates. Am. J. Respir. Crit. Care Med. 188, 1246–1252 (2013). This paper demonstrates that pharyngeal colonization by S. pneumoniae, H. influenzae or M. catarrhalis at 4 weeks of age is associated with an increased risk of respiratory tract infections during the first 3 years of life.
  Article PubMed Google Scholar
• Dominguez-Bello, M. G. et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat. Med. 22, 250–253 (2016). In this proof-of-principle study, the investigators aim to restore the initial microbial communities of newborns that are delivered by caesarean section by transferring the maternal vaginal microbiota.
  Article CAS PubMed PubMed Central Google Scholar
• Frank, D. N. et al. The human nasal microbiota and Staphylococcus aureus carriage. PLoS ONE 5, e10598 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Oh, J. et al. Biogeography and individuality shape function in the human skin metagenome. Nature 514, 59–64 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, Y. et al. Exploration of bacterial community classes in major human habitats. Genome Biol. 15, R66 (2014).
  PubMed PubMed Central Google Scholar
• Wos-Oxley, M. L. et al. Exploring the bacterial assemblages along the human nasal passage. Environ. Microbiol. 18, 2259–2271 (2016).
  Article CAS PubMed Google Scholar
• Yan, M. et al. Nasal microenvironments and interspecific interactions influence nasal microbiota complexity and S. aureus carriage. Cell Host Microbe 14, 631–640 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Segata, N. et al. Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples. Genome Biol. 13, R42 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• de Steenhuijsen Piters, W. A. et al. Dysbiosis of upper respiratory tract microbiota in elderly pneumonia patients. ISME J. 10, 97–108 (2016).
  Article CAS PubMed Google Scholar
• van den Bergh, M. R. et al. Associations between pathogens in the upper respiratory tract of young children: interplay between viruses and bacteria. PLoS ONE 7, e47711 (2012). This is the first study to investigate the prevalence and co-occurrence of potential bacterial respiratory pathogens and viruses in a large cohort of healthy children.
  Article CAS PubMed PubMed Central Google Scholar
• Wang, Y. et al. Metagenomic analysis of viral genetic diversity in respiratory samples from children with severe acute respiratory infection in China. Clin. Microbiol. Infect. 22, 458.e1–458.e9 (2016).
  Article CAS Google Scholar
• Wylie, K. M., Mihindukulasuriya, K. A., Sodergren, E., Weinstock, G. M. & Storch, G. A. Sequence analysis of the human virome in febrile and afebrile children. PLoS ONE 7, e27735 (2012). This study is the first to use metagenomics to assess the DNA and RNA virome in symptomatic and asymptomatic individuals, and reports that anelloviruses and enteroviruses are ubiquitous.
  Article CAS PubMed PubMed Central Google Scholar
• Eidi, S. et al. Nasal and indoors fungal contamination in healthy subjects. Health Scope 5, e30033 (2016).
  Article Google Scholar
• Charlson, E. S. et al. Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant. Am. J. Respir. Crit. Care Med. 186, 536–545 (2012).
  Article PubMed PubMed Central Google Scholar
• Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Cardinale, B. J. et al. Biodiversity loss and its impact on humanity. Nature 486, 59–67 (2012).
  Article CAS PubMed Google Scholar
• Huttenhower, C., Kostic, A. D. & Xavier, R. J. Inflammatory bowel disease as a model for translating the microbiome. Immunity 40, 843–854 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Kampmann, C., Dicksved, J., Engstrand, L. & Rautelin, H. Composition of human faecal microbiota in resistance to Campylobacter infection. Clin. Microbiol. Infect. 22, 61.e1–61.e8 (2016).
  Article CAS Google Scholar
• Fredricks, D. N., Fiedler, T. L. & Marrazzo, J. M. Molecular identification of bacteria associated with bacterial vaginosis. N. Engl. J. Med. 353, 1899–1911 (2005).
  Article CAS PubMed Google Scholar
• Ravel, J. et al. Vaginal microbiome of reproductive-age women. Proc. Natl Acad. Sci. USA 108, 4680–4687 (2011).
  Article CAS PubMed Google Scholar
• DiGiulio, D. B., Stevenson, D. K., Shaw, G., Lyell, D. J. & Relman, D. A. Reply to Keelan and Payne: microbiota-related pathways for preterm birth. Proc. Natl Acad. Sci. USA 112, E6415 (2015).
  CAS PubMed PubMed Central Google Scholar
• Hilty, M. et al. Nasopharyngeal microbiota in infants with acute otitis media. J. Infect. Dis. 205, 1048–1055 (2012).
  Article CAS PubMed Google Scholar
• Abreu, N. A. et al. Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis. Sci. Transl Med. 4, 151ra124 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Bomar, L., Brugger, S. D., Yost, B. H., Davies, S. S. & Lemon, K. P. Corynebacterium accolens releases antipneumococcal free fatty acids from human nostril and skin surface triacylglycerols. mBio 7, e01725-15 (2016). This in vitro study describes a mechanistic basis for the epidemiological association between Corynebacterium spp. and S. pneumoniae by demonstrating that C. accolens hydrolyses host triacylglycerols into free fatty acids that inhibit pneumococcal growth.
  Article PubMed PubMed Central CAS Google Scholar
• Laufer, A. S. et al. Microbial communities of the upper respiratory tract and otitis media in children. mBio 2, e00245-10 (2011).
  Article PubMed PubMed Central Google Scholar
• Kamada, N., Chen, G. Y., Inohara, N. & Núñez, G. Control of pathogens and pathobionts by the gut microbiota. Nat. Immunol. 14, 685–690 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Iwase, T. et al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature 465, 346–349 (2010).
  Article CAS PubMed Google Scholar
• Lysenko, E. S. et al. Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing. PLoS Pathog. 3, e118 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Huxley, E. J., Viroslav, J., Gray, W. R. & Pierce, A. K. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am. J. Med. 64, 564–568 (1978).
  Article CAS PubMed Google Scholar
• Bassis, C. M. et al. Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. mBio 6, e00037-15 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Segal, L. N. et al. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome 1, 19 (2013).
  Article PubMed PubMed Central Google Scholar
• Marsh, R. L. et al. The microbiota in bronchoalveolar lavage from young children with chronic lung disease includes taxa present in both the oropharynx and nasopharynx. Microbiome 4, 37 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Lohmann, P. et al. The airway microbiome of intubated premature infants: characteristics and changes that predict the development of bronchopulmonary dysplasia. Pediatr. Res. 76, 294–301 (2014).
  Article CAS PubMed Google Scholar
• Payne, M. S. et al. Molecular microbiological characterization of preterm neonates at risk of bronchopulmonary dysplasia. Pediatr. Res. 67, 412–418 (2010).
  Article PubMed Google Scholar
• Mourani, P. M., Harris, J. K., Sontag, M. K., Robertson, C. E. & Abman, S. H. Molecular identification of bacteria in tracheal aspirate fluid from mechanically ventilated preterm infants. PLoS ONE 6, e25959 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Dickson, R. P. et al. Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Ann. Am. Thorac. Soc. 12, 821–830 (2015). This paper demonstrates that spatial variation in the microbiota of healthy lungs is very minimal, which suggests that the community composition in the LRT is determined principally by immigration and the elimination of microbial communities that originate from the URT.
  Article PubMed PubMed Central Google Scholar
• Abbas, A. A. et al. The perioperative lung transplant virome: torque teno viruses are elevated in donor lungs and show divergent dynamics in primary graft dysfunction. Am. J. Transplant. http://dx.doi.org/10.1111/ajt.14076 (2016).
• Willner, D. et al. Metagenomic analysis of respiratory tract DNA viral communities in cystic fibrosis and non-cystic fibrosis individuals. PLoS ONE 4, e7370 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Young, J. C. et al. Viral metagenomics reveal blooms of anelloviruses in the respiratory tract of lung transplant recipients. Am. J. Transplant. 15, 200–209 (2015).
  Article CAS PubMed Google Scholar
• van Woerden, H. C. et al. Differences in fungi present in induced sputum samples from asthma patients and non-atopic controls: a community based case control study. BMC Infect. Dis. 13, 69 (2013).
  Article PubMed PubMed Central Google Scholar
• Cleland, E. J. et al. The fungal microbiome in chronic rhinosinusitis: richness, diversity, postoperative changes and patient outcomes. Int. Forum Allergy Rhinol. 4, 259–265 (2014).
  Article PubMed Google Scholar
• Charlson, E. S. et al. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am. J. Respir. Crit. Care Med. 184, 957–963 (2011).
  Article PubMed PubMed Central Google Scholar
• Venkataraman, A. et al. Application of a neutral community model to assess structuring of the human lung microbiome. mBio 6, e02284-14 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Willner, D. et al. Spatial distribution of microbial communities in the cystic fibrosis lung. ISME J. 6, 471–474 (2012).
  Article CAS PubMed Google Scholar
• Mashima, I. & Nakazawa, F. The influence of oral Veillonella species on biofilms formed by Streptococcus species. Anaerobe 28, 54–61 (2014).
  Article PubMed Google Scholar
• Cook, L. C., LaSarre, B. & Federle, M. J. Interspecies communication among commensal and pathogenic streptococci. mBio 4, e00382-13 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Armbruster, C. E. et al. Indirect pathogenicity of Haemophilus influenzae and Moraxella catarrhalis in polymicrobial otitis media occurs via interspecies quorum signaling. mBio 1, e00102-10 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Wos-Oxley, M. L. et al. A poke into the diversity and associations within human anterior nare microbial communities. ISME J. 4, 839–851 (2010).
  Article PubMed Google Scholar
• Regev-Yochay, G., Trzcinski, K., Thompson, C. M., Malley, R. & Lipsitch, M. Interference between Streptococcus pneumoniae and Staphylococcus aureus: in vitro hydrogen peroxide-mediated killing by Streptococcus pneumoniae. J. Bacteriol. 188, 4996–5001 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Selva, L. et al. Killing niche competitors by remote-control bacteriophage induction. Proc. Natl Acad. Sci. USA 106, 1234–1238 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Deasy, A. M. et al. Nasal inoculation of the commensal Neisseria lactamica inhibits carriage of Neisseria meningitidis by young adults: a controlled human infection study. Clin. Infect. Dis. 60, 1512–1520 (2015).
  Article PubMed Google Scholar
• Janek, D., Zipperer, A., Kulik, A., Krismer, B. & Peschel, A. High frequency and diversity of antimicrobial activities produced by nasal Staphylococcus strains against bacterial competitors. PLoS Pathog. 12, e1005812 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• Ramsey, M. M., Freire, M. O., Gabrilska, R. A., Rumbaugh, K. P. & Lemon, K. P. Staphylococcus aureus shifts toward commensalism in response to Corynebacterium species. Front. Microbiol. 7, 1230 (2016).
  Article PubMed PubMed Central Google Scholar
• Zipperer, A. et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535, 511–516 (2016).
  Article CAS PubMed Google Scholar
• Tong, T. T., Mörgelin, M., Forsgren, A. & Riesbeck, K. Haemophilus influenzae survival during complement-mediated attacks is promoted by Moraxella catarrhalis outer membrane vesicles. J. Infect. Dis. 195, 1661–1670 (2007).
  Article CAS Google Scholar
• de Steenhuijsen Piters, W. A., Sanders, E. A. & Bogaert, D. The role of the local microbial ecosystem in respiratory health and disease. Philos. Trans. R. Soc. B Biol. Sci. 370, 20140294 (2015).
  Article CAS Google Scholar
• Taubenberger, J. K., Reid, A. H. & Fanning, T. G. The 1918 influenza virus: a killer comes into view. Virology 274, 241–245 (2000).
  Article CAS PubMed Google Scholar
• Bosch, A. A., Biesbroek, G., Trzcinski, K., Sanders, E. A. M. & Bogaert, D. Viral and bacterial interactions in the upper respiratory tract. PLoS Pathog. 9, e1003057 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Sajjan, U., Wang, Q., Zhao, Y., Gruenert, D. C. & Hershenson, M. B. Rhinovirus disrupts the barrier function of polarized airway epithelial cells. Am. J. Respir. Crit. Care Med. 178, 1271–1281 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Avadhanula, V. et al. Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner. J. Virol. 80, 1629–1636 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Ramphal, R., Small, P. M., Shands, J. W., Fischlschweiger, W. & Small, P. A. Adherence of Pseudomonas aeruginosa to tracheal cells injured by influenza infection or by endotracheal intubation. Infect. Immun. 27, 614–619 (1980).
  Article CAS PubMed PubMed Central Google Scholar
• Siegel, S. J., Roche, A. M. & Weiser, J. N. Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source. Cell Host Microbe 16, 55–67 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Pittet, L. A., Hall-Stoodley, L., Rutkowski, M. R. & Harmsen, A. G. Influenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumoniae. Am. J. Respir. Cell Mol. Biol. 42, 450–460 (2010).
  Article CAS PubMed Google Scholar
• Raza, M. W., Blackwell, C. C., Elton, R. A. & Weir, D. M. Bactericidal activity of a monocytic cell line (THP-1) against common respiratory tract bacterial pathogens is depressed after infection with respiratory syncytial virus. J. Med. Microbiol. 49, 227–233 (2000).
  Article CAS PubMed Google Scholar
• Didierlaurent, A. et al. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J. Exp. Med. 205, 323–329 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sun, K. & Metzger, D. W. Inhibition of pulmonary antibacterial defense by interferon-γ during recovery from influenza infection. Nat. Med. 14, 558–564 (2008).
  Article CAS PubMed Google Scholar
• Robinson, K. M. et al. Influenza A virus exacerbates staphylococcus aureus pneumonia in mice by attenuating antimicrobial peptide production. J. Infect. Dis. 209, 865–875 (2014).
  Article CAS PubMed Google Scholar
• Ni, K. et al. Pharyngeal microflora disruption by antibiotics promotes airway hyperresponsiveness after respiratory syncytial virus infection. PLoS ONE 7, e41104 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Wyde, P. R., Six, H. R., Ambrose, M. W. & Throop, B. J. Muramyl peptides and polyinosinic-polycytodylic acid given to mice prior to influenza virus challenge reduces pulmonary disease and mortality. J. Biol. Response Mod. 9, 98–102 (1990).
  CAS PubMed Google Scholar
• Sajjan, U. S. H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression. FASEB J. 20, 2121–2123 (2006).
  Article CAS PubMed Google Scholar
• Gulraiz, F., Bellinghausen, C., Bruggeman, C. A. & Stassen, F. R. Haemophilus influenzae increases the susceptibility and inflammatory response of airway epithelial cells to viral infections. FASEB J. 29, 849–858 (2015).
  Article CAS PubMed Google Scholar
• Bellinghausen, C. et al. Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection. Respir. Res. 17, 68 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• de Steenhuijsen Piters, W. A. A. et al. Nasopharyngeal microbiota, host transcriptome and disease severity in children with respiratory syncytial virus infection. Am. J. Respir. Crit. Care Med. 1104–1115 (2016). This clinical study shows that the composition of the microbiota of the nasopharynx during early RSV infection is strongly associated with the differential expression of genes that are linked to innate immune pathways that, in turn, are associated with increased RSV disease severity.
• Scheiblauer, H., Reinacher, M., Tashiro, M. & Rott, R. Interactions between bacteria and influenza A virus in the development of influenza pneumonia. J. Infect. Dis. 166, 783–791 (1992).
  Article CAS PubMed Google Scholar
• Tashiro, M., Ciborowski, P., Klenk, H.-D., Pulverer, G. & Rott, R. Role of Staphylococcus protease in the development of influenza pneumonia. Nature 325, 536–537 (1987).
  Article CAS PubMed Google Scholar
• Short, K. R. et al. Bacterial lipopolysaccharide inhibits influenza virus infection of human macrophages and the consequent induction of CD8+ T cell immunity. J. Innate Immun. 6, 129–139 (2014).
  Article CAS PubMed Google Scholar
• Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl Acad. Sci. USA 108, 5354–5359 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Amit, I. et al. Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses. Science 326, 257–263 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Abt, M. C. et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37, 158–170 (2012). This study highlights that LPS signalling of commensal bacteria contributes to immune 'readiness' and an adequate innate immune response following viral infection.
  Article CAS PubMed PubMed Central Google Scholar
• Pride, D. T., Salzman, J. & Relman, D. A. Comparisons of clustered regularly interspaced short palindromic repeats and viromes in human saliva reveal bacterial adaptations to salivary viruses. Environ. Microbiol. 14, 2564–2576 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Williams, H. T. P. Phage-induced diversification improves host evolvability. BMC Evol. Biol. 13, 17 (2013).
  Article PubMed PubMed Central Google Scholar
• Segal, L. N. et al. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat. Microbiol. 1, 16031 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Boase, S. et al. Bacterial-induced epithelial damage promotes fungal biofilm formation in a sheep model of sinusitis. Int. Forum Allergy Rhinol. 3, 341–348 (2013).
  Article PubMed Google Scholar
• Diaz, P. I. et al. Synergistic interaction between Candida albicans and commensal oral streptococci in a novel in vitro mucosal model. Infect. Immun. 80, 620–632 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Xu, H. et al. Streptococcal co-infection augments Candida pathogenicity by amplifying the mucosal inflammatory response. Cell. Microbiol. 16, 214–231 (2014).
  Article CAS PubMed Google Scholar
• Briard, B., Heddergott, C. & Latgé, J.-P. Volatile compounds emitted by Pseudomonas aeruginosa stimulate growth of the fungal pathogen Aspergillus fumigatus. mBio 7, e00219 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Roux, D. et al. Candida albicans impairs macrophage function and facilitates Pseudomonas aeruginosa pneumonia in rat. Crit. Care Med. 37, 1062–1067 (2009).
  Article PubMed Google Scholar
• Linden, S. K., Sutton, P., Karlsson, N. G., Korolik, V. & McGuckin, M. A. Mucins in the mucosal barrier to infection. Mucosal Immunol. 1, 183–197 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Roy, M. G. et al. Muc5b is required for airway defence. Nature 505, 412–416 (2014).
  Article CAS PubMed Google Scholar
• Kiyono, H. & Fukuyama, S. NALT- versus Peyer's-patch-mediated mucosal immunity. Nat. Rev. Immunol. 4, 699–710 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Kawamoto, S. et al. Foxp3+ T cells regulate immunoglobulin A selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41, 152–165 (2014).
  Article CAS PubMed Google Scholar
• Sutherland, D. B., Suzuki, K. & Fagarasan, S. Fostering of advanced mutualism with gut microbiota by immunoglobulin A. Immunol. Rev. 270, 20–31 (2016).
  Article CAS PubMed Google Scholar
• LeVine, A. M. et al. Distinct effects of surfactant protein A or D deficiency during bacterial infection on the lung. J. Immunol. 165, 3934–3940 (2000).
  Article CAS PubMed Google Scholar
• Uehara, A., Fujimoto, Y., Fukase, K. & Takada, H. Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol. Immunol. 44, 3100–3111 (2007).
  Article CAS PubMed Google Scholar
• Kim, D.-Y. et al. The airway antigen sampling system: respiratory M cells as an alternative gateway for inhaled antigens. J. Immunol. 186, 4253–4262 (2011).
  Article CAS PubMed Google Scholar
• Jahnsen, F. L. et al. Accelerated antigen sampling and transport by airway mucosal dendritic cells following inhalation of a bacterial stimulus. J. Immunol. 177, 5861–5867 (2006).
  Article CAS PubMed Google Scholar
• Kopf, M., Schneider, C. & Nobs, S. P. The development and function of lung-resident macrophages and dendritic cells. Nat. Immunol. 16, 36–44 (2014).
  Article CAS Google Scholar
• Hussell, T. & Bell, T. J. Alveolar macrophages: plasticity in a tissue-specific context. Nat. Rev. Immunol. 14, 81–93 (2014).
  Article CAS PubMed Google Scholar
• Westphalen, K. et al. Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity. Nature 506, 503–506 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Holt, P. G. et al. Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages. J. Exp. Med. 177, 397–407 (1993).
  Article CAS PubMed Google Scholar
• Holt, P. G., Schon-Hegrad, M. A. & Oliver, J. MHC class II antigen-bearing dendritic cells in pulmonary tissues of the rat. Regulation of antigen presentation activity by endogenous macrophage populations. J. Exp. Med. 167, 262–274 (1988).
  Article CAS PubMed Google Scholar
• Soroosh, P. et al. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J. Exp. Med. 210, 775–788 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Margulies, M. et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437, 376–380 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Mills, B., Bradley, M. & Dhaliwal, K. Optical imaging of bacterial infections. Clin. Transl Imaging 4, 163–174 (2016).
  Article PubMed PubMed Central Google Scholar
• McLoughlin, K., Schluter, J., Rakoff-Nahoum, S., Smith, A. L. & Foster, K. R. Host selection of microbiota via differential adhesion. Cell Host Microbe 19, 550–559 (2016).
  Article CAS PubMed Google Scholar
• Liu, L. et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 379, 2151–2161 (2012).
  Article PubMed Google Scholar
• Zeevi, D. et al. Personalized nutrition by prediction of glycemic responses. Cell 163, 1079–1095 (2015).
  Article CAS PubMed Google Scholar
• Caporaso, J. G. et al. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J. 6, 1621–1624 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Goleva, E. et al. The effects of airway microbiome on corticosteroid responsiveness in asthma. Am. J. Respir. Crit. Care Med. 188, 1193–1201 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Salter, S. J. et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 12, 87 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Biesbroek, G. et al. Deep sequencing analyses of low density microbial communities: working at the boundary of accurate microbiota detection. PLoS ONE 7, e32942 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Dickson, R. P. et al. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat. Microbiol. 1, 16113 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Larsen, J. M. et al. Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology. Immunology 144, 333–342 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Bäckhed, F., Normark, S., Schweda, E. K. H., Oscarson, S. & Richter-Dahlfors, A. Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications. Microbes Infect. 5, 1057–1063 (2003).
  Article CAS PubMed Google Scholar
• Coats, S. R., Reife, R. A., Bainbridge, B. W., Pham, T. T.-T. & Darveau, R. P. Porphyromonas gingivalis lipopolysaccharide antagonizes Escherichia coli lipopolysaccharide at Toll-like receptor 4 in human endothelial cells. Infect. Immun. 71, 6799–6807 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Munford, R. S. Sensing Gram-negative bacterial lipopolysaccharides: a human disease determinant? Infect. Immun. 76, 454–465 (2008).
  Article CAS PubMed Google Scholar
• Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010).
  Article CAS PubMed Google Scholar
• Kao, C.-Y. et al. IL-17 markedly up-regulates β-defensin-2 expression in human airway epithelium via JAK and NF-κB signaling pathways. J. Immunol. 173, 3482–3491 (2004).
  Article CAS PubMed Google Scholar
• Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, J. et al. Bacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages. Nat. Commun. 4, 2106 (2013). This study shows that nasal S. aureus instillation results in TLR2-dependent polarization towards anti-inflammatory alveolar macrophages, which attenuates influenza virus-induced immune-mediated lung injury.
  Article PubMed CAS Google Scholar
• Rice, T. A. et al. Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection. Antiviral Res. 132, 131–140 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Clarke, T. B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat. Med. 16, 228–231 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Herbst, T. et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am. J. Respir. Crit. Care Med. 184, 198–205 (2011).
  Article CAS PubMed Google Scholar
• Naik, S. et al. Commensal–dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Krishnamoorthy, N. et al. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat. Med. 18, 1525–1530 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Rangel-Moreno, J. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol. 12, 639–646 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Scharschmidt, T. C. et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity 43, 1011–1021 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Virgin, H. W., Wherry, E. J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30–50 (2009).
  Article CAS PubMed Google Scholar
• McGeoch, D. J., Rixon, F. J. & Davison, A. J. Topics in herpesvirus genomics and evolution. Virus Res. 117, 90–104 (2006).
  Article CAS PubMed Google Scholar
• Barton, E. S. et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007).
  Article CAS PubMed Google Scholar
• Kim, E. Y. et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat. Med. 14, 633–640 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mejias, A. et al. Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection. PLoS Med. 10, e1001549 (2013).
  Article PubMed PubMed Central Google Scholar
• England, R. J., Homer, J. J., Knight, L. C. & Ell, S. R. Nasal pH measurement: a reliable and repeatable parameter. Clin. Otolaryngol. Allied Sci. 24, 67–68 (1999).
  Article CAS PubMed Google Scholar
• Brunworth, J. D., Garg, R., Mahboubi, H., Johnson, B. & Djalilian, H. R. Detecting nasopharyngeal reflux: a novel pH probe technique. Ann. Otol. Rhinol. Laryngol. 121, 427–430 (2012).
  Article PubMed Google Scholar
• Ayazi, S. et al. A new technique for measurement of pharyngeal pH: normal values and discriminating pH threshold. J. Gastrointest. Surg. 13, 1422–1429 (2009).
  Article CAS PubMed Google Scholar
• West, J. B. Regional differences in the lung. Chest 74, 426 (1978).
  CAS PubMed Google Scholar
• Keck, T. & Lindemann, J. Numerical simulation and nasal air-conditioning. GMS Curr. Top. Otorhinolaryngol. Head Neck Surg. http://dx.doi.org/10.3205/cto000072 (2010).
• Ingenito, E. P. et al. Indirect assessment of mucosal surface temperatures in the airways: theory and tests. J. Appl. Physiol. 63, 2075–2083 (1987).
  Article CAS PubMed Google Scholar
• McFadden, E. R. et al. Thermal mapping of the airways in humans. J. Appl. Physiol. 58, 564–570 (1985).
  Article PubMed Google Scholar
• Morgan, N. J., MacGregor, F. B., Birchall, M. A., Lund, V. J. & Sittampalam, Y. Racial differences in nasal fossa dimensions determined by acoustic rhinometry. Rhinology 33, 224–228 (1995).
  CAS PubMed Google Scholar
• Walsh, J. H. et al. Evaluation of pharyngeal shape and size using anatomical optical coherence tomography in individuals with and without obstructive sleep apnoea. J. Sleep Res. 17, 230–238 (2008).
  Article PubMed Google Scholar
• Hatch, T. F. Distribution and deposition of inhaled particles in respiratory tract. Bacteriol. Rev. 25, 237–240 (1961).
  Article CAS PubMed PubMed Central Google Scholar
• Prussin, A. J. & Marr, L. C. Sources of airborne microorganisms in the built environment. Microbiome 3, 78 (2015).
  Article PubMed PubMed Central Google Scholar