The lung microbiota: identifying key players to improve immune-mediated pathogen clearance

The microbiome is critical for maintaining health, in part by regulating our immune system. Here, we find that specific members of the airway microbiome induce a sub-clinical inflammatory response associated with improved clearance of a major bacterial pathogen from the lung.
The lung microbiota: identifying key players to improve immune-mediated pathogen clearance

Although the lungs are constantly exposed to bacteria, we know little regarding how individual species interact with our immune system. We were initially intrigued by the ability of Prevotella, which are among the most abundant bacteria in the lungs1-3, to promote secretion of the anti-inflammatory cytokine IL-10 from host innate immune cells4,5. As our recent work indicated that IL-10 induced by the pathogen Streptococcus pneumoniae exacerbates infection6, we initially suspected that Prevotella would increase susceptibility to S. pneumoniae. Contrary to our expectations, when we tried this experiment in mice, we found the opposite to be true. Mice exposed to Prevotella rapidly cleared S. pneumoniae from the lung, resulting in either reduced or undetectable burdens of S. pneumoniae within 24 hours. Others reported a similar protective effect with the same species of Prevotella, Prevotella melaninogenica, in combination with other airway commensals7. Together, these findings informed a new hypothesis; that P. melaninogenica is a ‘beneficial’ member of the airway microbiome because it enhances protection against bacterial pneumonia. 

While establishing causation in humans is difficult, next-generation microbiome sequencing studies support a protective role for airway Prevotella in the context of S. pneumoniae lung infection, as Prevotella are more abundant in the lungs of healthy individuals compared to those with pneumonia8,9. Further, Prevotella melaninogenica was ranked as the most discriminative bacterial species separating patients with S. pneumoniae pneumonia (who had less P. melaninogenica) from healthy controls (who had more P. melaninogenica)10. Critical work from Leopoldo N. Segal and colleagues showed that people with more Prevotella in their lungs had markers of sub-clinical inflammation, including increased numbers of activated lung neutrophils11. When we looked in mice, we observed a similar phenotype. Prevotella exposure was associated with increased neutrophil recruitment to the lung, and those neutrophils were better at killing S. pneumoniae.

But what about IL-10? We found it had an important role to play in Prevotella-mediated protection. While Prevotella induced an inflammatory response associated with neutrophil production of TNFα, which was critical for S. pneumoniae clearance, by 24 hours this inflammation was reduced, and IL-10 was increased. To our surprise, Prevotella-mediated protection was lost in IL-10 deficient mice. Analysis of lung myeloid cell populations indicated that in the absence of IL-10, several cell types over-expressed TNFα, which was systemically elevated in co-infected mice. These findings suggest a ‘Goldilocks effect’ regarding lung inflammation in this setting, where both too little (without Prevotella) or too much (without IL-10) renders the host more susceptible to S. pneumoniae infection.  

Finally, we wanted to know which Prevotella molecules interact with the immune system to enhance protection against S. pneumoniae. We found that TLR2 recognition of Prevotella lipoproteins was critical for protection, as TLR2 deficiency or lipoprotein digestion of Prevotella abrogated the protective effect. However, exposure to lipoproteins isolated from Prevotella wasn’t enough to improve protection, indicating a role for additional Prevotella-associated factors. To search for conserved protective features, we began to investigate other Prevotella isolates. We identified several additional airway Prevotella species which improved protection against S. pneumoniae and activated neutrophils in a TLR2-dependent manner. In contrast, the periodontal pathogen Prevotella intermedia was not protective against S. pneumoniae, consistent with a previous report12, and activated neutrophils regardless of TLR2, underscoring the importance of TLR2-associated neutrophil activation for Prevotella-enhanced clearance of S. pneumoniae (see Model).

Model. Exposure to protective Prevotella species enhances clearance of S. pneumoniae from the lung. Pathogen clearance in Prevotella primed individuals requires the recruitment and activation of neutrophil serine protease activity, which increases S. pneumoniae killing in a TLR2-dependent manner. Co-induction of IL-10 regulates Prevotella-induced inflammation.

The differential protection we observed among Prevotella species suggests that in people, the species-specific composition of Prevotella impacts individual susceptibility to bacterial pneumonia. In other words, aspirating ‘good’ rather than ‘bad’ Prevotella into the lung may improve your ability to get rid of the next S. pneumoniae to venture into your lower airway. Overall, the lung microbiome is known to contribute to protection against bacterial pneumonia and other respiratory tract diseases. However, as recently highlighted13, a large barrier to our ability to capitalize on this knowledge with therapeutic interventions is the lack of specific microbial targets and a better understanding of their interactions with the host immune system. Our work adds a new piece to the puzzle of how individual members of the lung microbiota impact immune-mediated protection against bacterial pathogens.

Read the paper here:

Horn, K.J., Schopper, M.A., Drigot, Z.G., Clark, S.E. Airway Prevotella promote TLR2-dependent neutrophil activation and rapid clearance of Streptococcus pneumoniae from the lung. Nat Commun 13, 3321 (2022).


  1. 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, 245–10 (2015).
  2. Dickson, R. P. et al. Bacterial Topography of the Healthy Human Lower Respiratory Tract. mBio 8, e02287–16 (2017).
  3. Hilty, M. et al. Disordered microbial communities in asthmatic airways. PLoS ONE 5, e8578 (2010).
  4. 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).
  5. Larsen, J. M. et al. Divergent pro-inflammatory profile of human dendritic cells in response to commensal and pathogenic bacteria associated with the airway microbiota. PLoS ONE 7, e31976–10 (2012).
  6. Clark, S. E., Schmidt, R. L., Aguilera, E. R. & Lenz, L. L. IL-10-producing NK cells exacerbate sublethal Streptococcus pneumoniae infection in the lung. Translational Research 226, 70–82 (2020).
  7. Wu, B. G. et al. Episodic Aspiration with Oral Commensals Induces a MyD88-dependent, Pulmonary T-Helper Cell Type 17 Response that Mitigates Susceptibility to Streptococcus pneumoniae. Am J Respir Crit Care Med 203, 1099–1111 (2020).
  8. He, Y. et al. Shared and Specific Lung Microbiota with Metabolic Profiles in Bronchoalveolar Lavage Fluid Between Infectious and Inflammatory Respiratory Diseases. Journal of Inflammation Research 15, 187–198 (2022).
  9. Bousbia, S. et al. Repertoire of Intensive Care Unit Pneumonia Microbiota. PLoS ONE 7, e32486–14 (2012).
  10. de Steenhuijsen Piters, W. A. A. et al. Dysbiosis of upper respiratory tract microbiota in elderly pneumonia patients. The ISME Journal 10, 97–108 (2016).
  11. Segal, L. N. et al. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome 1, 337–12 (2013).
  12. Nagaoka, K. et al. Prevotella intermedia Induces Severe Bacteremic Pneumococcal Pneumonia in Mice with Upregulated Platelet-Activating Factor Receptor Expression. Infection and Immunity 82, 587–593 (2014).
  13. Chotirmall, S. H. et al. Therapeutic Targeting of the Respiratory Microbiome. Am J Respir Crit Care Med 1–37 (2022). Advance online publication. doi: 10.1164/rccm.202112-2704PP

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