Sarah Clark, PhD

Our research is focused on understanding how the good ‘bugs’ in the airway protect us against infection. While it is clear that the airway microbiome plays a beneficial role, the specific members of this community which are important for protecting against infections, and how they mediate protection, are large unknowns. We focused on the impact of Prevotella, an abundant member of the airway microbiome, on lung infection. Next-generation microbiome sequencing studies have revealed that individuals with more Prevotella species, including Prevotella melaninogenica, have less bacterial pneumonia. The most common cause of bacterial pneumonia is the pathogen Streptococcus pneumoniae. Increased Prevotella in the lung correlates with reduced S. pneumoniae, suggesting a protective role. We recapitulated this relationship using an animal model and found that pre-exposure to P. melaninogenica dramatically improves rapid clearance of S. pneumoniae from the murine lung. P. melaninogenica-mediated protection was associated with the activation of an innate immune response in the lung, including the recruitment of neutrophils and induction of pro-inflammatory cytokines including TNF-alpha. Our hypothesis for this project was that P. melaninogenica activation of neutrophils and TNF-alpha are required for protection against S. pneumoniae. Our data thus far support this hypothesis, as the depletion of either neutrophils or TNF-alpha abrogates P. melaninogenica-mediated protection. Further, we found that neutrophils in the lungs of Prevotella-exposed mice are better at killing S. pneumoniae, suggesting that these cells are primed for enhanced pathogen clearance. Prevotella-enhanced killing was dependent on neutrophil expression of the innate immune receptor TLR2. In comparing wild-type to TLR2-deficient mice, we found that Prevotella-mediated protection is lost in the absence of TLR2. We also found that TLR2 recognizes lipoproteins expressed on the cellular membrane of P. melaninogenica. However, lipoproteins alone are not sufficient to improve clearance of S. pneumoniae from the lung, suggesting that other Prevotella-derived molecules contribute to immune stimulation and protection against S. pneumoniae. Currently, we are comparing P. melaninogenica with other airway Prevotella isolates to identify conserved bacterial features associated with protection. Our data suggest that non-pathogenic Prevotella species which activate neutrophils in a TLR2-dependent manner are protective against S. pneumoniae. In contrast, we found that the major periodontal pathogen Prevotella intermedia does not activate neutrophils in a TLR2-dependent manner and is not protective against S. pneumoniae. Together, these data suggest that the species-specific composition of Prevotella in the airway determines individual susceptibility to bacterial pneumonia. This work suggests that some Prevotella species may be used as immunobiotics to improve protection against S. pneumoniae by priming the airway innate immune system.

Update: Our research uses a co-infection model which recapitulates the clinical observation that individuals with increased abundance of the airway bacterium Prevotella have reduced infection by the bacterial pathogen Streptococcus pneumoniae. We found that exposure to Prevotella melaninogenica improves protection against S. pneumoniae lung infection by activating an innate immune response which requires neutrophils, the pro-inflammatory cytokine TNF-alpha, and the host receptor TLR2. Further, only non-pathogenic Prevotella strains which activate neutrophils in a TLR2-dependent manner are protective, suggesting that the species-specific composition of airway Prevotella informs infection risk.