Faculty Bibliography

Pneumonia is one of the deadliest and most common infections worldwide. Traditional management has focused on pathogen-directed therapy with antimicrobial drugs. However, continued increase of antimicrobial resistance represents a growing health care crisis and heightens the urgency of shifting the treatment focus outside of the traditional paradigm. Adjunctive and host-directed therapies (HDT) target the response to infection by either enhancing the host immune response or mitigating immunopathology. They encompass a broad range of treatments, repurposed medications, and interventions that alter how the host responds to infections. This review summarizes adjunctive and HDTs for bacterial, tuberculous, fungal, and viral pneumonia.

Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation that results from maladaptive responses to lung epithelial injury; however, the underlying mechanisms remain unclear, and treatment options are limited. Here, we showed that deficiency in the innate immune receptor toll-like receptor 5 (TLR5) is associated with IPF in humans and with increased susceptibility to bleomycin-induced pulmonary fibrosis in mice and that activation of lung epithelial TLR5 through a synthetic flagellin analog protected mice from experimental fibrosis. Mechanistically, epithelial TLR5 activation induced antimicrobial gene expression and ameliorated lung dysbiosis after injury. In contrast, TLR5 deficiency in mice and patients with IPF was associated with lung dysbiosis. Elimination of the microbiome in mice through administration of antibiotics abolished the protective effect of TLR5, and reconstitution of the microbiome by fecal microbiota transplantation rescued the observed phenotype. In conclusion, these studies revealed that TLR5 protects against pulmonary fibrosis through effects on the lung microbiota, providing insight into therapeutic approaches that may ultimately benefit patients with IPF.

RATIONALE/BACKGROUND:The discoveries of neutrophilic inflammation and Pseudomonas-dominant pulmonary dysbiosis have helped pave the way for host-directed therapy in bronchiectasis. Substantial knowledge gaps still remain about the interplay between neutrophilic signatures and microbes in non-tuberculous mycobacterial lung disease (NTM-LD), a phenotypically diverse lung infection that is increasingly prevalent in the United States and other parts of the world. OBJECTIVES/OBJECTIVE:Evaluate the lower airway microbiota and neutrophilic traits in NTM- and NTM+ bronchiectasis. METHODS:16S rRNA gene sequencing, cell counts, and neutrophil extracellular trap (NET) immunoassays were performed on bronchoscopic lower airway samples in 200 bronchiectasis subjects (108 NTM-, 92 NTM+). A preclinical model of oral commensal micro-aspiration and NTM infection was used to profile the murine lower airways with flow cytometry and a NET assay. MEASUREMENTS AND MAIN RESULTS/RESULTS:Lower airways of NTM+ bronchiectasis patients were enriched with Mycobacterium and oral commensals (e.g., Veillonella, Prevotella and Streptococcus). NET levels were higher in NTM+ BAL. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa were associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine micro-aspiration model, the combination of oral commensals and Mycobacterium led to a sustained pro-inflammatory immune response marked by an increase in Th17, γδT cells, PD-1+ T lymphocytes as well as higher NET levels. CONCLUSIONS:Our analyses showed that distinct microbiome features beyond the primary pathogen can contribute to neutrophilic inflammation and severe disease phenotypes in bronchiectasis/ NTM-LD.

PURPOSE OF REVIEW/OBJECTIVE:This review aggregates, analyzes, and summarizes the current understanding of the lung microbiome as it relates to pneumonia. We will review the composition and function of a healthy lung microbiome and conceptualize dysbiosis associated with pneumonia. Finally, we discuss how the lung microbiome impacts the diagnosis, prognostication and pathogenesis, and recovery from pneumonia. RECENT FINDINGS/RESULTS:The most tangible benefit of studying the lung microbiome has been the identification of pathogenic organisms in suspected pneumonia; however, as there is a growing body of evidence that suggest the lung microbiome is critical to pneumonia. Generally, detection of potential pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Escherichia coli can be found even when sampling the lung microbiome of healthy individuals, yet it is unclear what determines the transition from potential pathogens present as bystanders to pathogens driving the development of pneumonia. Analysis of the lung microbiome suggests that the loss of "oral commensals" (bacteria found in the oral microbiome) in the lower airways is associated with the development of pneumonia and may provide diagnostic and prognostic insights. SUMMARY/CONCLUSIONS:The lung microbiome is a rich and dynamic ecosystem comprised of numerous bacterial, fungal, and viral taxa that may contribute to pneumonia pathogenesis. There is increasing evidence that the lung microbiome may provide insight into factors that determine the pathogenicity of respiratory microbes and the susceptibility of individuals to those pathogens.