Immune response and mortality risk relate to distinct lung microbiomes in patients with HIV and pneumonia

Rationale: The potential role of the airway microbiota in dictating immune responses and infection outcomes in HIV-associated pneumonia is largely unknown. Objectives: To investigate whether microbiologically and immunologically distinct subsets of patients with HIV and pneumonia exist and are related to mortality. Methods: Bronchoalveolar lavage samples from Ugandan patients with HIV and pneumonia (n = 182) were obtained at study enrollment (following antibiotic treatment); patient demographics including 8-and 70-day mortality were collected. Lower airway bacterial community composition was assessed via amplification and sequencing of the V4 region of the 16S ribosomal RNA gene. Host immune response gene expression profiles were generated by quantitative polymerase chain reaction using RNA extracted from bronchoalveolar lavage fluid. Liquid and gas chromatography mass spectrometry was used to profile serum metabolites. Measurements and Main Results: Based on airway microbiome composition, most patients segregated into three distinct groups, each of which were predicted to encode metagenomes capable of producing metabolites characteristically enriched in paired serum samples from these patients. These three groups also exhibited differences in mortality; those with the highest rate had increased ceftriaxoneadministrationandculturable Aspergillus,anddemonstrated significantlyincreasedinductionofairwayT-helpercelltype2responses. The group with the lowest mortality was characterized by increased expression of T-cell immunoglobulin and mucin domain 3, which down-regulates T-helper cell type 1 proinflammatory responses and is associated with chronic viral infection. Conclusions: These data provide evidence that compositionally and structurally distinct lower airway microbiomes are associated with discrete local host immune responses, peripheral metabolic reprogramming, and different rates of mortality.