Microbial and Proteomic Signature of Acute Cellular Rejection in Lung Transplants.

RATIONALE: Acute cellular rejection (ACR) is a common cause of early post lung transplant morbidity and mortality. Identification of ACR biomarkers may provide a less invasive mechanism for diagnosing ACR, improve understanding of the mechanisms behind ACR, and identify novel pathways for intervention. OBJECTIVES: To determine whether unique microbial or protein signatures exist in lung transplant patients with ACR. METHODS: We performed a nested case-control study utilizing bronchoalveolar lavage (BAL) fluid and plasma from 9 lung transplant cases with mild ACR (A2) paired with 9 ACR-free controls (A0) matched for time since transplant. Proteins in the plasma and BAL samples were quantified with Liquid Chromatography-Tandem Mass Spectrometry (LC-MSMS). The microbiome of the BAL samples was profiled using 16S rRNA marker gene sequencing. MEASUREMENTS AND MAIN RESULTS: BAL Shannon diversity was lower in the ACR cases (P = .006), with lower relative abundance of Prevotella (q < 0.001) and Gemella (q = 0.05) relative to matched post-transplant controls. No bacterial taxon consistently had higher relative abundance as a marker of ACR. Proteomics analyses showed the ACR group had significantly higher fibrinogen alpha and beta chains in BAL samples and higher complement C4a, C9, and complement factor properdin in plasma samples compared to controls. The C4a and C9 proteins were negatively correlated with common airway bacteria Rothia, Prevotella, and Veillonella. CONCLUSIONS: This study identified microbial and host biomarkers of ACR. We detected candidate biomarkers that underscore the mechanistic implications of complement and fibrinogen in ACR and that may be useful as future diagnostic tools for ACR.