MiRNA profiling in blood and tissue samples in non‐human primates in response to Yersinia pestis infection using next generation sequencing approach

Abstract

MicroRNAs (miRNAs) are a class of small non‐coding RNA molecules (20–30 nucleotides long) that regulate gene expression negatively by transcriptional inhibition or post‐translational degradation. It is increasingly clear that miRNAs are an important part of the host response to microbes. In the current study, African green monkeys (Cercopithecus aethiops) were challenged intranasally with aerosolized Yersinia pestis strain CO92. Blood and tissue samples were collected post‐exposure from 6 hr through 42 hr time points. We used a next generation sequencing approach to profile miRNA expression patterns in different tissues and blood samples. Y. pestis is a gram‐negative facultative anaerobe and the causative agent of plague, which throughout history has had devastating effects on human populations. Our data enabled us to examine miRNA expression profiles during infection and identify tissue‐specific expression patterns during progression of the disease. We observed 180 upregulated miRNAs and 272 downregulated miRNAs across all time points in blood samples. At the 24 hr time point there were 52 differentially expressed (DE) miRNAs in blood samples that targeted 5381 genes. Functional analysis of DE miRNAs and their targets showed activation of TGF‐β and STAT3 pathways. TGF‐ β activated kinase 1 (TAK1, also called MAP3K7) is a known key regulator that inhibits innate immune signaling. In the kidney tissues there were a total of 32 DE miRNAs across all time points. At the 24 hr time point there were 11 unique mature DE miRNAs in exposed animal tissues as compared with non‐exposed animal tissues. In the lung tissues there were 67 DE miRNAs across all time points. At the 24 hr time point there were seven mature DE miRNAs when compared with non‐exposed animal tissues. These seven miRNAs were also DE in the blood samples. In the mediastinal lymph node tissues we had 52 DE miRNAs, eight of which were in common with blood samples. In the submandibular lymph nodes there were 25 DE miRNAs, three of which were in common with blood. We found that blood, lung, submandibular lymph and mediastinal lymph tissues shares two common miRNAs: mml‐miR‐590‐5p, which has 301 gene targets, and mml‐miR‐451, which has 17 gene targets. Both of these miRNAs are known to contribute to cytokine and grown factor activity, and miR‐590‐5p is a known circulating biomarker miRNA in cardiovascular and inflammatory diseases. Follow‐up comprehensive investigations are currently underway to further elucidate disease progression.Support or Funding InformationThis work was supported by the Defense Threat Reduction Agency, contractTMTI0029_09_WR_T