The role of microRNA in regulating antibacterial responses in innate immune cells

Respiratory infections are one of the major burdens to public health due to the ease of transmission and affect people of all ages. Respiratory infections are common and normal host defence mechanisms in the lung and are often adequate in clearing the invading pathogen. Infections, however, can be persistent or life threatening if patients have an underlying lung diseases such as chronic obstructive pulmonary disease (COPD) or if they are immunocompromised. Understanding the mechanisms and pathways responsible for regulating the host defence response to lung infections is central to developing new and novel therapeutic strategies. While the role of molecules such as pattern recognition receptors (PRRs) and the downstream signalling events they initiate to activate host defence has been extensively studied, the post-transcriptional regulation of molecules that are involved in immune regulation are just beginning to be explored. MicroRNAs are small non-coding RNA that bind to multiple target mRNA and regulate gene expression post-transcriptionally by repressing protein production. The role of miRNAs in initiating and controlling inflammation through cytokine production and toll-like receptor regulation in response to pathogens has received much attention. However, the role of specific miRNAs during bacterial lung infection, pathogen killing and phagocytosis remain unknown. Using a well-characterised model of respiratory infection with non-typeable Haemophilus Influenzae (NTHi), we show that miRNA-328 (miR-328) is downregulated in the lungs during NTHi infection. Further studies showed that pharmacological inhibition of miR-328 in vitro increased phagocytosis of bacteria by macrophages and neutrophils. Similarly, inhibiting miR-328 during infection of the lung improved bacterial clearance under normal conditions, and during heightened susceptibility to infection promoted by immune-suppression, and smoking-induced emphysema. Our studies uncover a novel role for miRNA in the regulation of phagocytosis and indicate the potential for the inhibition of miR-328 as a therapy for antibiotic resistant bacterial infections in the lung.