Molecular Control of Innate Immune Response to Pseudomonas aeruginosa Infection by Intestinal let-7 in Caenorhabditis elegans

Abstract

The microRNA (miRNA) let-7 is an important miRNA identified in Caenorhabditis elegans and has been shown to be involved in the control of innate immunity. The underlying molecular mechanisms for let-7 regulation of innate immunity remain largely unclear. In this study, we investigated the molecular basis for intestinal let-7 in the regulation of innate immunity. Infection with Pseudomonas aeruginosa PA14 decreased let-7:: GFP expression. Intestine- or neuron-specific activity of let-7 was required for its function in the regulation of innate immunity. During the control of innate immune response to P. aeruginosa PA14 infection, SDZ-24 was identified as a direct target for intestinal let-7. SDZ-24 was found to be predominantly expressed in the intestine, and P. aeruginosa PA14 infection increased SDZ-24::GFP expression. Intestinal let-7 regulated innate immune response to P. aeruginosa PA14 infection by suppressing both the expression and the function of SDZ-24. Knockout or RNA interference knockdown of sdz-24 dampened the resistance of let-7 mutant to P. aeruginosa PA14 infection. Intestinal overexpression of sdz-24 lacking 3’-UTR inhibited the susceptibility of nematodes overexpressing intestinal let-7 to P. aeruginosa PA14 infection. In contrast, we could observed the effects of intestinal let-7 on innate immunity in P. aeruginosa PA14 infected transgenic strain overexpressing sdz-24 containing 3’-UTR. In the intestine, certain SDZ-24-mediated signaling cascades were formed for nematodes against the P. aeruginosa PA14 infection. Our results highlight the crucial role of intestinal miRNAs in the regulation of the innate immune response to pathogenic infection.

Author Summary

Some microRNAs (miRNAs) have been identified recently to play important roles in the regulation of innate immunity in Caenorhabditis elegans. let-7 is one of important miRNAs identified to be involved in the control of innate immune response. However, the underlying molecular mechanism for let-7 in the regulation of innate immune response is still largely unknown. In C. elegans, let-7 could function in both the intestine and the neurons to regulate the innate immunity. We here focused on the examination of molecular basis for the intestinal let-7 in the regulation of innate immune response to Pseudomonas aeruginosa PA14 infection. We identified SDZ-24, an ortholog of human replication protein A1, as a direct target for intestinal let-7 in the regulation of innate immune response. For the molecular mechanisms of intestinal let-7 in the regulation of innate immunity, let-7 might negatively regulate the function of SKN-1 by suppressing the expression and function of its target of SDZ-24. Our results imply the important function of intestinal miRNAs, such as let-7, in the regulation of innate immune response to pathogenic infection.