Blood transcriptional profiling of childhood diarrheal diseases identifies gene signatures of Shigella and rotavirus infections

Globally, diarrheal diseases are a leading cause of death in children under five and disproportionately affect children in developing countries. To identify changes in gene expression associated with diarrheal disease, we performed RNA sequencing on whole blood of 192 children less than 10 years of age with acute diarrhea at the Hospital General O’Horan, and 47 age-matched healthy controls from Yucatan, Mexico. We found strong transcriptional signatures associated with rotavirus and Shigella infections relative to other diarrheal infections. The other organisms in our study ( Salmonella, E. coli , norovirus, and adenovirus) did not produce transcriptional changes that could be detected in whole blood. Weighted gene correlation network analysis was used to generate modules of genes with similar expression patterns that could be linked to biological functions. In the case of Shigella and rotavirus infections, differentially expressed genes with increased expression were grouped in modules associated with immune system functions. In Shigella infections, modules enriched for genes in adaptive immunity, especially in lymphocyte activation, showed decreased expression while modules enriched for innate immunity, including genes involved in complement activation, an inflammatory response and a response to bacteria, had increased expression. In rotavirus, but not other viral infections, the expression of a module containing genes involved in a type 1 interferon response was increased. Our data suggest that immune gene expression in peripheral blood may distinguish diarrheal diseases caused by Shigella and rotavirus infections from diseases caused by other organisms.