Despite intense research for many decades, the mechanisms of protective immunity against malaria are poorly understood. Systems immunology integrates molecular immune profiling data collected upon infection and offers the potential to provide new insights into the key mechanisms involved in host immunity. MicroRNAs are small non-coding RNAs implicated in post transcriptional gene regulation. Of particular interest is the crucial role of microRNAs in signaling pathways driving the immune response to infection. However, host microRNAs expression during Plasmodium infection in humans has not yet been investigated. This study aimed to define the expression profile of circulating microRNAs during P. falciparum infection, using a unique human experimental blood stage infection model.
Blood was collected before and one week post infection from 14 individuals and microRNA expression was measured by qRT-PCR using a T cell and B cell activation PCR array (Qiagen). Unexpectedly, subjects segregated into two groups based on their fold change in microRNA expression early post infection with P. falciparum: individuals that down-regulated most of the microRNAs upon infection (low miRNAs responders) and individuals that up-regulated most of the microRNAs upon infection (high miRNAs responders). High miRNAs responders presented a higher frequency of circulating lymphocytes expressing the activation marker CD38 one week post infection, a stronger P. falciparum specific antibody response four weeks post infection, and reduced blood stage parasitemia, as compared to low miRNAs responders. Findings were further validated with 14 additional subjects.
Three microRNAs were inversely correlated with parasitemia. Analysis of their potential targets and upstream regulators associated these microRNAs with TCR and BCR signaling, as well as TP53/Bcl2 mediated apoptosis.
Our studies provide a unique insight into the molecular mechanism of cell mediated immunity to malaria. Future studies will further investigate the role of these microRNAs and signaling pathways in immune response from naturally infected individuals.