Plasma MicroRNA Profiling of Plasmodium falciparum Biomass and Association with Severity of Malaria Disease

Abstract

Severe malaria (SM) is a major public health problem in malaria-endemic countries. Sequestration of Plasmodium falciparum –infected erythrocytes in vital organs and the associated inflammation leads to organ dysfunction. MicroRNAs (miRNAs), which are rapidly released from damaged tissues into the host fluids, constitute a promising biomarker for the prognosis of SM. We applied next-generation sequencing to evaluate the differential expression of miRNAs in SM and in uncomplicated malaria (UM) in children in Mozambique. Six miRNAs were associated with in vitro P. falciparum cytoadhesion, severity in children, and P. falciparum biomass. Relative expression of hsa-miR-4497 quantified by TaqMan-quantitative reverse transcription PCR was higher in plasma of children with SM than those with UM (p<0.048) and again correlated with P. falciparum biomass (p = 0.033). These findings suggest that different physiopathological processes in SM and UM lead to differential expression of miRNAs and suggest a pathway for assessing their prognostic value malaria.

Plasma levels of hsa‐miR‐3158‐3p microRNA on admission correlate with MRI findings and predict outcome in cerebral malaria

“…TaqMan-advanced quantitative reverse transcription PCR (RT-qPCR) assays were used to measure miRNA levels using 50 μl of plasma (supplementary materials). 4 The selection of miRNAs was based on published reports (supplementary materials; Figure S2). Cycle threshold values were <24 in all samples, with a coefficient of variance < 6% for the exogenous control (cel-miR-39-3p) amplified by RT-qPCR, indicative of a successful cDNA preparation.…”

Harnessing the Potential of miRNAs in Malaria Diagnostic and Prevention

“…Thus, determining direct or indirect markers of early and still progressing organ dysfunction in the context of SM could revolutionize its clinical management. A recent, large-scale study using a combination of in vitro models and plasma samples from Mozambican children infected with Pf and diagnosed with SM or UM demonstrated for the first time the association between both hsa-miR-3158-3p and hsa-miR-4497 with SM, its complications, and Pf biomass ( Figure 1c ) ( Gupta et al., 2021a ). These findings suggest that although unable to produce miRNAs ( Xue et al., 2008 ), Plasmodium may manipulate the production of host miRNAs.…”

“…Higher levels of miR-3158–3p were measured in Mozambican children who had acidosis or ARDS compared to UM children. In contrast, miR-4497 was associated with severe anemia and ARDS ( Figure 1c ) ( Gupta et al., 2021a ). A review suggested that miR-210; miR-125b and miR-181b; as well as miR 17–92 and miR-24 could be promising miRNA-based biomarkers of acidosis, ARDS and renal failure, respectively ( Figure 1c ) ( Chamnanchanunt et al., 2017 ).…”

“…New approaches are therefore needed for large scale populations screening. miR-3158-3p and miR-4497 were found associated with parasite biomass ( Gupta et al., 2021a ) so it could be postulated that these miRNAs are promising candidate to identify sub-patent infections. However, further investigations are warranted to determine the parasitemia detection threshold afforded by these miRNAs.…”

“…Both reticulocytes and asexual Pv parasites were observed in the splenic tissue, suggesting that the measure of the peripheral parasitemia alone vastly underestimates the Pv biomass in AM ( Kho et al., 2021a ). miR-4497 may play an important role in detecting hidden splenic parasites in AM individuals, as it was found associated with parasite biomass and SA ( Gupta et al., 2021a ). In addition, another study reported the downregulation of 25 miRNAs in the spleen obtained from mice infected with P. chabaudi ( Al-Quraishy et al., 2012 ).…”