A new wave of Covid-19 cases driven by the delta variant has arrived. Hospitalizations will follow suit. There is an urgent need to discern which patients will need the most support. Those arriving at the hospital with Covid-19 may have significantly varying outcomes and some hospitalized patients will develop serious symptoms. Biomarkers are badly needed that allow hospitals to allocate scarce resources to save the lives of those most likely to die. A recent report from Zheng et al notes the observation of such a marker in severe Covid-19 patients: a small RNA fragment known as microRNA.
Although it was originally believed that microRNAs, or miRNAs, were a product of eukaryotic cells, over the past few years studies have suggested that some viruses also produce miRNAs as well, some of which are functional like in H5N1 influenza and Dengue viruses. These miRNAs negatively regulate genes that serve as part of the cell’s innate immune recognition of infection. Some miRNAs produced by cells and viruses can be found in host blood circulation. Presumably, miRNAs circulate packaged in exosomes, which bud from the cell surface.
Analyzing the blood samples of 159 patients, Zheng et al. uncovered a total of eight miRNA, five of which were detected in severe patients. Because miRNA precursors usually fold into stem-loop hairpin structures, the five candidates were cross-referenced with the SARS-CoV-2 genome. This survey resulted in one miRNA of particular interest. Derived from an 85 nucleotide precursor of the NSP3 gene of the virus, the miRNA, denoted miR-nsp3-3p, was conserved among SARS-CoV-2 strains and appeared regularly in severe Covid-19 patients. Figure 1 below denotes the location of NSP3 within the SARS-CoV-2 genome and figure 2 shows the nucleotide sequence of miR-nsp3-3p and its position within the NSP3 protein, which lies in the acidic C-terminal domain.
FIGURE 1: NSP3 within the SARS-CoV-2 genome, highlighted in red.
FIGURE 2: Genomic position and stem-loop structure of the 85 nucleotide precursor of miR-nsp3-3p. Mature miR-nsp3-3p is indicated in red.
The discovery of this miRNA in severe Covid-19 patient sera was followed by the monitoring of a 20 patient testing cohort. As patients were progressing from moderate to severe Covid-19, miR-nsp3-3p was detected on a consistent basis. The detection of miR-nsp3-3p accurately predicted the severe 7.4 days in advance of symptom appearance with a 97.1% accuracy (Figure 3). To reiterate, the detection of miR-nsp3-3p, which is produced by SARS-CoV-2 early in infection, accurately captures the risk of critical illness over a week before symptom appearance.
FIGURE 3: The cumulative accuracy rate of miR-nsp3-3p compared to the four other detected in severe patient sera (D-dimer, CRP, LDH, and PLC in predicting the risk of critical illness and monitoring disease progression.Larger studies are needed to confirm this finding, but a result of 97% accuracy is remarkable. Through the surveillance and detection of miR-nsp3-3p, hospitals will have a much stronger understanding of which patients need the most treatment and attention. This will not only serve to save many lives but also will allow the efficient allocation of resources, which are oftentimes limited, particularly in low and middle-income countries. If these results turn out to be reproducible in general, we would do well to propel this biomarking technique to widespread use.