miR-146a, miR-221, and miR-155 are Involved in Inflammatory Immune Response in Severe COVID-19 Patients

Abstract

COVID-19 infection triggered a global public health crisis during the 2020–2022 period, and it is still evolving. This highly transmissible respiratory disease can cause mild symptoms up to severe pneumonia with potentially fatal respiratory failure. In this cross-sectional study, 41 PCR-positive patients for SARS-CoV-2 and 42 healthy controls were recruited during the first wave of the pandemic in Mexico. The plasmatic expression of five circulating miRNAs involved in inflammatory and pathological host immune responses was assessed using RT-qPCR (Reverse Transcription quantitative Polymerase Chain Reaction). Compared with controls, a significant upregulation of miR-146a, miR-155, and miR-221 was observed; miR-146a had a positive correlation with absolute neutrophil count and levels of brain natriuretic propeptide (proBNP), and miR-221 had a positive correlation with ferritin and a negative correlation with total cholesterol. We found here that CDKN1B gen is a shared target of miR-146a, miR-221-3p, and miR-155-5p, paving the way for therapeutic interventions in severe COVID-19 patients. The ROC curve built with adjusted variables (miR-146a, miR-221-3p, miR-155-5p, age, and male sex) to differentiate individuals with severe COVID-19 showed an AUC of 0.95. The dysregulation of circulating miRNAs provides new insights into the underlying immunological mechanisms, and their possible use as biomarkers to discriminate against patients with severe COVID-19. Functional analysis showed that most enriched pathways were significantly associated with processes related to cell proliferation and immune responses (innate and adaptive). Twelve of the predicted gene targets have been validated in plasma/serum, reflecting their potential use as predictive prognosis biomarkers.

miRNAs as a Potential Biomarker in the COVID-19 Infection and Complications Course, Severity, and Outcome

“…In the discovery cohort, miR-126 was described to have protective effects on endothelia, and the damage was downregulated [ 28 ]. Furthermore, it was noticed that when adjusted for age and gender, miR-155, miR-146a, and miR-221 were shown to be significant in the identification of patients with severe COVID-19 disease, where miR-122-3p has the potential to target toll-like receptors (TLRs), tumor necrosis factor alpha (TNF-α), interleukin 6, interleukin 8, as well as transcription factors (NF-kB) that have essential roles in immune response [ 29 ]. Mc Donald et al demonstrated, using the COVID-19 RNA sequencing patient data, that miR-2392 is the only upregulated miRNA [ 30 ].…”

Beauty and the beast: host microRNA-155 versus SARS-CoV-2

“…SARS-CoV-2 appears to induce host innate immunity earlier and twice as effectively as CoV-1, including miR-155 [88]. In clinical SARS-CoV-2 infection, upregulated miR-155 levels have been reported to date, in all but two studies (Table 2) [90][91][92][93][94][95][96][97][98][99]. Elevated miR-155 levels could differentiate between different degrees of COVID-19 severity [90][91][92][93][94][95][96][97][98][99].…”

“…In clinical SARS-CoV-2 infection, upregulated miR-155 levels have been reported to date, in all but two studies (Table 2) [90][91][92][93][94][95][96][97][98][99]. Elevated miR-155 levels could differentiate between different degrees of COVID-19 severity [90][91][92][93][94][95][96][97][98][99]. The contradictory findings in the two studies could be due to differences in sampling timing and elevated BMI and advanced age, factors known to be associated with blunted miR-155 expression [98][99][100][101].…”

“…As a multifunctional miRNA, miR-155 critically modulates innate, humoral, and cellular immune responses during viral infections [155]. In the current review, we propose that the elevated miR-155 levels in SARS-CoV-2 infection appear, anticipatorily and purposefully, to prepare the host for a SARS-CoV-2-S-ACE2-induced RAAS hyperactivity [88,[90][91][92][93][94][95][96][97][98][99]. At a young age, and in the absence of comorbidities or pharmacological interventions, a judiciously initiated and choreographed miR-155 circuitry is expected to promote immediate, early, and late protection against SARS-CoV-2 and its complications [2,4,70,73,85,156].…”

Emerging role of microRNAs and long non-coding RNAs in COVID-19 with implications to therapeutics

“…Lukas et al found that miR-200c was upregulated during disease progression in COVID-19 human patients and the expression correlated with the severity of disease ( van de Sand et al, 2022 ). Another study demonstrated the involvement of miR-146a, miR-221, and miR-155 in inflammatory immune response in severe COVID-19 patients ( Gaytán-Pacheco et al, 2022 ).…”