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. 2024 Feb 15;35(1):102149.
doi: 10.1016/j.omtn.2024.102149. eCollection 2024 Mar 12.

Therapeutic role of miR-19a/b protection from influenza virus infection in patients with coronary heart disease

Yanan Xing  1   2 , Lin Chen  3 , Bin Hu  1   2 , Yi Li  1   2 , Huan Mai  4 , Gaojian Li  1   2 , Shuyi Han  1   2 , Ye Wang  1   2 , Yanyi Huang  1   2 , Ying Tian  5 , Wei Zhang  5 , Yan Gao  4 , Hongxuan He  1
Affiliations

Therapeutic role of miR-19a/b protection from influenza virus infection in patients with coronary heart disease

Yanan Xing et al. Mol Ther Nucleic Acids. .

Abstract

Patients with pre-existing medical conditions are at a heightened risk of contracting severe acute respiratory syndrome (SARS), SARS-CoV-2, and influenza viruses, which can result in more severe disease progression and increased mortality rates. Nevertheless, the molecular mechanism behind this phenomenon remained largely unidentified. Here, we found that microRNA-19a/b (miR-19a/b), which is a constituent of the miR-17-92 cluster, exhibits reduced expression levels in patients with coronary heart disease in comparison to healthy individuals. The downregulation of miR-19a/b has been observed to facilitate the replication of influenza A virus (IAV). miR-19a/b can effectively inhibit IAV replication by targeting and reducing the expression of SOCS1, as observed in cell-based and coronary heart disease mouse models. This mechanism leads to the alleviation of the inhibitory effect of SOCS1 on the interferon (IFN)/JAK/STAT signaling pathway. The results indicate that the IAV employs a unique approach to inhibit the host's type I IFN-mediated antiviral immune responses by decreasing miR-19a/b. These findings provide additional insights into the underlying mechanisms of susceptibility to flu in patients with coronary heart disease. miR-19a/b can be considered as a preventative/therapy strategy for patients with coronary heart disease against influenza virus infection.

Keywords: MT: non-coding RNAs; SOCS1; coronary heart disease; influenza virus; innate immunity; miR-19a/19b.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Expression of miR-19a/miR-19b in the coronary heart disease of patients and mice (A) The basic information of patients with coronary heart disease and healthy people. (B) RT-qPCR of miR-19a and miR-19b in patients with coronary heart disease in PBMCs. n = 15. (C) Schematic diagram of experimental protocol for coronary heart disease mouse model. (D) Myocardial contractility (FS, fractional shortening). (E) Biochemical indicators of NC mice and ApoE−/− mice. (F) ApoE−/− mice and healthy mice of miRNA sequencing in lungs. (G) Scheme of miRNA quantification process. (H) KEGG enrichment of miRNA target genes in lungs of ApoE−/− mice and NC mice. Data are presented as mean ± SD. Asterisks denote the significance levels: ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001.
Figure 2
Figure 2
Direct injection of agomir-miR-19a/b can reduce the mortality of mice infected with influenza (A) ApoE−/− mice were injected with the mixture of micrON agomir-miR-19a/b and agomir-NC by tail vein once every 3 days, 5 nmol each time, for 3 weeks. (B and C) Expression of miR-19a detected by RT-qPCR in PBMCs of NC mice, ApoE−/−+agomir-NC-treated mice, and ApoE−/−+agomir-miR-19a/b-treated mice. (D) Changes in the weight of five groups (n = 10). (E) Survival curves of five groups (n = 10). Data are presented as mean ± SD. Asterisks denote the significance levels: ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001.
Figure 3
Figure 3
Pathogenicity of lungs in BJ05/H1N1 influenza virus-infected mice (A–C) From day 1 to 5 after influenza virus infection in NC mice, ApoE−/−+agomir-NC-treated mice, and ApoE−/−+agomir-miR-19a/b-treated mice, pathological lesions in the lungs of mice, H&E staining, and immunofluorescence. (D) Quantification of immunofluorescence of NP protein. (E) The expression of inflammatory factors in NC mice, ApoE−/−+agomir-NC-treated mice, and ApoE−/−+agomir-miR-19a/b-treated mice was quantitatively analyzed. Asterisks denote the significance levels: ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001.
Figure 4
Figure 4
miR-19a/b inhibits influenza virus replication in A549 cells (A) Different concentrations of agomir-miR-19a/b influenced H1N1 by TCID50. (B) Expression of NP or M1 after infection with H1N1 in NC, agomir-NC, and agomir-miR-19a/b of cells. (C and D) The expression of miR-19a/b was time- and dose dependent on H1N1 virus infection detected by quantitative analysis. Asterisks denote the significance levels: ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001.
Figure 5
Figure 5
microRNA-19a/b target site analysis (A) Related target genes of miR-19a/b. (B) miR-19a and miR-19b target interaction network. Nodes: genes or miRNAs, lines: connections, green: miR-19a and miR-19b, pink: target genes, and red: SOCS1. (C) The binding region of SOCS1 3′ UTR and miR-19a/b; dual-luciferase reporter experiment. (D) The lung of NC mice, ApoE−/−+agomir-NC-treated mice, and ApoE−/−+agomir-miR-19a/b-treated mice that expressed SOCS1 as detected by western blotting. (E) The protein expression levels of NP, M1 and socs1 at different times after influenza virus infection of A549 cells. (F and G) The expression of SOCS1 was time- and dose dependent on influenza infection detected by quantitative analysis. Asterisks denote the significance levels: ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001.
Figure 6
Figure 6
Overexpression miR-19a/b inhibited the expression of SOCS1 (A) KEGG pathways of ApoE−/−+agomir-NC/NC, ApoE−/−+agomir-miR19a/b/NC, and ApoE−/−+agomir-miR19a/b/ApoE−/−+agomir-NC mice. (B) A549 cells were transfected with agomir-miR-19a/b and agomir-NC at different concentrations and 24 hpi with BJ05/H1N1, and then detected NP, M1, and SOCS1 expression levels were analyzed using western blot. (C) Western blot detection of SOCS1, JAK2, STAT1, and p-STAT1 in A549 cells treated as in (B). (D) Western blot detection of NP and SOCS1 in four groups of A549 cells 24 hpi with BJ05/H1N1. (E) Quantitative analysis of cytokines 6, 12, and 24 h after influenza virus infection of A549 cells. Data represent means ± SEM. p values were determined by one-way ANOVA comparisons test. Asterisks denote the significance levels: ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001.
Figure 7
Figure 7
SOCS1 knockdown inhibited NP expression A549 cells were transfected with pcDNA3.1-SOCS1, lenti-crisprv2-SOCS1, and empty vector for 48 h and then infected with BJ05/H1N1 24 hpi. (A and B) The NP level was detected by RT-qPCR at different times. (C and D) Western blot detection of NP level in A549 cells transfected with pcDNA3.1-SOCS1, lenti-crisprv2-SOCS1, and empty vector at different times. (E and F) The levels of inflammatory factors were detected by RT-qPCR in A549 cells transfected with pcDNA3.1-SOCS1 and lenti-crisprv2-SOCS1. Data represent means ± SEM. p values were determined by one-way ANOVA comparisons test. Asterisks denote the significance levels: ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001.
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