Evaluation of the immunomodulatory and antiviral effects of small interfering RNAs Nup98.1 and Nup205.1 in an in vivo influenza model

Abstract

BACKGROUND: Influenza remains a significant global public health challenge. Currently, the challenges of viral resistance to existing antiviral drugs and the immunosuppressive effects induced by the influenza virus remain urgent issues. A promising strategy involves developing antiviral agents that inhibit cellular gene activity via RNA interference.

AIM: To evaluate the immunomodulatory and anti-influenza effects of small interfering RNAs targeting cellular genes in a murine model of influenza virus infection.

METHODS: The study utilized the mouse-adapted influenza virus strain A/California/7/09 (H1N1) and BALB/c mice. Small interfering RNA administration and viral infection were performed intranasally. Changes in cytokine profiles and viral replication were assessed using molecular-genetic and virological methods.

RESULTS: Based on the evaluation of cytokine expression dynamics, no statistically significant differences were observed in systemic cytokine levels (blood), except for IL-6, TNF-α, and IL-10, between the experimental and control groups. In the lungs, intranasal administration of all small interfering RNA complexes resulted in decreased IL-1β and TNF-α expression, while IL-1β and IL-6 expression increased in upper respiratory tract lavage samples. The use of small interfering RNAs Nup98.1 and Nup98.1/Nup205.1 led to a significant increase in IL-10 expression in the lungs by day 3, whereas Nup205.1 resulted in a significant increase in IL-10 levels in the upper respiratory tract by the same time point. TGF-β1 expression decreased in the lungs but increased in the blood by day 3 across all small interfering RNA complexes. Significant differences in the expression of pro- and anti-inflammatory cytokines were observed at the local level. The most pronounced immunomodulatory effects were observed in the upper respiratory tract and lungs, the primary sites of small interfering RNA administration. Parallel to these immune profile alterations, viral replication was reduced by 1–2.5 orders of magnitude compared to control groups.

CONCLUSIONS: This study provides evidence that small interfering RNAs targeting one or more cellular genes in an in vivo model can significantly reduce viral replication while modulating cytokine profiles.

Keywords

RNA interference / influenza virus / infection / small interfering RNA / cytokines

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RIGHTS & PERMISSIONS

Pashkov E.A., Faizuloev E.B., Milchakov D.V., Lushnikov R.E., Bogdanova E.A., Rozhkova L.S., Svitich O.A., Zverev V.V.