Mouse model of respiratory syncytial virus infection mimicking acute human pathology

Abstract

Introduction. Human respiratory syncytial virus (RSV) is one of the common causes of lower respiratory tract inflammation in children and elderly persons. RSV infection being a serious public health problem is characterized by high morbidity and mortality, especially in children. There are no licensed vaccines and inexpensive medications for RSV prevention and treatment. The lack of universal animal model which mimics all aspects of human pathology is one of the main obstacles to develop new therapy approaches.

The aim of the study was to develop the model of RSV infection using BALB/c mice and purified and concentrated virus, which allows reproducing the main features of human pathology.

Material and methods. Mice were divided into 4 groups (n = 10). Animals of the 1st group (RSV hd) were intranasally infected with purified RSV strain A2 at a high dose of 5 - 106 pfu/mouse in a volume of 50 mcl of phosphate buffered saline. The 2nd group (RSV ld) received non-purified virus at low dose 105 pfu/mouse. Мice of the 3rd group (RSV-UV) were treated with the same dose (5 - 106 pfu/mouse) and volume (50 mcl) of the UV-inactivated RSV. Animals of the 4th group (Intact) were left untreated. The following indicators were measured: the airway hyperreactivity, cell composition in broncho-alveolar lavage (BAL) samples, the severity of inflammation and levels of pro-inflammatory cytokines in lungs. The body weight of the animals was monitored daily throughout the experiment. In separate experiments mice infected with high dose (5 - 106 pfu/mouse) of purified RSV received ribavirin orally twice a day in dose 85 mg/kg for 5 days.

Results. The virus was detected in the respiratory tract of animals for 5 days after the infection. Additionaly, a 12% body weight loss was observed on day 3, indicating successful infection. Presented protocol allows to induce many manifestations of the human pathology such as: increased airway hyperreactivity (AHR), mucus secreting goblet cell metaplasia in the bronchial epithelium and lung inflammation associated with the proinflammatory cell infiltration. Proinflammatory cytokine genes (Ifng and Tbet) expression was increased compared to intact mice. At the same time, the expression of Th2 cytokines gens (Il4, Il13 and Gata3) didn’t change significantly after infection with RSV. These data indicate the ability of RSV productively replicate in the respiratory tract, induce pulmonary inflammation and shift the immune response toward Th1-type. We also investigated the effect of ribavirin treatment on the replication of RSV in the current model and how it correlated with lung inflammation and airway hyperreactivity. In the experiment, oral daily administration of ribavirin significantly reduced viral load in lungs and lymphocytes number in the BAL. In addition, improvement in airway hyperreactivity was observed after ribavirin-mediated suppression of RSV replication. Thus, this model is sensitive to known antiviral drugs and may be useful for testing new drugs against RSV.

Conclusion. We described the experimental model of RSV infection in mice. This model mimics the main features of human pathology. The described model can be useful for the testing of novel anti-RSV drugs and further understanding of RSV infection immunopathogenesis.

Keywords:human respiratory syncytial virus; murine models; human pathology modeling

For citation: Shilovskiy I.P., Barvinskaia E.D., Nikolskii A.A., Nikonova A.A., Smirnov V.V., Kovchina V.I., Vishnyakova L.I., Yumashev K.V., Kaganova M.M., Rusak T.E., Mitin A.N., Komogorova V.V., Litvina M.M., Sharova N.I., Kudlay D.A., Khaitov M.R. Mouse model of respiratory syncytial virus infection mimicking acute human pathology. Immunologiya. 2022; 2022; 43 (4): 423–39. DOI: https://doi.org/10.33029/0206-4952-2022-43-4-423–439

Funding. The study was supported by Russian Science Foundation grant No. 22-25-00182.

Conflict of interests. The authors declare no conflict of interests.

Authors contribution. Study conception and design – Shilovskiy I.P., Smirnov V.V., Khaitov M.R., Mitin A.N.; material collection and processing – Barvinskaia E.D., Nikolskii A.A., Kovchina V.I., Vishnyakova L.I., Yumashev K.V., Kaganova M.M., Rusak T.E., Komogorova V.V., Litvina M.M., Sharova N.I.; statistical processing – Barvinskaia E.D., Yumashev K.V.; manuscript preparation – Barvinskaia E.D., Shilovskiy I.P.; editing – Kaganova M.M., Kudlay D.A., Nikonova A.A.

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EDITOR-IN-CHIEF
EDITOR-IN-CHIEF
Musa R. Khaitov

Corresponding member of Russian Academy of Sciences, MD, Professor, Director of the NRC Institute of Immunology FMBA of Russia

Вскрытие
Medicine today

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