Possibility of using a mouse SCID as a model animal to variola virus for evaluating anti-smallpox drug efficacy. K. A. Titova, Al. A. Sergeev, A. S. Kabanov, L. E. Bulychev, Ar. A. Sergeev, D. O. Galahova, A. S. Zamedyanskaya, L. N. Shishkina, O. S. Taranov, V. V. Omigov, E. L. Zavjalov, A. P. Agafonov, A. N. Sergeev

Abstract:

At present, there is no animal model for smallpox that reflects the weakened immune system in people and can therefore help assess the prophylactic (highly preventive) efficiency of antiviral drugs. To fill in the gap, we have explored the possibility of using outbred immunodeficient SCID mice as a model animal for smallpox with the aid of virolo­gical, histological and electron microscopic and sta­tistical methods. There was no clinical evidence of disease by intranasal infection of mice at a dose of 5.2 log10 PFU (plaque forming units). At the same time, the 50 % infective dose (ID50) of VARV estimated for animals by registering the presence of the virus in their lungs after 4 days post i.n. infection was 3.5 log10 PFU and was relatively similar to that in humans, theoretically determined by identification of the clinical picture of the disease. Virus replication was detected only in the respiratory organs of mice challenged i.n. with VARV at a dose of 5.2 log10 PFU (50 ID50). The values for its concentrations in the lungs and nose resembled those for affected people and well-known animal models (Macaca cynomolgus and ICR mice), respiratorily infected with VARV at similar doses. The existing model animals were not significantly different from SCID mice in the duration jav sub strictlygirlz of viral presence in the lungs. Moreover, in SCID mice, as in humans and other animal models, similar pathomor- phological changes of inflammatory necrotic nature in the respiratory organs have been reported. Using SCID mice in assessing the prophylactic efficacy of the antiviral drugs NIOCH-14 and ST-246 demonstrated the adequacy of the results obtained to those described in the literature. This opens up the prospect of using SCID mice as an animal model for smallpox to develop antiviral drugs intended for people with severe immuno­suppressive states. Check sideeffects.com/drugs/lialda

About The Authors:

K. A. Titova. State Research Center of Virology and Biotechnology «Vector», Russian Federation, Novosibirsk region, Koltsovo

Al. A. Sergeev. State Research Center of Virology and Biotechnology «Vector», Russian Federation 

Novosibirsk region, Koltsovo

A. S. Kabanov. State Research Center of Virology and Biotechnology «Vector», Russian Federation 

Novosibirsk region, Koltsovo

L. E. Bulychev. State Research Center of Virology and Biotechnology «Vector», Russian Federation, Novosibirsk region, Koltsovo

Ar. A. Sergeev. State Research Center of Virology and Biotechnology «Vector», Russian Federation 

Novosibirsk region, Koltsovo

D. O. Galahova. State Research Center of Virology and Biotechnology «Vector», Russian Federation, Novosibirsk region, Koltsovo

A. S. Zamedyanskaya. State Research Center of Virology and Biotechnology «Vector», Russian Federation, Novosibirsk region, Koltsovo

L. N. Shishkina. State Research Center of Virology and Biotechnology «Vector», Russian Federation, Novosibirsk region, Koltsovo

O. S. Taranov. State Research Center of Virology and Biotechnology «Vector», Russian Federation 

Novosibirsk region, Koltsovo

V. V. Omigov. State Research Center of Virology and Biotechnology «Vector», Russian Federation 

Novosibirsk region, Koltsovo

E. L. Zavjalov. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

A. P. Agafonov. State Research Center of Virology and Biotechnology «Vector», Russian Federation, Novosibirsk region, Koltsovo

A. N. Sergeev. State Research Center of Virology and Biotechnology «Vector», Russian Federation, Novosibirsk region, Koltsovo

References:

1. Bailey T.R., Rippin S.R., Opsitnick E., Burns C.J., Pevear D.C., Collett M.S., Rhodes G., Tohan S., Huggins J.W., Baker R.O., Kern E.R., Keith K.A., Dai D., Yang G., Hruby D., Jordan R. N-(3,3a,4,4a,5, 5a,6,6a-Octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2-(1H)-yl)carboxamides: identification of novel orthopoxvirus egress inhibitors. J. Med. Chem. 2007;50(7):1442-1444.

2. Belizário J.E. Immunodeficient mouse models: An overview. Open Immunol. J. 2009;2:79-85.

3. Cann J.A., Jahrling P.B., Hensley L.E., Wahl-Jensen V. Comparative pathology of smallpox and monkeypox in man and macaques. J. Comp. Path. 2013;148:6-21.

4. Hahon N., Wilson B.J. Pathogenesis of variola in Macaca irus monkeys. Amer. J. Hyg. 1960;71:69-80.

5. Huggins J., Goff A., Hensley L., Mucker E., Shamblin J., Wlazlowski C., Johnson W., Chapman J., Larsen T., Twenhafel N., Karem K., Damon I.K., Byrd C.M., Bolken T.C., Jordan R., Hruby D. Nonhuman primates are protected from smallpox virus or monkeypox virus challenges by the antiviral drug ST-246. Antimicrob. Agents Chemother. 2009;53(6):2620-2625.

6. Jahrling P.B., Hensley L.E., Martinez M.J., LeDuc J.W., Rubins K.H., Relman D.A., Huggins J.W. Exploring the potential of variola virus infection of cynomolgus macaques as a model for human smallpox. Proc. Natl Acad. Sci. USA. 2004;101(Iss. 42):15197-15200.

7. Kaptsova, T.I. Razrabotka eksperimental’nykh modeley natural’noy ospy. Diss. cand. med. nauk [The development of experimental models for smallpox. Ph. D. med. sci. diss.]. Moscow, 1967.

8. Leparc-Goffart I., Poirier B., Garin D., Tissier M.-H., Fuchs F., Crance J.-M. Standartization of a neutralizing anti-vaccinia antibodies titration method: an essential step for titration of vaccinia immunoglobulins and smallpox vaccines evaluation. J. Clin. Virol. 2005; 32:47-52.

9. Marennikova S.S., Shchelkunov S.N. Orthopoxviruses Pathogenic for Humans. Springer: N.Y., USA, 2005.

10. Mayr A., Herrlich A. Zuchting des Variolavirus in der infantilen Maus. Arch. Ges. Virusforsch. 1960;10(2):226-235.

11. Mucker E.M., Goff A.J., Shamblin J.D., Grosenbach D.W., Damon I.K., Mehal J.M., Holman R.C., Carroll D., Gallardo N., Olson V.A., Clemmons C.J., Hudson P., Hruby D.E. Efficacy of Tecovirimat (ST-246) in nonhuman primates infected with variola virus (smallpox). Antimicrob. Agents Chemother. 2013;57(Iss. 12):6246-6253.

12. Murti B.R., Shrivastav J.B. A study biological behavior of variola virus. II. Experimental inoculation of laboratory animals. Indian J. Med. Sci. 1957;11(Iss. 8):580-587.

13. National research Council: Guidelines on laboratory animal care and use, 8th ed. National research Council of the National Academies, Washington: The National Academies Press, 2011.

14. Sarkar J.K., Mitra A.C., Mukherjee M.K., De S.K., Guha Mazumdar D. Virus excretion in smallpox. I. Excretion in the throat, urine and conjunctive of patients. Bull. WHO. 1973;48:517-522.

15. Sergeev A.A., Kabanov A.S., Bulychev L.E., Sergeev A.A., Pyankov O.V., Bodnev S.A., Galahova D.O., Zamedyanskaya A.S., TitovaK.A., Glotov A.G., Taranov O.S., Omigov V.V., Shishkina L.N., Agafonov A.P., Sergeev A.N. The possibility of using the ICR mouse as an animal model to assess anti-monkeypox drug efficacy. Transbound. Emerg. Dis. 2015a; DOI: 10.1111/tbed.12323

16. Sergeev A.A., Kabanov A.S., Bulychev L.E., Sergeev A.A., Pyankov O.V., Bodnev S.A., Galahova D.O., Zamedyanskaya A.S., Titova K.A., Glotova T.I., Taranov O.S., Omigov V.V., Shishkina L.N., Agafonov A.P., Sergeev A.N. Using the ground squirrel (Marmota bobak) as an animal model to assess monkeypox drug efficacy. Transbound. Emerg. Dis. 2015b; DOI: 10.1111/tbed.12364

17. Sergeev Ar.A., Kabanov A.S., Bulychev L.E., Sergeev Al.A., Taranov O.S., Titova K.A., Pyankov O.V., Zamedyanskaya A.S., Gorbatovskaya D.O., Agafonov A.P., Sergeev A.N., Shishkina L.N. Sposob otsenki aktivnosti lechebno-profilakticheskikh preparatov protiv virusa natural’noy ospy [A method to assess of activity of anti-smallpox therapeutic and prophylactic drugs]. Patent RF, no. 2522483. Bul. no. 20 dated 07.20.14.

18. Shishkina L.N., Sergeev A.N., Agafonov A.P., Sergeev A.A., Kabanov A.S., Bulychev L.E., Sergeev A.A., Gorbatovskaya D.O., Pyan­kov O.V., Bormatov N.I., Schukin G.I., Selivanov B.A., Tihonov A.Ia. Lechebno-profilakticheskoe sredstvo protiv virusa natural’noy ospy i sposoby ego polucheniya i primeneniya [A therapeutic and prophylactic drug against variola virus and methods for its preparation and use]. Patent RF, no. 2543338. Bul. no. 6 dated 02.27.15.

19. Smith S.K., Olson V.A., Karem K.L., Jordan R., Hruby D.E., Damon I.K. In vitro efficacy of ST246 against smallpox and monkeypox. Antimicrob. Agents Chemother. 2009;53:1007-1012.

20. Wahl-Jensen V., Cann J.A., Rubins K.H., Huggins J.W., Fisher R.W., Johnson A.J., de Kok-Mercado F., Larsen T., Raymond J.L., Hensley L.E., Jahrling P.B. Progression of pathogenic events in cynomolgus macaques infected with variola virus. PLoS One. 2011;6: e24832.

21. Zaks L. Statisticheskoe otsenivanie [Statistical Estimation]. Moscow, Statistika, 1976.

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