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Persistence of Replicating Coxsackievirus B3 in the Athymic Murine Heart is Associated with Development of Myocarditic Lesions

¹ Department of Bacteriology, Iwate Medical University, 19-1, Uchimaru, Morioka 020, Japan,
² Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, 14th & Alaska Avenues, Washington D.C., U.S.A.
³ Third Department of Internal Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyoku, Tokyo 113
and⁴ Department of Immunology, Juntendo University, 2-1-1, Hongo, Bunkyoku, Tokyo 160, Japan

Coxsackievirus B3 (CVB3)-induced myocarditis was studied in euthymic (nu/+) and athymic (nu/nu) C3H/HeN (H-2^k) mice. Mice were inoculated intraperitoneally with 10⁶ p.f.u. of CVB3 (Nancy strain) and sacrificed at intervals up to 92 days post-inoculation (p.i.). Viraemia peaked at day 2 to 3 p.i. and ceased at day 5 to 7 p.i. in a synchronized manner in both sets of mice. Very few infectious particles were detected in the blood of nu/nu mice after day 14 p.i. In nu/nu mice, CVB3 persisted in myocardial tissue with constant titres between 2.7 ± 1.9 x 10⁴ and 7.6 ± 5.2 x 10⁴ p.f.u./mg from day 3 to 92 p.i., which were comparable to those of nu/+ mice in the acute phase. In nu/+ mice, the virus was recovered from all animals examined by day 11 p.i. and from three out of 13 mice between days 14 and 21 p.i., yet no virus was recovered from nu/+ mice at day 42 p.i. In nu/nu mice, sense and antisense RNA for CVB3 was detected in the myocardial tissue up to day 42 p.i. by in situ hybridization and up to day 92 p.i. by reverse transcriptase-PCR. Neither sense nor antisense RNA was detected after day 21 p.i. in nu/+ mice with the same techniques. Myocardial tissue damage was analysed morphologically. At day 92 p.i., the area of myocardial injury peaked at 23% of the section in nu/nu mice. In contrast, less than 0.6% of tissue sections contained lesions in nu/+ mice. A neutralizing antibody response to CVB3 was observed in both nu/nu and nu/+ mice. The mean titre of neutralizing antibody was significantly higher at day 21 p.i. in nu/+ mice, but similar at day 42 p.i. with nu/nu and nu/+ mice. Perforin-producing natural killer-like cells, which are considered to play an important role in causing acute myocarditic lesions in immunocompetent mice, were found in the lesions of nu/nu mice persistently infected with CVB3. Prolonged tumour necrosis factor- mRNA synthesis detected in nu/nu mice appears to reflect the continuous activation of macrophages, which extend phagocytic reactions to virus-infected myocytes. These immunological results suggested that the host immune response devoid of antigen-specific T cell function is not sufficient to terminate CVB3 infection in nu/nu mice. Also, it appears that competent cellular immunity, on the whole, plays a role in curing rather than in aggravating myocarditis in nu/+ mice. In conclusion, our results indicate that the presence of replicating CVB3 is an important factor in the development of myocarditic lesions in C3H/HeN mice.

Received 6 January 1994; accepted 10 June 1994.

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