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Role of Nitric Oxide Synthase Type 2 in Acute Infection with Murine Cytomegalovirus¹

Satoshi Noda^2,*, Kazuo Tanaka^*, Sada-aki Sawamura^*, Masafumi Sasaki, Takako Matsumoto^*, Katsunaka Mikami^*, Yuji Aiba^*, Hideaki Hasegawa, Noboru Kawabe and Yasuhiro Koga^*

^* Department of Infectious Diseases and Cell Biology Research Laboratory, Tokai University School of Medicine, Isehara, Kanagawa, Japan; and Department of Virology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

Whether or not NO plays a critical role in murine CMV (MCMV) infection has yet to be elucidated. In this study, we examined the role of NO in acute infection with MCMV using NO synthase type 2 (NOS2)-deficient mice. NOS2^-/- mice were more susceptible to lethal infection with MCMV than NOS2^+/+ mice and generated a much higher peak virus titer in the salivary gland after acute infection. A moderate increase in the MCMV titer was also observed in other organs of NOS2^-/- mice such as the spleen, lung, and liver. The immune responses to MCMV infection including NK cell cytotoxicity and CTL response in NOS2^-/- mice were comparable with those of NOS2^+/+ mice. Moreover, the ability to produce IFN- is not impaired in NOS2^-/- mice after MCMV infection. The peritoneal macrophages from NOS2^-/- mice, however, exhibited a lower antiviral activity than those from NOS2^+/+ mice, resulting in an enhanced viral replication in macrophages themselves. Treatment of these cells from NOS2^+/+ mice with a selective NOS2 inhibitor decreased the antiviral activity to a level below that obtained with NOS2^-/- mice. In addition, the absence of NOS2 and NOS2-mediated antiviral activity of macrophages resulted in not only an enhanced MCMV replication and a high mortality but also a consequent risk of the latency. It was thus concluded that the NOS2-mediated antiviral activity of macrophages via NO plays a protective role against MCMV infection at an early and late stage of the infection.

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