Role of nitric oxide synthase type 2 in acute infection with murine cytomegalovirus.
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-gamma 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.
Noda
S
S
Department of Infectious Diseases, Tokai University School of Medicine, Isehara, Kanagawa, Japan. snoda@is.icc.u-tokai.ac.jp
Tanaka
K
K
Sawamura
S
S
Sasaki
M
M
Matsumoto
T
T
Mikami
K
K
Aiba
Y
Y
Hasegawa
H
H
Kawabe
N
N
Koga
Y
Y
D000208:Acute Disease; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006566:Herpesviridae Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology / Q000821:virology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000254:growth & development / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology / Q000821:virology; D019562:Viral Load; D010948:Viral Plaque Assay; D017735:Virus Latency / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse