A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection.
Coxsackieviral infections have been linked etiologically to multiple diseases. The serotype CB4 is associated with acute pancreatitis and autoimmune type 1 diabetes. To delineate the mechanisms of host survival after an acute infection with CB4 (strain E2), we have investigated the role of nitric oxide (NO), generated by the inducible form of nitric oxide synthase (NOS2), in viral clearance and pancreatic beta-cell maintenance. Mice deficient in NOS2 (NOS2-/- mice) and their wild-type (wt) counterparts were injected with CB4, after which both groups developed severe pancreatitis, hepatitis, and hypoglycemia within 3 days. Within 4 to 7 days postinfection (p.i.), most of the NOS2-/- mice died and at a strikingly higher mortality rate than wt mice. Histological examination of pancreata from both infected NOS2-/- and infected wt mice revealed early and complete destruction of the pancreatic acinar tissue, but intact, insulin-stained islets. When examined up to 8 weeks p.i., neither surviving NOS2-/-mice nor surviving wt mice developed hyperglycemia. However, the clearance of infectious CB4 was different between the mice. The spleens of NOS2-/- survivors were cleared of infectious virus with kinetics similar to that of wt mice, but the livers, pancreata, kidneys, and hearts of the NOS2-/- groups cleared virus more slowly than those of the wt group. This delayed clearance was particularly prominent in the livers of infected NOS2-/- mice, which also showed prolonged histopathological features of viral hepatitis. Taken together, this outcome suggests that NOS2 (and NO) is not required for the prevention of pancreatic beta-cell depletion after CB4 infection. Instead the critical actions of NOS2 apparently occur early in the host immune response, allowing mice to survive and clear virus. Moreover, the data support the existence of an organ-specific dependency on NO for a rapid clearance of CB4.
Department of Immunology, The Scripps Research Institute, 10 550 North Torrey Pines Road, La Jolla, California 92037, USA.
M
M
Flodström
M S
MS
Horwitz
A
A
Maday
D
D
Balakrishna
E
E
Rodriguez
N
N
Sarvetnick
D000818:Animals; D003384:Coxsackievirus Infections / Q000201:enzymology / Q000401:mortality / Q000821:virology*; D004770:Enterovirus / Q000302:isolation & purification / Q000472:pathogenicity*; D005260:Female; D006505:Hepatitis / Q000201:enzymology / Q000473:pathology; D007003:Hypoglycemia / Q000201:enzymology / Q000473:pathology; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D010179:Pancreas / Q000473:pathology / Q000821:virology; D010195:Pancreatitis / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D010948:Viral Plaque Assay; D014779:Virus Replication; D014781:Viscera / Q000821:virology
D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse