Neuronal cell death in alphavirus encephalomyelitis.
Alphaviruses are mosquito-borne, enveloped, plus-strand RNA viruses that cause a spectrum of diseases in humans that include fever, rash, arthritis, meningitis, and encephalomyelitis. Sindbis virus (SINV) is the prototype alphavirus, causes encephalomyelitis in mice, and provides a model system for studying the pathogenesis of alphavirus-induced neurological disease. Major target cells for SINV infection in the central nervous system (CNS) are neurons, and both host and viral factors determine the fate of infected neurons. Young animals are most susceptible to fatal disease. This correlates with the ability of SINV to induce apoptosis in immature neurons. In vitro, apoptotic death of neuroblastoma cells can be induced by fusion of the virus envelope with the endosomal membrane and does not require infectious virus. This fusion process activates acid sphingomyelinase that cleaves sphingomyelin to release ceramide, an initiator of apoptosis. Within an hour, poly(ADP-ribose) polymerase is activated, and this is followed by release of cytochrome c and activation of effector caspases. SINV-induced cell death can be delayed or prevented by treatment with antioxidants or caspase inhibitors and by intracellular expression of Bcl-2, Beclin-1, or protease inhibitors. Older animals survive infection unless infected with a neurovirulent strain of SINV. In these mice, anterior horn motor neurons die by a primarily necrotic process that is influenced by excitotoxic amino acids and inflammation, whereas hippocampal neurons can be either apoptotic or necrotic. Death also occurs in uninfected neurons in the vicinity of infected neurons and can be delayed or prevented by treatment with glutamate receptor antagonists.
Griffin
D E
DE
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St, Rm E5132, Baltimore, MD 21205, USA. dgriffin@jhsph.edu
D018354:Alphavirus Infections / Q000473:pathology* / Q000821:virology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004679:Encephalomyelitis / Q000473:pathology* / Q000821:virology; D006801:Humans; D009474:Neurons / Q000473:pathology* / Q000821:virology; D012845:Sindbis Virus / Q000502:physiology*