Journal of NeuroVirology, 9: 253–258, 2003 c  2003 Taylor & Francis ISSN 1355-0284/03 $12.00+.00 DOI: 10.1080/13550280390193975 Rabies virus infection: An update Alan C Jackson Departments of Medicine and Microbiology and Immunology, Queen’s University, Kingston, Ontario, Canada There are still many unanswered questions in the pathogenesis of rabies, but recent progress has been made. During most of the long incubation period of rabies, the virus likely remains close the site of viral entry. Centripetal spread to the central nervous system and spread within the central nervous system occur by fast axonal transport. Neuronal dysfunction, rather than neuronal death, is responsible for the clinical features and fatal outcome in natural rabies. Recent work has changed our perspective on the ecology of rabies virus under particular circumstances in certain species. Hopefully, advances in our understanding of rabies pathogenesis will lead to advances in the treatment of this dreaded disease. Journal of NeuroVirology (2003) 9, 253–258. Keywords: apoptosis; axonal transport; CNS infection; encephalitis; gene expression; neural apoptosis; neuronal apoptosis; neuronal dysfunction; neu- ronotropism; neuropathogenesis; neurotransmitters; neurotropism; neuroviru- lence; pathogenesis; rabies; rabies virus; rhabdovirus; viral pathogenesis; viral receptor; virulence; virus Introduction Rabies is normally a rapidly fatal neurological dis- ease and to date therapeutic efforts in humans have proved futile except in rare cases in which rabies vac- cine was administered prior to the onset of clinical disease (Jackson, 2002a; Jackson et al, 2003). A better understanding of rabies pathogenesis may be helpful in making future advances in therapy. In this review, selected topics in the pathogenesis of rabies, includ- ing the events at the site of viral entry, transport of rabies virus to the central nervous system (CNS), neu- ronal dysfunction and death, and nonfatal outcome of infection will be discussed. A comprehensive review on rabies pathogenesis has recently been published (Jackson, 2002b). Events at the site of viral entry There is a long and variable incubation period in hu- man and animal rabies, usually lasting 20 to 90 days, but sometimes it lasts longer than 1 year (Smith et al, Address correspondence to Dr. Alan C. Jackson, Kingston Gen- eral Hospital, Connell 725, 76 Stuart Street, Kingston, Ontario, Canada K7L 2V7. E-mail: jacksona@post.queensu.ca Received 19 August 2002; revised 8 October 2002; accepted 9 October 2002. 1991). Although there is uncertainty about the pre- cise events during this incubation period, a delay in the movement of rabies virus likely occurs at the site of viral entry or inoculation. The best experimen- tal animal studies to date, examining the events that take place during the incubation period, were per- formed in striped skunks using a Canadian isolate of street rabies virus obtained from skunk salivary glands (Charlton et al, 1997). Studies performed us- ing reverse transcriptase–polymerase chain reaction (RT-PCR) amplification showed that viral genomic RNA was frequently present in the inoculated mus- cle (found in four of nine skunks), but not in ei- ther spinal ganglia or the spinal cord, when skunks were sacrificed 62 to 64 days post inoculation. Im- munohistochemical studies performed prior to the development of clinical disease showed evidence of infection of extrafusal muscle fibers and occasional fibrocytes at the site of inoculation. Although it is unclear, the infection of muscle fibers may be a crit- ical pathogenetic step for the virus to gain access to the peripheral nervous system. Rabies virus binds to nicotinic acetylcholine receptors at the neuromuscu- lar junction (Lentz et al, 1982), and recent studies using nerve-muscle cocultures indicate that the neu- romuscular junction is the major site of entry into neurons (Lewis et al, 2000). Two additional putative rabies virus receptors have recently been reported: the neural cell adhesion molecule (Thoulouze et al,