Aparajita Sohoni

Humans and Viruses
Human Biology 115A
Winter, 1999
Robert Siegel, instructor


+ Introduction

The rhabdoviridae represent one of the oldest and most feared viral families to plague humankind. Two of the genera within the family, Vesiculovirus and Lyssavirus, are more familiarly known as the causative agents of Vesicular Stomatitis and Rabies in humans.

This single stranded, negative,monopartite RNA genome, carefully enveloped within a helical nucleocapsid, has felled the princes and paupers of all mammals alike. Its potency, misrepresented by the relatively small size of the genome, is more accurately belied by the characteristic deathly bullet shaped morphology which connotes the 100% mortality rate caused by the virus within. Unique in that its transmission occurs through the biting of one host by another, the virus is able to generate coordinated behavior in the host to enable further dissemination of its virion.

The long incubation period enables the rhabdo virus to exist within the host for an incubation period ranging up to seven years before expressing itself. However, this extended latency period has allowed mere mortals the opportunity to attack the virus before the wild type overtakes the body. If administered prior to the development of clinical symptoms, the post-exposure vaccination can save individuals from the otherwise secure death sentence that rabies promises.

The rhabdoviridae are truly beautiful yet deadly creations of nature-- ones whose virulence humanity must never underestimate or assume to control.

+ Historical notes

The term "rabies" originates from the Sanskrit term rabhas, meaning "to do violence". The Greek term "lyssa" is derived from the root lud, also connoting violence. These references to diseases caused by the bite of animals demonstrate the understanding of rabies maintained in ancient civilizations (see Iranian picture).

The first recorded reference to rabies comes from the 23rd century BC, where the Eshmuna Code of Babylon writes, "If a dog is mad and the authorities have brought the fact to the knowledge of its owner; if he does not keep it in, and it bites a man and causes his death, then the owner shall pay two-thirds of a min (40 shekels) of silver. If it bites a slave and causes his death he shall pay 15 shekels of silver" (Fields 1137).

Famous Greek works dating to 700 BC, such as The Iliad, demonstrate this civilization's familiarity with rabies by using terms such as "rabid dog" (Fields 1137). In the 4th century BC, Aristotle "exempted humans from contracting rabies" from a mad dog's bite due to his erroneous classification of rabies as a disease of animals.

The Roman writer Cordamus demonstrated increasingly concrete understanding of rabies by suggesting that a "poison" in the saliva causes the hydrophobic condition.

His contemporary, the Roman Aulus Cornelius Celsus, composed a clinical description of rabies in humans. Celsus categorized the rabies infection as engendering an altered mind set in the patient, causing his/her torture by thirst and simultaneous "invincible repulsion toward water" (Fields 1137). Celsus recommended treating rabies by "[excising] bitten tissue, [cauterizing] the wound by hot iron, and ducking the victim into a pool" (Fields 1137). This treatment continued with the implementing of nitric acid rather than hot iron into the 1800's. Additionally, ingesting the liver of the mad dog, crayfish eyes, cock's brain, or cock's comb were recommended for rabies prophylaxis.

During the Renaissance, Italian physician and savant Girolamo Fracastoro published The Incurable Wound, a treatise describing a clinical case of rabies infection in humans. His vivid descriptions of the patient "[shrinking] from water and all liquids, [flinging] himself hither and thither...like a madman" hold true through the present day (Fields 1138).

The existence of rabies in the Americas and the Oceania is evidenced in reports such as the De Rebus Oceanicis et de Orbi Novi Decades Octo written by the first bishop of Oceania after the discovery of the Americas. Thus, the knowledge of the presence of rabies and its zoonotic transmission from animals to humans became increasingly clear as the global society entered the 1800's.

During the nineteenth century, rabies ravaged Europe and fear towards this condition escalated to hysteria as patients committed suicide when bitten by a dog if the remotest possibility of contracting rabies existed. Thus, an international realm of terror emerged which could only be calmed by the scientific innovations soon to come under the guidance of Louis Pasteur.

+ Timeline

+ Replication

The Vesicular Stomatitis Virus exists as the prototype for rhabdovirus and all negative stranded RNA virus replication. In replication, the following steps occur:


Initially, the G glycoprotein on the virion surface binds to host cell receptors.
The virion enters the cell by endocytosis.
The viral envelope fuses with the membrane of the endosome.
Acidification of the vesicle results in the release of the helical nucleocapsid into the cytoplasm.
Transcription occurs via the viral transcriptase complex (L+P) which is an RNA-dependent RNA polymerase. This transcription results in the formation of five separate monocistronic mRNA species (N, P (NS), M, G, and L) which are translated into five viral proteins. The multifunctional enzyme encoded by the L protein allows the 5' capping to occur, while the polyadenylation occurs via "polymerase slippage" at each stretch of noncoding intergenic sequences.
As only one promoter exists, the encounter between the transcriptase complex and the intergenic sequence of seven U residues results in the former moving to the next open reading frame. The complex moves with less than 100% efficiency, which explains the transcription of the five genes in decreasing molar abundance from N at the 3' end to L at the 5' end (of the template strand).
The virion enters the replication mode after synthesizing the N protein which enables the polymerase to ignore the polyadenylation, capping signals, and intergenic transcription termination in order to produce the complementary positive strand of genomic RNA. This positive strand serves as a template from which to generate new genomes.
Meanwhile, the membrane-bound ribsomes synthesize the G protein which is then processed by the Golgi apparatus and delivered to the surface of the cell in membrane vesicles.
The virion reassembles in two phases: The first phase occurs in the cytoplasm where both plus and minus strands of the genome associate with the N protein and subsequently with the polymerase proteins L and NS to form the nucleocapsid. In the se cond phase, the nucleocapsid gets enveloped and released at the cell plasma membrane. The interaction between the M protein and the plasma membrane glycoprotein G modified areas induces coiling of the nucleocapsid back into its condensed form. The virus t then buds through the plasma membrane and is released when the entire nucleocapsid is enveloped.

The aforementioned events all occur in a portion of the cytoplasm called a Negri body, which serves as a virus factory and demonstrates teh appearance of a characterisitc cytoplasmic inclusion body. A crucial distinction between the behavior of VSV and Rabies viruses is that in VSV, rapid cytopathology occurs because protein M inhibits cellular mRNA transcription whereas rabies virus replication is un usually noncytopathic. Rabies virus replication includes the presence of Defective Interfering Particles. These DI virus particles are shorter, contain complex deletion mutations within their genome, and have a smaller RNA molecule than normal infectious particles. The prevalence of DI's increases preferentially in serial passage because their shortened RNA genomes require less time to be replicated, are less often diverted to be templates for transcription fo mRNA, and have enhanced affinity for the vir al replicase. Useful Web Links: http://www.pasteur.fr/Bio/rage/rageanglais.html http://www.tulane.edu/~dmsander/WWW/335/Rhabdoviruses.html http://oms.b3e.jussieu.fr/rabnetS/ http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/00056176.htm http://gsbs.utmb.edu/m icrobook/ http://www.cdc.gov/epo/mmwr/mmwr.html http://www.uct.ac.za/depts/mmi/stannard/virarch.html http://homeport.tcs.tulane.edu/~dmsander/Big_Virology/BVRNArhabdo.html#rhabdo

+ Family Updates

+ Useful web links

+ References


Created: February 1, 1999
Last modified: February 1, 1999