1. Arenavirus Presented by Presented by Sue Y. Hwang

2. What are the Arenaviridae? Arenaviridae Arenaviridae * A family of viruses whose members are generally associated with rodent- transmitted disease in humans. * A family of viruses whose members are generally associated with rodent- transmitted disease in humans.

3. Taxonomy Family: Arenaviridae Family: Arenaviridae Genus: Arenavirus Genus: Arenavirus Subgroup (2): Subgroup (2): A) LCM-LASV Complex (Old World Arenaviruses) A) LCM-LASV Complex (Old World Arenaviruses) B) Tacaribe Complex (New World Arenaviruses) B) Tacaribe Complex (New World Arenaviruses)

4. What viruses are included in the virus family? The arenaviruses are divided into two groups: the New World or Tacaribe complex and the Old World or LCM/Lassa complex. The arenaviruses are divided into two groups: the New World or Tacaribe complex and the Old World or LCM/Lassa complex. Of the fifteen Arenaviruses known to infect animals, five cause disease in humans: Lassa virus, Junin virus, Machupo virus, Guanarito virus, and lymphocytic choriomeningitis virus. All arenaviruses contain a set of internal cross-reacting antigens as well as species-specific envelope antigens. Of the fifteen Arenaviruses known to infect animals, five cause disease in humans: Lassa virus, Junin virus, Machupo virus, Guanarito virus, and lymphocytic choriomeningitis virus. All arenaviruses contain a set of internal cross-reacting antigens as well as species-specific envelope antigens. Source: Source: http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/arena.htm http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/arena.htm VirusDisease Lassa virus Lassa fever Junin virus Argentine hemorrhagic fever Machupo virus Bolivian hemorrhagic fever Guanarito virus Venezuelan hemorrhagic fever Sabia Brazilian hemorrhagic fever

6. Virus Morphology Spherical Spherical An average diameter of 110-130 nm An average diameter of 110-130 nm Enveloped in a lipid membrane. Enveloped in a lipid membrane. Has grainy particles that are ribosomes acquired from their host cells. (derived from the Latin "arena," which means "sandy." ) Has grainy particles that are ribosomes acquired from their host cells. (derived from the Latin "arena," which means "sandy." ) Their genome is composed of RNA only. Their genome is composed of RNA only. New viral particles, called virions, are created by budding from the surface of their hosts’ cells. New viral particles, called virions, are created by budding from the surface of their hosts’ cells.

8. This image shows extracellular virus particles budding from the cell surface. Magnification approx. 12,000 times. Image courtesy Cynthia Goldsmith, MS, Infectious Disease Pathology Activity, DVRD, NCID, CDC.

9. Genome Each virion contains multiple copies of genome (multipartite) Virions contain 2 % nucleic acid. * Two segments of (RNA L and S) linear negative-sense single stranded RNA. * Two segments of (RNA L and S) linear negative-sense single stranded RNA. - S encodes the major structure of the virion (NP, GP-1, and GP-2). - L encodes the viral RNA-dependent RNA polymerase (L), and a regulatory protein (Z). - S encodes the major structure of the virion (NP, GP-1, and GP-2). - L encodes the viral RNA-dependent RNA polymerase (L), and a regulatory protein (Z). Total genome length is 5000-7400 nt. Total genome length is 5000-7400 nt. * Each segment forms a circle by hydrogen bonding of its end. (Nucleotide sequences of 3'-terminus largely complementary to similar regions on the 5' end) The hairpin serves as the transcription termination signal. * Each segment forms a circle by hydrogen bonding of its end. (Nucleotide sequences of 3'-terminus largely complementary to similar regions on the 5' end) The hairpin serves as the transcription termination signal. * Genome itself is non-infectious

10. From Ray Baumann, at the University of Mississippi School of Medicine Ray BaumannRay Baumann

11. Replication Replication cycle is not fully understood yet. Replication cycle is not fully understood yet.

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13. Replication continued 1. Virions attach to undefined receptors and enter host cells. 2. Virus uncoating occurs in the cytoplasm; the viral nucleic acid is delivered to the cell cytoplasm; the site of mRNA 3. Early genes are expressed during genome uncoating. 4. Transcription of the genome and replication is confined to the cytoplasm. 5. Non-structural proteins involved in transcription. -The viral genome is transcribed from the viral sense strand either from the 3' end or from the 5' end -The viral genome is transcribed from the viral sense strand either from the 3' end or from the 5' end - By a viral RNA-dependent RNA polymerase into 2 mRNA(s) (S and L mRNA). - By a viral RNA-dependent RNA polymerase into 2 mRNA(s) (S and L mRNA).

14. 6. The small (S) RNA in the virion encodes 6. The small (S) RNA in the virion encodes - in the negative sense a nucleoprotein (NP) - in the negative sense a nucleoprotein (NP) - in the positive or message sense a precursor glycoprotein (GPC), which is cleaved into two virion glycoproteins (GP1 and GP2). - in the positive or message sense a precursor glycoprotein (GPC), which is cleaved into two virion glycoproteins (GP1 and GP2). The large (L) RNA in the virion encodes The large (L) RNA in the virion encodes -in the negative sense an RNA-dependent RNA polymerase (L) -in the negative sense an RNA-dependent RNA polymerase (L) -in the positive sense a zinc-binding protein (Z) which binds to the ribonucleoprotein complex. -in the positive sense a zinc-binding protein (Z) which binds to the ribonucleoprotein complex. 7. Specific termination sequences have been identified. Termination is caused by characteristic GC-rich, strongly base-paired stem loop- structure. 8. The virus buds from the plasma membrane, incorporating host lipids into the virus membrane.

15. 9. Host cells remain intact. Virus is released from host cell by budding through the cell membrane and gain an envelope. Virus is released from host cell without causing death.

17. Pathogenesis Pathogenesis Chronic infection in rodent host. Chronic infection in rodent host. (However, the viruses do not appear to cause obvious illness in them.) –Rodents that carry the Old World arenaviruses can transmit the virus from mother to offspring during pregnancy. Thus, virus remains in the rodent population generation after generation –New World arenavirus carrying rodents can only transmit among adult rodents, so only a portion of mice are infected at one time. This leads to cyclic trends in the incidence of human cases. Human infection occurs by contact with rodent excretions Human infection occurs by contact with rodent excretions –Contaminated food –Dust with urine (inhale) –Exposed wounds Secondary spread (person-person) Secondary spread (person-person) –Nosocomial –Contact with infected blood and other excretions –Contact with contaminated medical equipment

18. Pathogenesis.. continued Zoonotic Zoonotic (In nature, the virus is found in animals) Each virus is associated with either one species or a few closely related rodents. Each virus is associated with either one species or a few closely related rodents. EX: EX: 1. Tacaribe complex viruses are associated with the New World rats. 1. Tacaribe complex viruses are associated with the New World rats. 2. The LCM/Lassa complex viruses are associated with the Old World rats. 2. The LCM/Lassa complex viruses are associated with the Old World rats.

20. Symptoms The onset of the hemorrhagic fevers caused by Lassa, Junin, Machupo, and Guanarito viruses: The onset of the hemorrhagic fevers caused by Lassa, Junin, Machupo, and Guanarito viruses: - within 7 to 14 days, - within 7 to 14 days, -pyrexia -pyrexia -headache -headache -sore throat -sore throat -myalgia -myalgia Virus can be recovered from the blood and serum for up to 3 weeks after onset of the infection. Virus can be recovered from the blood and serum for up to 3 weeks after onset of the infection. Lassa virus can be recovered from the urine for up to 5 weeks. Lassa virus can be recovered from the urine for up to 5 weeks.

21. Host Defenses Interferon is induced by Arenavirus infection. Interferon is induced by Arenavirus infection. Slow humoral response. Slow humoral response. Cell-mediated immunity is probably of prime importance Cell-mediated immunity is probably of prime importance

22. Epidemiology The arenaviruses that affect humans exist in nature as benign infections in restricted rodent hosts The arenaviruses that affect humans exist in nature as benign infections in restricted rodent hosts

23. Frequent hospital-acquired infections in West Africa brought Lassa virus to the attention of the medical world 25 years ago. It is transmitted at the village level and that most infections are asymptomatic. For those sick enough to be admitted to the hospital, mortality is about 15 percent. Frequent hospital-acquired infections in West Africa brought Lassa virus to the attention of the medical world 25 years ago. It is transmitted at the village level and that most infections are asymptomatic. For those sick enough to be admitted to the hospital, mortality is about 15 percent. 1. The case fatality rates associated with Junin, Machupo, and Guanarito viruses range from 5 to 35 percent. 2. LCM virus, which is found worldwide in Mus musculus (the common field mouse), is considered to be the agent in about 5 percent of CNS infections. These infections are rarely fatal.

25. Diagnosis Differential clinical diagnosis is complex; the diagnosis is confirmed only by detecting a rise in antibody titers (IgM, IgG) or by isolating the virus. Differential clinical diagnosis is complex; the diagnosis is confirmed only by detecting a rise in antibody titers (IgM, IgG) or by isolating the virus. The traditional methods of diagnosis: The traditional methods of diagnosis: -Virus isolation -Virus isolation - Virus neutralization - Virus neutralization - Detection of antibodies - Detection of antibodies - Polymerase chain reaction technology. - Polymerase chain reaction technology.

26. Prevention Keep food in rodent proof containers Keep food in rodent proof containers Reduce rodent population Reduce rodent population At a hospital setting At a hospital setting –Wear protective clothing –Sterilize equipment

27. Treatment Therapy with ribavirin (anti-viral) is proven to be effective in treating some infections in Africa and South when given early in infection. Therapy with ribavirin (anti-viral) is proven to be effective in treating some infections in Africa and South when given early in infection. The sooner treatment is started after infection, the better the chances of survival. The sooner treatment is started after infection, the better the chances of survival.

28. Control Elimination of rodents is effective but often not practical Elimination of rodents is effective but often not practical Vaccines and antiviral agents Vaccines and antiviral agents (e.g., ribavirin) (e.g., ribavirin).

29. Sources http://www.cdc.gov/ncidod/dvrd/spb/mnpa ges/dispages/arena.htm http://www.cdc.gov/ncidod/dvrd/spb/mnpa ges/dispages/arena.htm http://www.cdc.gov/ncidod/dvrd/spb/mnpa ges/dispages/arena.htm http://www.cdc.gov/ncidod/dvrd/spb/mnpa ges/dispages/arena.htm http://www.virology.net/Big_Virology/BVR NAarena.htm http://www.virology.net/Big_Virology/BVR NAarena.htm http://gsbs.utmb.edu/microbook/ch057.htm http://gsbs.utmb.edu/microbook/ch057.htm