LASSA VIRUS

Lassa Virus is a member of the arenaviridae and is found primarily in rural Sub-Saharan regions of western Africa. It causes multi-organ febrile infection and is frequently fatal if untreated. Exact pathalogical mechanisms are largely unknown. Immunogenic properities are unclear. A vaccine has been developed and if unvaccinated it can be treated by ribavirin.

Detection / Laboratory Diagnostics

Lassa virus is isolated from blood or serum during the febrile phase of the disease up to 14 days postonset. Viral antigen can be detected by ELISA in acute cases, but becomes negative when antibodies become detectable. Severe cases of Lassa Fever result in death before antibody production. Antibodies (IgM, IgG) to Lassa are assayed by IFA or ELISA. Viral RNA can be detected by the third day of hospitalization by reverse transcriptase PCR. Primers used have been designed to well conserved regions (between isolates from different areas of Africa) of the S RNA segment coding for viral glycoprotiens.

Lassa virus is rated as Biosafety Level IV containment by the CDC. Live virus can be inactivated by -radiation. Viral proteins have been expressed in the Bacculovirus system under the polyhedrin promoter and have shown similar antigenicity to the live virus.

Properties of Virion

• arenaviridae family; pleomorphic in shape; spheroidal
• bisegmented, probably 2 filamentous helical nucleocapsids per envelope ; replication in cytoplasm, budding at plasma membrane, encorporating host ribosomes by chance
• surface projection spikes (10nm) evenly distibuted
• virion composed of 2% nucleic acid, genomic and non-viral - ssRNA, bipartite, ambisense
• each virion contains multiple segments of genome, not in equimolar proportions
• sequence at 3' term largely complimentary to similar region at 5'
• genome organized into L (7.2kb) and S segment (3.4kb)
• S encodes nucleocapsid and glycoprotein (GP) precursor
• GP posttranslationally modified to GP1, GP2 ( assembled to form tetrameric virion spike
• GP1: interacts with viral receptors; recognized by neutralizing antibodies of host
• GP2: promotes acid dependent (pH 4.5 - 5.5) membrane fusion for viral ent

Epidemiology

Lassa virus was first described in Lassa, a village of northern Nigeria, in the central region of Africa. Small outbreaks have occurred in Zorzor, Liberia, and various other parts of Nigeria. Serological evidence of human infection have been documented in Guinea, Senegal, Mali, Sierra Leone and Zaire. The virus is largely confined to West Africa, but there have been incidences where the virus has been introduced outside of Africa mainly through health care workers.

The natural reservoir of Lassa is Mastomys natalensis, a rodent prevalent throughout Africa south of the Sahara. In this rodent, Lassa causes a chronic, inapparent infection with persistent viremia. Lassa is excreted from the rat through urine and saliva. While nosocomial spread (aerosols) are rare for most arenaviridae, Lassa can be spread through aerosols or contact. Reservoir hosts are congenitally transmitted, and horizontal transmission to uninfected rats are through the mentioned secretions. Humans are primarily infected by eating an infected rat, or by eating food contaminated with rat excretions. Infection is also possible through the inhalation of dried infecte urine. Low levels of sanitation and the high prevalence of the natural reservoir favor promote the spread of Lassa virus. The most efficient mechanism of infection is by a rodent bite.

Reported cases do not favor a particular sex, and both children and adults can be infected, with a lower incidence in children. Interhuman transmission of arenaviridae is rare except in the case of Lassa. Person to person transmission is mainly via direct contact, and is possible through contamination of skin breaks with infected blood, and aerosol spreads. Hospitals and dispensaries are ideal environments for the spread of Lassa, and the worst epidemics documented have occurred in these places. As the virus is present in bodily secretions such as urine, salive, and semen, it can be spread through sexual contact.

• The number of cases of Lassa fever annually is esimated at 200000 - 400000 cases with several thousand fatal. Overall mortality among hospital cases is about 15%. In untreated cases, mortalility rises to 60%. Mortality is 2-3x higher in pregnant/post portum women, and pregnancies invariably end in abortion/neonatal death. In endemic areas such as Sierra Leone, antibodies to the virus in the population may reach 40%, and overall mortality is <2%,>

Viral Treatment

Summary

• treated effectively with ribavirin
• ribavirin is an IMP dehydrogenase inhibitor
• treatment best if iniated within first six days of fever
• major side effect is anemia
• human trials completed
  

Lassa viral infection can be treated by 1--Dribofuranosyl-1,2,4-triazole-3-carboxamide, virazole, better known as ribavirin This drug, and many similar derivatives, are broad spectrum antiviral agents and trials in monkeys have shown that the drug does increase their survival rate when infected. Ribavirin acts as an inosinate (IMP) dehydrogenase inhibitor. IMP cannot be converted to XMP, due to the irreversibe competetive inhibition of ribavirin, which is very similar in structure to IMP. Blocking the IMP to XMP conversion severely reduces the levels of GMP, GDP and GTP, which effectively suppresses viral RNA synthesis This drug attacks a host system that the virus is dependent upon, in turn meaning that the host is affected. Indeed, the monkey trials showed that there was anemia as red blood cells were not produced. However, when the use of the drug was discontinued the anemia disappeared.

A human trial was conducted in Sierra Leone by the CDC. After serum tests of infected individuals were completed, observation of their recovery led to the establishment of three categories. These categories were minimal risk, having a low mortality rate, medium and high risk with mortality rates of 55% and 76% respectively. If ribavirin was administered for ten days, commencing within the first six days of fever onset, the mortality rates dropped to 5% and 9% for the medium and high risk groups. However, if the drug therapy was started seven days or more after fever onset, the mortality rates were 26% and 47%. Further tests with Lassa convalescent plasma did not significantly reduce the mortality rate, either alone or with ribavirin. The side effect of anemia noted in monkeys was again present. The use of an oral form of ribavirin, which can be stored at room temperature, was suggested as the reduction of mortality was significant.