Lassa virus

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A Microbial Biorealm page on the genus Lassa virus

Classification

Virus; ssRNA virus; ssRNA negative-strand virus; Arenaviridae; Arenavirus; Old world arenavirus


Description and significance

The Lassa virus causes Lassa fever, which is a hemorrhagic fever that is severe and can often be fatal. Some sources state that it affects 2-3 million people yearly (killing 5,000-10,000), while others maintain that it affects only 100,000-300,000. The virus is carried by multimamate rats of the genus Mastomys and transmitted to humans via the inhalation of the rat’s urine (the virus is carried by primary aerosols), contact with the rat’s urine, feces, saliva, or respiratory secretions, or ingestion of contaminated foods. Food can either be contaminated by coming into contact with the rat’s excreta or, in some countries, the rats themselves are eaten. The virus is also spread via contaminated hospital equipment because in most of the countries it is found, simple sterilization and barrier methods are more costly than the hospital can afford. The virus does not normally spread from humans to other humans unless contact with bodily fluids occurs. Although research has discovered that the virus can be recovered from semen up to three months after the infection, no studies have been undertaken to reveal whether or not the virus can be transmitted sexually. One study found that rats caught in houses were contaminated with the virus more often than those caught in the surrounding agriculture, which indicates that the transmission of the virus mostly probably happens in the home.

For a long time vaccines for Lassa fever were not being researched because Lassa virus is primarily found in poorer regions where no profit could be found from discovering a vaccine. However, there has been speculation that the virus could possibly be used as a biological weapon, so it is now being studied at greater lengths.


Genome structure

The Lassa virus is part of the Arenaviridae family which contains viruses that all consist of a small single-strand of RNA. These viruses vary from 10-19 kilobases and replicate via the negative replication strategy. It contains two species of RNA called the small and large units and each unit has two genes at opposite ends that do not overlap. The small unit has some double stranded areas that form stem-loop structures. The large species of RNA encodes for the Z and L proteins at the 5’ and 3’ ends respectively and the small species of RNA encodes for glycoprotein and nucleoprotein at the 5’ and 3’ ends respectively. The gene that encodes for the nucleoprotein is 1,710 nucleotides long and the protein has 569 amino acids. The gene that encodes for the glycoprotein is 1,473 nucleotides long. Lassa virus consists of four lineages, which have a strain variation of 27% in relation to their nucleotides and 15% in relation to their amino acids.


Cell structure, metabolism & life cycle

Lassa virus is a single-stranded RNA virus that is enveloped in lipid with glycoprotein spikes protruding from the outside surface. Its initial sites of replication include dendritic cells and macrophage-monocyte cells and it is then delivered throughout the entire body. It has been shown to decrease platelet counts, decrease leukocyte counts, and increase clotting time in patients. It can endure outside the body in the environment for only one week.

When initiating an infection, the Lassa virus attaches to a receptor on the cell surface with the glycoprotein GP-1. The receptor, which is proteinaceous, is associated with a cell’s vulnerability to the virus. Because the receptor, when purified and sequenced, showed complete homology to a dystroglycan precursor, it is assumed that the receptor is, in fact, dystroglycan. Dystroglycan is made of two parts (alpha and beta) that extend throughout the entire plasma membrane so it can mediate exchanges between the cell and the extracellular matrix. Many tissues in the body contain cells with dystroglycan. The Lassa virus has been shown to use the NH2-terminus in its attachment to alpha-dystroglycan. The glycoprotein GP-1 which is used to join the virus and host cell together, is created when the glycosylated precursor protein (GP-C) is cleaved into GP-1 and GP-2. GP-C has a total size of 76-kDa and when it is split at the peptide bond between leucine259 and glycine260, GP-1 has a total size of 44-kDa and GP-2 has a total size of 36-kDa. The enzyme that cleaves GP-C into GP-1 and GP-2 has been found to be SKI-1/SIP and it cleaves GP-C in the endoplasmic reticulum which is an earlier cleavage stage than what happens in most viruses. While GP-1 binds to the receptor, GP-2 aids in cell membrane attachment by fusing the viral envelope with the cell membrane via pH-dependent fusion.


Ecology (including pathogenesis)

The Lassa virus is so named because, in 1969, it was first isolated and correlated as the causative agent of Lassa fever in a small town called Lassa in North-eastern Nigeria. Lassa fever is mostly found in West Africa, specifically in Sierra Lione, Guinea, Liberia, and Nigeria. As stated above, Lassa virus consists of four lineages. Three of these lineages (which are ancestral to the fourth) are located in Nigeria, while the other can be found in Guinea, Liberia, and Sierra Lione. Often, phylogenetic distance correlates with temporal distance, but in the four lineages of the Lassa virus, it actually correlates more with geographical distance. When people inhabiting Sierra Lione were tested for antibodies for the virus, it was found that those living in the eastern province had the highest amount of antibodies, while those living in the southern coastal areas had the lowest. It was also discovered that people under the age of 20 and over the age of 50 had fewer antibodies and those under the age of one year had none. While many people have antibodies to the virus, the outcome of the virus is usually more dependent on its viremia rather than how many antibodies the person has to respond. One study found that patients with viremia of 103TCID50/ml or higher and aspartate aminotransferase of 120 IU/liter or higher had a statistically higher chance of mortality than those with less. As stated above, the virus is transferred to humans via a rat vector.

Some of the characteristic symptoms of the virus include: fever, muscle aches, sore throat, nausea, vomiting, chest and abdominal pain, weakness, cough, headache, exudative pharyngitis, anemia, low blood pressure, and diarrhea. Because its symptoms are similar to other febrile illness found in Africa, Lassa virus is hard to diagnose. It can eventually can cause pulmonary edema, pleural and pericardial effusion, facial edema, bleeding from mucosal surfaces, neurological complications, deafness, lymphocytopenia, thrombocytopenia, and ascites. Often sore throat, vomiting, and bleeding are associated with higher fatality. Microscopically, the virus causes hepatocellular necrosis and capillary lesions that can cause certain organs to hemorrhage. Lassa virus travels through the body via the blood, lymph vessels, respiratory tract, and digestive tract. Because of the multitude of dissemination strategies in the body, it is able to infect almost every organ in the human body. It has even been found in the cerebrospinal fluid which suggests a malfunction or defect of the blood brain barrier. Even though the virus targets the entire body, the liver is usually the organ that is most affected. The virus escapes detection by suppressing the immune system. There are four clinical stages of Lassa fever. The first stages occurs within the first three days and its symptoms include a high fever, weakness, and a general depression in activity. The second stage transpires from day 4 to day 7 where the patient experiences some of the more common/characteristic symptoms as stated above. The third stage begins at the seventh day and includes more severe symptoms such as: facial edema, convulsions, mucosal bleeding, internal bleeding, and disorientation. The fourth stage usually occurs after the 14th day and ends in coma and death.

Lassa virus has an incubation period of 1-24 days and death usually occurs within 12 days after the onset. Only 20% of people who contract Lassa fever have severe multisystem trauma, meaning that 80% of people have only the milder symptoms. It has also been found that most cases of Lassa fever occur as the seasons change from dry to wet.

The Lassa virus is diagnosed several ways including the discovery of the viral antigen, antibodies, or virus culture. One way to detect the virus antigen is to use the virus’s antibodies in enzyme-linked immunosorbent assays (ELISAs). The virus can also be revealed though indirect immunoflourescence which detects the virus antibodies IgM and IgG. Lastly, the virus can be uncovered using reverse transcription PCR after first reverse transcribing the RNA of the virus into DNA.

While, at present, there is no vaccine for Lassa virus, the broad-spectrum nucleoside analogue ribaviran has been demonstrated to have therapeutic effect on patients suffering from Lassa fever. Ribaviran works by mutating the progeny genomes of the virus by incorporating itself into the virus’s RNA. While this method has been proven to reduce mortality, it is most successful if it is given within 6-7 days of the start of symptoms. Ribaviran by itself is not enough, the patient also needs rigorous care in the hospital setting. Someone suffering from Lassa virus needs to have their fluids and electrolytes kept in balance, they require the proper amount of oxygen, their blood pressure needs to be monitored, and they need prompt treatment for any complications that may arise.


Interesting feature

The most interesting feature of this virus is how differently it affects pregnant women in comparison with non-pregnant women. When a pregnant woman contracts Lassa virus, it is much more likely to be severe or fatal, though, this high risk pertains more to women in their third trimester than women in their first or second. Women who were diagnosed with the virus while pregnant showed a much lower mortality rate if their uteri were evacuated though abortion or normal delivery. Because the risk of fetal fatality was found to be 87% from the virus, evacuating the uterus to save the mother is often the best option if the fetus is probably going succumb to death from the virus anyway.


References

Bowen, M. D., P. E. Rollin, T. G. Ksiazek, H. L. Hustad, D. G. Bausch, A. H. Demby, M. D. Bajani, C. J. Peters, and S. T. Nichol. "Genetic Diversity among Lassa Virus Strains." Journal of Virology 74.15 (2000): 6992-7004.

Cao, Wei, Michael D. Henry, Persephone Borrow, Hiroki Yamada, John H. Elder, Eugene V. Ravkov, Stuart T. Nichol, Richard W. Compans, Kevin P. Campbell, and Michael B.A. Oldstone. "Identification of Alpha-dystroglycan as a Receptor for Lymphocytic Choriomeningitis Virus and Lassa Fever Virus." Science 282 (1998): 2079-081.

Günther, Stephan, Boye Weisner, Andreas Roth, Thomas Grewing, Marcel Asper, Christian Drosten, Petra Emmerich, Jochen Petersen, Martin Wilczek, and Herbert Schmitz. "Lassa Fever Encephalopathy: Lassa Virus in Cerebrospinal Fluid but Not in Serum." The Journal of Infectious Diseases 184.3 (2001): 345-49.

Idemyor, Vincent. "Lassa Virus Infection in Nigeria: Clinical Perspective and Overview." Journal of the National Medical Association 102.12 (2010): 1243-246.

Johnson, Karl M., Joseph B. McCormick, Patricia A. Webb, Ethleen S. Smith, Luanne H. Elliot, and Isabel J. King. "Clinical Virology of Lassa Fever in Hospitalized Patients." The Journal of Infectious Diseases 155.3 (1987): 456-64.

Lashley, Felissa R., and Jerry D. Durham. Emerging Infectious Diseases: Trends and Issues. 2nd ed. New York: Springer Pub., 2007.

"Lassa Virus." NCBI. Accessed 01 Nov. 2011. <http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info>.

Lenz, Oliver, Jan Ter Meulen, Hans-Dieter Klenk, Nabil G. Seidah, and Wolfgang Garten. "The Lassa Virus Glycoprotein Precursor GP-C Is Proteolytically Processed by Subtilase SKI-1/S1P." PNAS 98.22 (2001): 12701-2705.

McCormick, Joseph B., Patricia A. Webb, John W. Krebs, Karl M. Johnson, and Ethleen S. Smith. "A Prospective Study of the Epidemiology and Ecology of Lassa Fever." The Journal of Infectious Diseases 155.3 (1987): 437-44.

Price, M. E., S. P. Fisher-Hoch, R. B. Craven, and J. B. McCormick. "A Prospective Study of Maternal and Fetal Outcome in Acute Lassa Fever Infection during Pregnancy." Bmj 297.6648 (1988): 584-87.

Richmond, J. K., and Deborah J. Baglole. "Lassa Fever: Epidemiology, Clinical Features, and Social Consequences." Bmj 327.7426 (2003): 1271-275.