Lymphocytic choriomeningitis

Lymphocytic choriomeningitis (LCM) is a rodent-borne viral infectious disease that presents as aseptic meningitis, encephalitis or meningoencephalitis. Its causative agent is lymphocytic choriomeningitis mammarenavirus (LCMV), a member of the family Arenaviridae. The name was coined by Charles Armstrong in 1934. Lymphocytic choriomeningitis (LCM) is a rodent-borne viral infectious disease that presents as aseptic meningitis, encephalitis or meningoencephalitis. Its causative agent is lymphocytic choriomeningitis mammarenavirus (LCMV), a member of the family Arenaviridae. The name was coined by Charles Armstrong in 1934. Lymphocytic choriomeningitis (LCM) is 'a viral infection of the membranes surrounding the brain and spinal cord and of the cerebrospinal fluid'. The name is based on the tendency of an individual to have abnormally high levels of lymphocytes during infection. Choriomeningitis is 'cerebral meningitis in which there is marked cellular infiltration of the meninges, often with a lymphocytic infiltration of the choroid plexuses'. LCMV infection manifests itself in a wide range of clinical symptoms, and may even be asymptomatic for immunocompetent individuals. Onset typically occurs between one or two weeks after exposure to the virus and is followed by a biphasic febrile illness. During the initial or prodromal phase, which may last up to a week, common symptoms include fever, lack of appetite, headache, muscle aches, malaise, nausea, and/or vomiting. Less frequent symptoms include a sore throat and cough, as well as joint, chest, and parotid pain. The onset of the second phase occurs several days after recovery, and consists of symptoms of meningitis or encephalitis. Pathological findings during the first stage consist of leukopenia and thrombocytopenia. During the second phase, typical findings include elevated protein levels, increased leukocyte count, or a decrease in glucose levels of the cerebrospinal fluid). Occasionally, a patient improves for a few days, then relapses with aseptic meningitis, or very rarely, meningoencephalitis.Patients with meningitis may have a stiff neck, fever, headache, myalgia, nausea and malaise. In some occasions, meningitis occurs without a prodromal syndrome. Meningoencephalitis is characterized by more profound neurological signs such as confusion, drowsiness, sensory abnormalities and motor signs. Under reported complications include myelitis, Guillain–Barré-type syndrome, cranial nerve palsies, transient or permanent hydrocephalus, sensorineural hearing loss, orchitis, arthritis and parotitis. LCMV infections have also been associated with pancreatitis, pneumonitis, myocarditis and pericarditis. The entire illness usually lasts 1 to 3 weeks, nonetheless, temporary or permanent neurological damage is possible in all central nervous system infections, especially in cases of meningoencephalitis. Chronic infections have not been reported in humans and deaths rarely occur. There are several strains of LCM virus, among which the most widely used are LCMV Armstrong and LCMV Clone 13. Armstrong is the original virus strain which was isolated from the brain by Charles Armstrong in 1934. It triggers a vigorous cytotoxic T lymphocytes(CTL) response and thus, it is cleared rapidly by the host. This is referred to as acute (Armstrong) LCMV infection. On the other hand, Clone 13 is a variant of the Armstrong viral strain, isolated from the spleen and is consequently tropic for visceral organs. It was first isolated from mice which sustained a persistent LCMV infection from birth. This variant potentiates a less vigorous CTL response in the immune system, and thus can ultimately persist in the host organism indefinitely. The latter is referred to as chronic (Clone 13) LCMV infection. LCMV is a spherical enveloped virus with a diameter between 60 and 300 nm. The helical nucleocapsid contains an RNA genome consisting of two negative single-stranded RNA segments. The negative RNA strand, complementary to the necessary mRNA strand, indicates that it must first be transcribed into a positive mRNA strand before it can be translated into the required proteins. The L strand is ambisense RNA, encoding multiple proteins in opposite directions, separated by an intergenic region. It is approximately 7.2 kb in size and encodes a high-molecular-mass protein (L; 200 kDa) and an 11 kDa small polypeptide Z with unknown function and a ring finger motif. The viral RNA-dependent RNA polymerase is encoded by the L protein which contains conserved characteristic motifs throughout all the RNA-dependent, RNA-polymerases. The S strand is ambisense and approximately 3.4 kb in size. It encodes the two main structural proteins: nucleo-protein (63 kDa) and glycoprotein C (75kDa). The latter undergoes posttranslational cleavage and results in the synthesis of two mature virion glycoproteins, GP-1 (40 to 46 kDa) and GP-2 (35 kDa). The spikes present on the virion envelope are dictated by tetramer formation of GP-1 and GP-2. When LCMV attacks a cell, the process of replication starts by attachment of the virus to host receptors through its surface glycoproteins. It is then endocytosed into a vesicle inside the host cell and creates a fusion of the virus and vesicle membranes. The ribonucleocapsid is then released in the cytoplasm. The RNA-dependent, RNA-polymerase brought along with the virus initially binds to a promoter on the L and S segments and begins transcription from negative-stranded to a positive-stranded mRNA. The formation of a strong hairpin sequence at the end of each gene terminates transcription. The mRNA strands are capped by the RNA-dependent, RNA-polymerase in the cytoplasm and are then subsequently translated into the four proteins essential for LCMV assembly. The ribonucleocapsid interacts with the Z matrix protein and buds on the cell membrane, releasing the virion out from the infected cell. The first arenavirus, Lymphocytic choriomeningitis mammarenavirus (LCMV), was isolated in 1933 by Charles Armstrong during a study of an epidemic in St. Louis. Although not the cause of the outbreak, LCMV was found to be a cause of nonbacterial or aseptic meningitis. In 1996, Peter Doherty and Rolf Zinkernagel shared the Nobel Prize in Medicine and Physiology, for their work with LCMV which led to a fundamental understanding of the adaptive immune response, MHC restriction. In the 1970s, studies concerning the importance of MHC locus were done exclusively in transplantation and tumor rejection. Taking this into consideration, Doherty and Zinkernagel were working on the response of mice to virus infections. They observed that T-cell receptors must recognise a complex of foreign antigen and an MHC antigen in order to destroy infected cells. Their key experiment involved harvesting of splenocytes containing LCMV-specific cytotoxic T lymphocytes(CTL) from an infected mouse strain A. These were then mixed in vitro with virus infected fibroblasts or macrophages from two different mouse strains, A and B. By the method of Cr-release cytotoxicity assay, thereby tagging the CTL with chromium-51 (Cr-51), the CTL destruction of infected cells was quantified by release of Cr-51. The results showed that CTL killed only the infected cells from strain A, and they did not lyse uninfected cells or infected cells from strain B. They concluded that these virus specific CTLs only lyse cells carrying the same molecules of the major histocompatibility site (MHC) as the CTLs themselves. Thus, the virus-specific CTLs are 'MHC-restricted'. This discovery lead to a greater understanding of an important aspect of the immune system.