Mimivirus is a viral genus that contains the only discovered species Acanthamoeba polyphaga mimivirus (APMV). The Mimivirus holds the largest capsid in diameter compared to the other known classic viruses like HIV or the influenza virus. Because of these features, scientists had first mistaken the virus to be a bacterium. Mimivirus was first discovered in 1992 by a French Scientist in Marseille. These scientists were investigating Legionnaires' disease, in which they came upon by accident, a "coccus-like" bacterium. It wasn't until 2003, when a journal was first published in discovery of the Mimivirus. The journal was written by a bacteriologist at the Universite de la Mediterranee in France, whom confirmed the identification of APMV. Mimivirus have a unique feature that is almost similar to a bacterium on Gram staining (Scola, 2003). So the name Mimivirus, originates from its initial misidentification of a Gram-positive bacteria, thus dubbed as the "microbe mimicking" virus. The discovery of Mimiviruses contradicts the accepted theories of viruses being small in size and genome.
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Mimiviruses are double-stranded DNA with a genome size of approximately 1.2 million base pairs and 1018 protein coding genes including the new genes discovered recently. The Mimivirus genome is circular and belongs in the family Mimiviridae. Some scientists argue that the genome of Mimivirus is linear and NOT circular, however there were no sources confirming the conformation of the genome. Based on an electron microscopy study, the virions are nonenveloped icosahedrons with a diameter of 400-750 nm (Kuznetsov, 2010). Atomic force microscopy (AFM) is an imaging method with capabilities of observing small microorganisms at a very high-resolution. This method was able to demonstrate the 20-icosahedral faces of the Mimivirus capsids (Xiao, 2009). The Mimivirus contains an 80 nm fibrils attached to the capsid and is classified as Baltimore classification I.
Figure 1. Picture from: http://upload.wikimedia.org/wikipedia/commons/thumb/e/e1/Mimivirus.jpg/790px-Mimivirus.jpg
Mimivirus contains a coated layer of proteins on the icosahedral capsid that in some ways mimic the cell wall of Gram-positive bacteria. This protein coat was believed to be a concealment to fool the ameboid host into thinking that the virion is a bacterium, which causes the host to submit to eating its lunch (Claverie, 2009). Scientists believed that the outer protein coat may serve for another purpose.
LIFE CYCLE: AMOEBA
Amoebas are considered a genus of Protozoa and obtain their food (algae, bacteria, other protozoans, and tiny particles of dead plant or animal matter) via phagocytosis. This is important to know because the Mimivirus infection is triggered by phagocytosis (Ghigo, 2008 & Monti, 2007). First off, the Mimivirus has a strong resemblance towards Gram-positive bacteria due to its large size and mimic abilities of Gram positive cell wall. Because of those characteristics, the amoeba, with no distinctive abilities, thought that the large virus was a bacterium and swallowed the virus via the mechanism of phagocytosis. Once the viral particle is absorbed by phagocytosis, a vacuole surrounds the viral particle and fuses to become a phagosome (figure 2). The absorbed viral particles in the phagosome will then merge with the lysosome. The degradation from the lysosomal activity in the amoeba will weaken the outer fiber layer, which will produce an opening of the five icosahedral faces on the vertex of the capsid (Zauberman, 2006 and Xiao, 2009). This allows the virus to release its DNA to the host cell nucleus. From there, the Mimivirus replication will break into three different zones known as the viral factory (VF). The three VF zones are: (1) inner replication center, (2) intermediate assembly zone, and (3) peripheral zone (Monti, 2007). The replication center will produce viral proteins and the assembly zone will assemble these proteins into capsids. The peripheral zone will add the fibers to the capsid. Empty or filled DNA capsids will then accumulate near the central core, which will result in the formation of a large massive membrane, to which the host cell could not withstand the large massive membrane and bursts (process known to be amoebal lysis). The viral nucleocapsid DNA is released into the cell cytoplasm (Monti, 2007). Future studies of the Mimivirus may be linked with finding out its attachment phase and possibly a more in depth detail on its transcription factors.
Figure 2. Schematic representation of APMV replication cycle (Monti, 2007). (a1) Phagocytosis of viral particle. (a2) Fusion of phagosome and lysosome, (b3-b4) Virus releases DNA to host nucleus (c5) Mimivirus DNA came out the host nucleus to form the virus factory (VF) replication center. (d6) Replication center produce viral proteins, assembly zone assembles capsids, and peripheral zone adds the fibers, (e7) Empty or DNA filled capsids accumulate near the central core resulting in the formation of a large massive membrane. (f8) Host cells could not withstand the large massive membrane and bursts (amoebal lysis), viral nucleocapsid DNA is released into the cell cytoplasm.
LIFE CYCLE: HUMAN
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The life cycle of the Mimivirus in humans is similar to amoebas, in that, entry is mediated via phagocytosis. Resources did not state how the virus attaches to, replicates, assemble, or released in the host. However, scientist had proposed that the Mimivirus could cause further penetration of the cytoplasm by using enzymatic activities necessary for the opening of the five icosahedral faces at the vertex of the capsid (Zauberman, 2006 and Xiao, 2009). Sources were not clear. The question still remains whether or not consider Mimivirus as a potential pneumonia agent. Some studies had found relations correlating Mimivirus to pneumonia patients, but were unsure if the virus was the cause of the disease. See medical relevance for more details.
LIFE CYCLE: SPUTNIK VIRUS
Recent studies discovered a satellite virus called "Sputnik virophage." Satellite viruses are viruses that depend on the co-infection of the helper virus in the host cell for its replication. The Sputnik is an icosahedral small virus (50 nm in diameter) with 18.343 kb circular dsDNA genome and uses the other virus' machinery for replication. Investigations of this small virus suggest that Sputnik cannot reproduce in host amoeba cells without the infection of Mimivirus. Sputnik reproduction occurs within the replication machinery of the Mimivirus VF.
Figure 3 shows Sputnik initiating its replication cycle using Mimivirus as a helper virus to penetrate the host cell for entry. Once inside the host, Sputnik first travels to the viral factory created by the Mimivirus, and then invade the Mimivirus VF to replicate its own genome. The resulting viral mRNA would be translated in the host cytoplasm. Sputnik proteins will then assemble into viral particles at the periphery of the Mimivirus factories and eventually be released in the cell cytoplasm via lysis. The effects this will have on Mimivirus are that few of its own viruses will be produced much lesser and that they will become deformed and less infectious. There was also evidence of a partial thickening of the capsid. Details of the replication were not provided.
Figure 3. Replication of traditional satellite virus, Sputnik (Claverie, 2011). Following entry within the host cytoplasm, Mimivirus and Sputnik goes separate ways. Mimivirus generates factors where the viral replication takes place. Sputnik takes advantage of the Mimivirus VF zone for the replication of its genome to generate its transcripts. At the assembly stage, Sputnik requires the help of Mimivirus.
The Mimivirus genome exhibits the same transcription related core genes as found in Poxviridae, suggesting that the transcription of some Mimivirus genes occurs in the cytoplasm (Raoult, 2004). Mimivirus encodes a large number of the components of its transcription apparatus (Legendre, 2011). These components can be classified in four generic functional categories: protein translation, DNA repair enzymes, chaperones, and new enzymatic pathways. Where these components play a role is another story. Mimivirus possesses 6 tRNAs known to be three Leu, one Trp, one Cys, and one His. Functions and some gene expression of Mimivirus are still unknown, further investigations are currently preceded. Table 1 shows a list of genes found in the Mimivirus and its possible functions.
In addition to these tRNAs, the Mimivirus also exhibits proteins that functions in translation. These are known to be aminoacyl-tRNA synthetases and translation initiation factor 4E (e.g. mRNA cap binding) (Raoult, 2004). Sources did not provide information on how or when Mimivirus use these proteins. Based on what was found, the two largest RNA polymerase II subunits are R501 and L244. The Mimivirus also contains four smaller RNA polymerase II subunits: Rpb3/Rpb11 (R470), Rpb5 (L235), Rpb6 (R209), and Rpb7/E (L376). Roles of these RNA polymerase II are to catalyze the transcription of DNA to synthesize precursors of mRNA. Again, it was not known when Mimivirus use RNA polymerase II. Mimivirus also possesses a poly (A) polymerase (R341), and a series of transcription factors such as L250, R339, R350, R429, R450, and R559.
Mimiviruses contains a few DNA topoisomerases. These DNA topoisomerases are enzymes in charge of solving the entanglement problems associated with DNA replication, transcription, recombination, and chromatin remodeling. R480, R194, and L221 are some examples of DNA topoisomerases found in the Mimivirus.
Genomes can be damaged by chemical mutagens, ultraviolet (UV) light or ionizing radiations (Raoult, 2004). The Mimivirus genome revealed several types of DNA repair enzyme, which in its own purpose prevent DNA errors. These include L315 and L720 genes, which serves as enzymes that locate and excise oxidized purines. Studies also suggest that the Mimivirus genome exhibits a UV-damage endonculease, which cleaves DNA that was damaged by UV light off. Another DNA repair enzyme is L359, which is involved in DNA mismatch repair and recombination (process by which a nucleic acid is broken and then joined to a different one). L386 and R555 are in charge of repair for UV-induced DNA damage. Overall, Mimivirus appears uniquely well equipped and prepared to repair DNA mismatch and damages caused by oxidation, alkylating agent or UV light (Raoult, 2004). Due to this ability, Mimivirus particles are thus quite resistant to adverse conditions. However, 15 minutes of 35 kilograys of irradiation with gamma rays or exposure of UV light would instantly kill the Mimivirus, despite their ability of DNA repair (Raoult, 2004).
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Table 1. Majorly identified Mimivirus genome (Raoult, 2004). There are 1018 protein coding genes (including the new genes discovered) and 6 tRNAs in the Mimivirus. This table shows a list of genes found in the Mimivirus with its possible role and functions. dTDP = 3'-deoxy-thymidine-5' diphosphate; ADP = adenosine 5'-diphosphate.
Mimivirus Newly Discovered Genes (Legendre, 2011). There are 1018 protein coding genes (including the new genes discovered) and 6 tRNAs in the Mimivirus. This reveals some of the recent new 75 genes found in 2011, list of genes generated from the fusion of previously identified ORFs, and list of deleted or renamed genes.
MEDICAL RELEVANCE: IMMUNITY AND PATHOGENESIS
Pneumonia infections are sometimes unknown in 20%-50% cases around the world (La Scola, 2005). However, some correlations indicated that Mimivirus was associated with community and hospital-acquired pneumonia. Studies have reported serologic evidence of APMV infection in 7.1% - 9.7% of patients with community acquired pneumonia (La Scola, 2005 & Berger, 2006).
In the study done by La Scola, 2005, serum samples of 376 Canadian patients with community-acquired pneumonia and 511 healthy control subjects was tested to see if Mimivirus was the cause of infection. The control showed twelve people with the antibody for the Mimivirus, while 36 patients in the pneumonia infected group had antibodies to the Mimivirus, suggesting that the study had evidence supporting that Mimivirus is found in some cases of pneumonia. This study does not show that the Mimivirus is the cause for this infection. They were only able to show Mimivirus colonization, but not the cause of infection. If Mimivirus is found to be the cause of pneumonia then more studies should be done to find out how to treat it. It also raises questions on how effective are human antibodies in stopping the Mimivirus life cycle.
Another study done to research the effect Mimivirus had on humans is performed by Khan in 2007. Results showed that the Mimivirus could infect mammalian cells in laboratory conditions. In the study, they inoculated adult mice and found that they developed pneumonia within the range of 3 to 7 days. The Mimivirus was introduced to the host mouse by an intracardiac route (Khan, 2007). The mouse was then tested for pneumonia by looking at the thickening of alveoli walls. Khan concluded the study, stating that the mice presented thick alveoli walls, which supports the theory of Mimivirus links with pneumonia. While this study showed mammalian cells could be infected, further investigations is needed to confirm.
In another recent study, antibodies against Mimivirus were found in patients with community-acquired pneumonia. These antibodies were detected using microimmunofluorescence assays. It appeared that the virus was found more frequently in community-acquired than in control patients. The study showed that patients with community-acquired pneumonia and serologic evidence of Mimivirus were more frequently re-hospitalized even after discharge. This was probably due to the lack of human antibodies in stopping the Mimivirus. The study suggests that Mimivirus is might be an etiologic agent of pneumonia that is acquired in institutions (Standford University).
There is still very little known about what cells the Mimivirus attacks, which makes it difficult to predict the role of Mimivirus in the unknown causes of pneumonia. If Mimivirus does target tissues in the lungs, as evidenced by the thickening of mouse alveoli, then we may be able to understand the importance of these results in the medical field. Not enough studies have been conducted yet to determine the Mimivirus infection, but the relationship between viral infection and human disease is worth exploring since the causes of many pneumonia cases are still unknown.
Figure 5 (Scola, 2005). Mimivirus antigen is observed by scanning electronic microscopy. (A) Mimivirus antibody recognition from the microimmunofluorescence assay, (B) Mimivirus antibody recognition from the Confocal microscope, (C) Mimivirus particles in amoebas are recognized by antibodies in the transmission electronic microscopy. (D) Mimivirus particle size 400 nm in TEM.
ENVIRONMENTAL RELEVANCE: EPIDEMIOLOGY
Investigation of suspected Legionnaire's pneumonia outbreak in 1992 led to the isolation of a new microorganism from a water cooling tower in West Yorkshire mill town of Bradford, England. Timothy Rowbotham, the officer in charge of Britain's Public Health Laboratory Service, was investigating the possible source of pneumonia outbreak and accidentally discovered the Mimivirus. A study performed by Claverie et al. 2009 revealed from an environmental DNA sample that there is an unexpected abundance of large DNA viruses related to the Mimivirus within the marine environment (Ghedin, 2005 & Monier, 2008). These Mimivirus related large DNA appears to be a significant component in the ecology of micro- and pico- plankton populations throughout the oceans and probably in fresh water environments. It was also suggested that these large DNA viruses may have a significant ecological impact through their regulation of planktonic populations, and infection of ubiquitous marine invertebrates. There was also some indirect evidence of Mimivirus links to marine invertebrates such as corals and sponges (Caverie, 2009). Following this line of thought a little further, Claverie believed that some Mimiviridae may have evolved to infect marine animals and rely on environmental phagocytosis as its main nutrition system. Further investigations on environmental relevance are still needed.
Studies done thus far for the Mimivirus have involved genome sequencing and looking into its origin. There were several serology studies of humans with clinical cases of pneumonia, which have shown a detectable immune response to Mimiviruses, suggesting current or previous infection; however there were also other studies that have NOT found any Mimivirus association with pneumonia patients (Reynolds, 2010). Because of this debate of these "mixed research," results of Mimivirus began to raise doubt. If Mimivirus is found to be the cause of pneumonia then more studies should be done to find out how to treat it. Since, the correlations are still a bit confusing; scientists are not researching the treatments at the moment, at least not until these relations are cleared up.