Modoc Virus
   HOME

TheInfoList



OR:

Modoc virus (MODV) is a rodent-associated
orthoflavivirus ''Flavivirus'', renamed ''Orthoflavivirus'' in 2023, is a genus of positive-strand RNA viruses in the family ''Flaviviridae''. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus ...
. Small and enveloped, MODV contains positive single-stranded
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
. Taxonomically, MODV is part of the ''
Flavivirus ''Flavivirus'', renamed ''Orthoflavivirus'' in 2023, is a genus of positive-strand RNA viruses in the family ''Flaviviridae''. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika viru ...
'' genus and ''
Flaviviridae ''Flaviviridae'' is a family of Viral envelope, enveloped positive-strand RNA viruses which mainly infect mammals and birds. They are primarily spread through arthropod vector (epidemiology), vectors (mainly ticks and mosquitoes). The family gets ...
'' family. The
Flavivirus ''Flavivirus'', renamed ''Orthoflavivirus'' in 2023, is a genus of positive-strand RNA viruses in the family ''Flaviviridae''. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika viru ...
genus includes nearly 80 viruses, both vector-borne and no known vector (NKV) species. Known flavivirus vector-borne viruses include
Dengue virus Dengue virus (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family ''Flaviviridae''; genus '' Flavivirus''. Four serotypes of the virus have been found, and a reported fifth has yet to be ...
, Yellow Fever virus,
tick-borne encephalitis virus Tick-borne encephalitis virus (TBEV) is a positive-strand RNA virus associated with tick-borne encephalitis in the genus '' Flavivirus''. Classification Taxonomy TBEV is a member of the genus '' Flavivirus''. Other close relatives, members of ...
, and
West Nile virus West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family ''Flaviviridae'', from the genus ''Flavivirus'', which also contains the Zika virus, dengue virus, and yellow fever virus. The virus ...
. In 1958, MODV was first isolated from the
mammary gland A mammary gland is an exocrine gland that produces milk in humans and other mammals. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in primates (for example, human ...
tissue of a white-footed deer mouse (''
Peromyscus maniculatus ''Peromyscus maniculatus'', the eastern deermouse, is a rodent native to eastern North America. It is a species of the genus ''Peromyscus'', a closely related group of New World rats and mice, New World mice often called "deermice". When former ...
'') captured in Modoc County, California. Since the first isolation, the MODV has also been isolated from deer mice in Oregon, Colorado, and Montana. There are other anti-genetically and genetically related viruses which also have no known vector such as Jutiapa virus, the Cowbone Ridge virus, the Sal Vieja virus, and the San Perlita virus. Little information is known about these viruses as well.


Structure

The MODV virus has a particle size of about 45 nm which is comparable with other flaviviruses particles that are about 40-60 nm in diameter. A mature flavivirus has a spherical shape and contains multiple copies of three structural proteins (C, M, and E), a host-derived membrane bilayer, and a single copy of a positive-sense RNA genome of approximately 11,000 nucleotides. The first structure of a flavivirus, the
Dengue virus Dengue virus (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family ''Flaviviridae''; genus '' Flavivirus''. Four serotypes of the virus have been found, and a reported fifth has yet to be ...
, was determined by using cryo-electron microscopy and an electron density map fitted with the known structure of glycoprotein E (Fig.1).


Genome

Flaviviruses have positive (+) ssRNA genomes about 11kb in size. The MODV genome is 10,600 nucleotides in length with a single
open reading frame In molecular biology, reading frames are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible reading frames ...
extending from nucleotides 110 to 10,234, encoding 3374 amino acids. The ORF has the gene order C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5 which is consistent with mosquito- and tick-borne flaviviruses (Fig.2).


Replication cycle

Similar to most positive (+) ssRNA viruses, flaviviruses generate organelle-like structures in the
endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
(ER) of the host organism for replication. Since the ER is involved ''in de novo'' biogenesis of some cell organelles, viruses take advantage of the replication location to take over some of the organelle functions for its own replication cycle. Viral genome replication in the ER occurs in structures called virus replication organelles. The organelles include two distinct subdomains, vesicle packets (VP) and convoluted membranes (CMs). The site of viral genome replication is found within the vesicle packets which are clusters of small vesicle compartments. The function of CMs is relatively unknown, but they are described as electron-dense amorphous structures near the VPs. The large single polypeptide encoded by the genome is processed in the ER membrane by host or viral
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
s. The large polypeptide is divided into three structural proteins (capsid, prM, and E) and a group of non-structural proteins (NS1-NS5). The viral genomic RNA forms a nucleocapsid complex with the capsid protein which aids in genome packaging into mature virus particles. The prM and E proteins are considered significant components of the virus particle and can even form spherical virus particles. The exact functions of NS proteins are relatively unknown, however, they are assumed to play a role in the formation of virus particle replication organelles. The NS1 protein has a large ectodomain which is believed to function in the deformation of the ER membrane from the luminal side. NS2B protein, a transmembrane protein, directly interacts with NS3 which is a soluble protein anchored to the membrane. With its
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
activity and RNA
helicase Helicases are a class of enzymes that are vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic double helix, separating the two hybridized ...
activity, the NS3 protein is involved in viral polyprotein processing and viral RNA replication. NS5 plays a role in the replication of the viral genomic RNA and the formation of the 5’-cap structure for protein translation with its RNA dependent and RNA polymerase (RdRp) activity and methyltransferase activity. The 5′-end possesses a type I cap (m7GpppAmp) that is not seen in viruses of the other genera. Proteins N2SA, NS4A, and NS4B are membrane-integrated proteins but have no clear function.


Life cycle


Entry into cell

To enter the cell, MODV virus is assumed to invade the cell via steps similar to the ''Flavivirus'' family. Through
endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
, the virus enters the host cell and then releases its positive (+) ssRNA genome into the
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
through membrane fusion.


Replication

The MDOV genome codes for a single ORF, which is processed by both cellular and viral proteases to form three structural proteins and at least seven non-structural proteins. On either side of the ORF, untranslated regions (UTRs) are present and fold into complex stem-loop structures required for replication. The 5’ UTR consists of 109 nucleotides and the 3’ UTR consists of 366 nucleotides. Comparing MODV to 20 other flaviviruses, several regions with high sequence similarity appeared. The regions corresponded to functionally important domains and conserved sites for proteolytic cleavage by viral and cellular proteases.


Assembly and release

The rough endoplasmic reticulum is believed to be the site of viral assembly. Following genome replication, the newly synthesized RNA interacts with the capsid and buds into the ER lumen along with immature prM and E proteins which undergo maturation in the Golgi and
endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...
s. For instance, the prM protein is cleaved by furin or a furin-like cellular protease to generate mature virions. The virion moves through the cytoplasm until it is released from the cell via
exocytosis Exocytosis is a term for the active transport process that transports large molecules from cell to the extracellular area. Hormones, proteins and neurotransmitters are examples of large molecules that can be transported out of the cell. Exocytosis ...
.


Transmission and tropism

Since no vector has been identified for MODV, the exact mode transmission is not known. However, the studied field strain of MODV showed persistent infection of the virus in deer mouse lungs that may be transmitted horizontally through close, prolonged contact of infected and susceptible individuals. Direct contact (i.e., salivary secretions) or indirect contact (i.e., fomites, aerosols and urine) may enable viral spread. Rodent nests during the winter provide conditions suitable for the horizontal transmission of viruses. In addition, transmission presumably occurs horizontally since attempts to infect ticks and mosquitoes as cultured cell lines or in vivo have been unsuccessful. Other studies suggest cannibalism does not play a direct role in viral transmission, but the possibility of sexual transmission has yet to be explored. The molecular determinants of transmission are unknown, but comparison of the conserved sequence differences between the two groups suggests vector-borne conserved pentanucleotide sequence (CPS) nor variable region (VR) of the conserved sequences are required for vector-borne transmission. A transient
viremia Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to ''bacteremia'', a condition where bacteria enter the bloodstream. The name comes from combining the word "virus" wi ...
in deer mice (''
Peromyscus maniculatus ''Peromyscus maniculatus'', the eastern deermouse, is a rodent native to eastern North America. It is a species of the genus ''Peromyscus'', a closely related group of New World rats and mice, New World mice often called "deermice". When former ...
'') produced a measurable production of antibody titers and showed persistence in the lungs. While deer mice are accepted as the main host organism, the presence of antibodies in chipmunks (''
Tamias minimus The least chipmunk (''Neotamias minimus'') is the smallest species of chipmunk and the most widespread in North America. Description It is the smallest species of chipmunk, measuring about in total length with a weight of . The body is gray to ...
'') and red squirrels ( ''Tamias-ciurus hudsonicus'') suggests the virus has multiple hosts. Virus transmission in chipmunks and red squirrels was more successful than in deer mice, which may be due to a difference in viral shedding under experimental conditions and field conditions. Field conditions may cause more stress due to cold temperatures and food shortages.


Associated diseases

A rodent-associated virus, MODV has the potential to cause disease in humans similar to other flaviviruses. It was determined that MODV was the responsible virus for a case of
aseptic meningitis Aseptic meningitis is the inflammation of the meninges, a membrane covering the brain and spinal cord, in patients whose cerebral spinal fluid test result is negative with routine bacterial cultures. Aseptic meningitis is caused by viruses, mycob ...
when the virus was first discovered in California. Typically, flaviviruses cause
encephalitis Encephalitis is inflammation of the Human brain, brain. The severity can be variable with symptoms including reduction or alteration in consciousness, aphasia, headache, fever, confusion, a stiff neck, and vomiting. Complications may include se ...
in host organisms. MODV causes flavivirus-like encephalitis in SCID (
severe combined immunodeficiency Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in diff ...
) mice and in hamsters with histopathological features reminiscent of flavivirus encephalitis in man. Studies suggest envelope (E) proteins encoded for by the genome may play a dominant role as a determinant of flavivirus neurovirulence. A single amino acid substitution was shown to cause major effects on neurovirulence. The mechanisms and determinants involved in Flavivirus neuroinvasiveness remains unknown. However, evidence suggests neuroinvasiveness depends entirely on envelope proteins E and prM (pre-membrane) In a study investigating the effects of MODV on hamsters, severe
encephalitis Encephalitis is inflammation of the Human brain, brain. The severity can be variable with symptoms including reduction or alteration in consciousness, aphasia, headache, fever, confusion, a stiff neck, and vomiting. Complications may include se ...
, bilateral hindlimb
paralysis Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...
, and complete paralysis with an intact corneal reflex were observed. MODV-induced encephalitis in hamsters was characterized by movement of monocytes and lymphocytes into the cortex and ''bulbus olfactorius'', causing massive destruction of the tissue structure. In all surviving hamsters, IgM and HI
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
to MODV were present in the blood after subcutaneous infection. Of all infected hamsters, no substantial microscopic lesions were observed in the liver, spleen, lung, and heart. However, rare focal portal inflammation of the liver and mild reactive lymphoid hyperplasia of the spleen were noted. Considerable pathological changes were observed in the brain and spinal cord during early infection. During early infection, the lesions in the spinal cord were more severe than those observed in the brain. In immunocompetent mice, MODV causes 100% morbidity and mortality when the virus was inoculated directly into the brain. Alternatively, when inoculated via the intranasal route, 50% morbidity and mortality was observed Infectious MODV was also isolated from kidney tissue for at least eight months after infection, specifically the epithelium of the renal tubules. Despite the presence of antibodies, infected hamsters continued to shed viruses in the urine for up to four months. Due to viral shedding in the urine, there is the potential use of urinalysis to monitor the effectiveness of therapy on viral replication by monitoring the viral RNA in the urine using quantitative
RT-PCR Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA (in this context called complementary DNA or cDNA) and amplification of specific DNA targets using polymerase chain ...
assays


References

{{Taxonbar, from=Q18968182 Flaviviruses