Feline morbillivirus

Feline morbillivirus comes from the family Morbillivirus, specifically influencing wild and domestic cats. The first report of a Feline morbillivirus outbreak occurred in Hong Kong in 2012. Approximately 10% of stray cats in Hong Kong and mainland China were reported to possess the virus at the time with additional infections found in Japan as well. 40% of cats tested in Japan were Fmo-PV positive and exhibited early symptoms of kidney failure. While the first cases of Feline morbillivirus were found in China, Hong Kong and Japan, the virus can also be found in Italy, Germany, and the United States. Feline morbillivirus exhibits a substantial amount of genetic diversity, yet cases in Japan and Hong Kong proved to have identical nucleotide sequences. It is also hypothesized that the morbillivirus has high adaptability due to its presence in multiple species. It is often found in dogs, cats, cattle, whales, dolphins, porpoises, and even humans. It likely originated from an ancestral version and underwent viral evolution to adapt to transmission in different species. Other common morbilliviruses include: measles, rinderpest virus, canine distemper virus and peste des petits ruminants virus.[1][2]

Feline morbillivirus
Virus classification
(unranked):	Virus
Realm:	Riboviria
Kingdom:	Orthornavirae
Phylum:	Negarnaviricota
Class:	Monjiviricetes
Order:	Mononegavirales
Family:	Paramyxoviridae
Genus:	Morbillivirus
Species:	Feline morbillivirus

Genome

Feline morbillivirus, like all morbilliviruses, possesses a negative-strand RNA genome.

Structure

This virus has a spherical shape with an enveloped capsid and is approximately 150 nm in diameter. The capsid is covered by fusion and hemagglutinin proteins. Inside the capsid exists the negative-sense RNA genome, which is covered by nucleoproteins and matrix proteins, as well as a polymerase and phosphoprotein toward the end of the genetic material. The genome itself is arranged in a linear pattern and is about 15-16kb in length. It is known as the largest of all morbilliviruses due to its makeup of 16,050 base pairs. Guanine and cytosine pairings make up a considerable portion of the viral genome, ranging from 35.1% to 35.3%, in comparison to adenine and thymine. Morbilliviruses have a 3’ leader sequence and a 5’ trailer sequence typically made up of 40 or 41 nt. Feline morbillivirus, however, breaks the typical 5’ trailer sequence rule and has an unusually long sequence of 400 nt.[3] The genome encodes for eight different proteins: N, C, P, V, M, F, H, and L. The L protein, also called large protein, is involved in ATP binding, RNA polymerase activity and mRNA methyltransferase activity. Thus, it is a multifunctional enzyme. The N gene exhibits the greatest incidence of nucleotide polymorphism, while P protein has the highest incidence of amino acid polymorphism.[4]

Viral classification

The viral classification scheme of the species Feline morbillivirus is as follows:

Order: Mononegavirales

Family: Paramyxoviridae

Subfamily: Paramyxovirinae

Genus: Morbillivirus.

Species: Feline Morbillivirus

Replication cycle

The genus morbillivirus is fairly well known among various wild and domesticated species, while the discovery of this virus in felines is relatively novel. Therefore, what is known about the replication cycle in felines can be extrapolated from experiments done on other animals. A ferret model was used to test the entry, spread and transmission of the virus in the organism. In the ferret model, the virus was transmitted through contact with bodily fluids, infected foods and airborne contact with an infected ferret.[5] While Fmo-PV is most often associated with attacking associated renal tissues, the virus is also compatible with receptors on the following cells: epithelial, glial, fibroblastic, and lymphoid cells. This increases the risk of transmission to other areas of the body, as well as subsequent failure of the affected tissues.[6]

Entry

Morbilliviruses enter into the cell through attaching onto the host cell via viral glycoproteins. Specifically, CD150 acts as a receptor for viral entry into the cell. The receptor itself is often expressed on dendritic cells, macrophages, B- and T-cells. This offers clear information as to why morbilliviruses can very quickly infect immune cells. Another newly discovered cellular receptor called PVRL4 allows for morbillivirus entry into bronchial epithelial cells and keratinocytes. Additionally, the Feline morbillivirus F protein is known to have a single cleavage site that splits the protein into separate F1 and F2 proteins which play an important role in fusing the viral and cellular membranes together during entry.[5][4]

Replication and transcription

Since this virus possesses a negative-sense RNA genome, its replication and transcription cycles follow that of the negative-RNA genome. Therefore, to replicate, the negative, single-stranded RNA genome must use RNA-dependent RNA polymerase to generate the positive strand of RNA, which can directly be made into protein by host ribosomes. Likewise, both the positive and negative RNA strands must be present for replication of the genome to occur. RNA-dependent RNA polymerase binds the 3’ end of the viral genome and begins transcription, regularly identifying start and stop signals along the way which edge the genes. During mRNA synthesis, the viral “L” protein aids in capping and polyadenylating the product. Replication occurs in the cytoplasm of the host cell; it begins by the viral H glycoprotein attaching to the surface of the host cell. The virus is then fused with the cell and releases its ribonucleocapsid, allowing for transcription of the genome into mRNA, as well as sequential capping and polyadenylation of the mRNA. Before replication starts, enough nucleoprotein must be available to shield the viral genome.[4]

Assembly and release

Assembly takes place in the cytoplasm while release of the virion takes place via budding off from the host cell membrane. The virus transmits from host to host via respiratory droppings, which was revealed via the ferret model.[4]

Modulation of host processes

The virion interacts with its host and manipulates its cell machinery in various ways. It enters using the cell's own receptors, which were not originally designed for viral entry. Specifically, the receptors CD150 and PVRL4 are used for viral entry into their respective bodily regions. CD150 can be found on many immune cells including: macrophages, dendritic cells, B-cells and T-cells. PVRL4 is present in keratinocytes of the epidermis and bronchial epithelial cells. Additionally, the viral V protein is known to have a role in inhibiting MDA-5 antiviral signaling, which acts to increase interferon production in the face of infection. Once virally infected, MDA-5 sends out signals corresponding with an antiviral state in order that fewer interferons be produced to interfere with viral replication. While the virus uses its own enzyme to make a copy of its genome, it hijacks host ribosomes to translate its RNA into protein. Specifically in felines, the virus is known to interact with the renal system, but in other species it has been known to negatively influence the respiratory, epithelial, immune and central nervous systems.[5]

Associated diseases

This virus is often affiliated with tubulointerstitial nephritis in domestic cats. A study was done on domestic cats by Woo et al., and those tested Fmo-PV positive also exhibited symptoms of kidney disease, namely necrosis of the tissues and degeneration of the renal tubules. Expression of cauxin protein was also diminished, which correlates with tubulointerstitial nephritis. Cauxin plays a role in the production of felinine and glycine, which act as feline pheromones; cats use these as territorial markers. In cases of tubulointerstitial nephritis brought on by feline morbillivirus, cauxin levels will be significantly depleted.[7] In other animals as well, morbillivirus is connected to acute febrile respiratory tract infection. It is also hypothesized that Fmo-PV could be linked to CNS disease due to the fact that G355-5 cells are susceptible to feline morbillivirus, and these cells originate from astrocytes, glial cells of the central nervous system.

Tropism

The specific body tissues associated with morbillivirus growth and proliferation include: epithelial, renal, immune and central nervous tissues. In these various systems, the virus is able to bind to the receptors available and successfully hijack cell machinery in order to replicate and create viral proteins.

Zoonosis

Morbillivirus can be found in dogs, cats, cattle, whales, dolphins, porpoises, and even humans. Symptoms and effects of the virus are similar in other species in comparison to felines, for example SLAM (CD150) is a common receptor the virus acts on in other organisms, which implicates detrimental effects on the immune system. There is currently a greater risk for transmission to humans in Hong Kong, where the virus likely originated from, due to the increase of the divorce rate and decrease of both marriage and birth rates. Since fewer people are getting married and having kids, more are adopting household pets to make up for the absence of a child and are therefore at risk of acquiring the viral pathogens their pets may be a reservoir for.[3][8]

References

1. Darold, Gabriela Molinari; Alfieri, Amauri Alcindo; Muraro, Lívia Saab; Amude, Alexandre Mendes; Zanatta, Rosana; Yamauchi, Kelly Cristiane Ito; Alfieri, Alice Fernandes; Lunardi, Michele (2017-02-01). "First report of feline morbillivirus in South America". Archives of Virology. 162 (2): 469–475. doi:10.1007/s00705-016-3124-0. ISSN 0304-8608. PMID 27804021.
2. Park, Eun-Sil; Suzuki, Michio; Kimura, Masanobu; Maruyama, Keiji; Mizutani, Hiroshi; Saito, Ryuichi; Kubota, Nami; Furuya, Tetsuya; Mizutani, Tetsuya (2014-11-01). "Identification of a natural recombination in the F and H genes of feline morbillivirus". Virology. 468-470 (Supplement C): 524–531. doi:10.1016/j.virol.2014.09.003. PMID 25262470.
3. Woo, Patrick C. Y.; Lau, Susanna K. P.; Wong, Beatrice H. L.; Fan, Rachel Y. Y.; Wong, Annette Y. P.; Zhang, Anna J. X.; Wu, Ying; Choi, Garnet K. Y.; Li, Kenneth S. M. (2012-04-03). "Feline morbillivirus, a previously undescribed paramyxovirus associated with tubulointerstitial nephritis in domestic cats". Proceedings of the National Academy of Sciences of the United States of America. 109 (14): 5435–5440. Bibcode:2012PNAS..109.5435W. doi:10.1073/pnas.1119972109. ISSN 0027-8424. PMC 3325679. PMID 22431644.
4. "Morbillivirus". ViralZone. Retrieved 2017-10-30.
5. Ludlow, Martin; Rennick, Linda J; Nambulli, Sham; de Swart, Rik L; Paul Duprex, W (2014-02-01). "Using the ferret model to study morbillivirus entry, spread, transmission and cross-species infection". Current Opinion in Virology. Virus entry / Environmental virology. 4 (Supplement C): 15–23. doi:10.1016/j.coviro.2013.11.001. PMID 24525290.
6. Sakaguchi, Shoichi; Koide, Rie; Miyazawa, Takayuki (2015). "In vitro host range of feline morbillivirus". Journal of Veterinary Medical Science. 77 (11): 1485–1487. doi:10.1292/jvms.15-0213. PMC 4667668. PMID 26027844.
7. Miyazaki, Masao; Yamashita, Tetsuro; Taira, Hideharu; Suzuki, Akemi (2008). Chemical Signals in Vertebrates 11. Springer, New York, NY. pp. 51–60. doi:10.1007/978-0-387-73945-8_4. ISBN 9780387739441.
8. Zeltina, Antra; Bowden, Thomas A.; Lee, Benhur (2016-02-25). "Emerging Paramyxoviruses: Receptor Tropism and Zoonotic Potential". PLOS Pathogens. 12 (2): e1005390. doi:10.1371/journal.ppat.1005390. ISSN 1553-7374. PMC 4767434. PMID 26915013.