Editing Cowpox (section)

=== Life cycle ===
The genome for the CPXV is over 220kbp. This makes it the largest genome in the Orthopoxviral species. It can be divided into three different regions. There are two end regions called R1 and R2 and a main central region that is roughly half of the size of the genome. There are also inverted terminal repeats that are located at the terminal sites of the genome and measure around 10kbp. These inverted terminal repeats can then be divided into two more distinct regions. The first section is around 7.5kbp long and includes a coding region. The other section includes a terminal region that can be repeated up to as many times as thirty and is composed of 50 nucleotides.<ref>{{cite journal | vauthors = Pickup DJ, Ink BS, Parsons BL, Hu W, Joklik WK | title = Spontaneous deletions and duplications of sequences in the genome of cowpox virus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 21 | pages = 6817–6821 | date = November 1984 | pmid = 6093123 | pmc = 392023 | doi = 10.1073/pnas.81.21.6817 | bibcode = 1984PNAS...81.6817P | doi-access = free }}</ref> The CPXV genome encodes only 30-40% of products of which are involved in the pathogenesis of the virus.<ref>{{cite journal | vauthors = Carroll DS, Emerson GL, Li Y, Sammons S, Olson V, Frace M, Nakazawa Y, Czerny CP, Tryland M, Kolodziejek J, Nowotny N, Olsen-Rasmussen M, Khristova M, Govil D, Karem K, Damon IK, Meyer H | display-authors = 6 | title = Chasing Jenner's vaccine: revisiting cowpox virus classification | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23086 | date = 2011-08-08 | pmid = 21858000 | pmc = 3152555 | doi = 10.1371/journal.pone.0023086 | bibcode = 2011PLoSO...623086C | doi-access = free }}</ref> The CPXV genome has the most complete set of genes out of all of the orthopoxviruses. This unique feature of CPXV makes it ideal to be able to mutate into different strains of the virus.<ref>{{cite journal | vauthors = Xu Z, Zikos D, Osterrieder N, Tischer BK | title = Generation of a complete single-gene knockout bacterial artificial chromosome library of cowpox virus and identification of its essential genes | journal = Journal of Virology | volume = 88 | issue = 1 | pages = 490–502 | date = January 2014 | pmid = 24155400 | pmc = 3911729 | doi = 10.1128/JVI.02385-13 }}</ref> It is a double stranded DNA virus. The virus does have an envelope that surrounds the virion.<ref>{{cite journal |last1=Payne |first1=L. G. |title=The existence of an envelope on extracellular cowpox virus and its antigenic relationship to the vaccinia envelope |journal=Archives of Virology |date=March 1986 |volume=90 |issue=1–2 |pages=125–133 |doi=10.1007/BF01314150 |pmid=3729722 |doi-access=free }}</ref> The cowpox's genome allows the virus to encode its own transcription machinery along with its own DNA replication machinery. The replication then takes place in the cytoplasm after the virus is in the cell and the virion is uncoated. The virion is then assembled and released from the host cell.<ref>{{cite journal | vauthors = Alzhanova D, Früh K | title = Modulation of the host immune response by cowpox virus | journal = Microbes and Infection | volume = 12 | issue = 12–13 | pages = 900–909 | date = November 2010 | pmid = 20673807 | pmc = 3500136 | doi = 10.1016/j.micinf.2010.07.007 }}</ref>

The genome is arranged so that both of the ends contain the genes responsible for evading the defenses from the immune system of the host which is only activated in the extracellular portion. These receptors are able to be stopped by cytokine and chemokine secretion by blocking the cytokine and chemokine found extracellularly. This is the process responsible for attachment and entry of the virion into the host cell.<ref>{{cite journal | vauthors = Soares JA, Leite FG, Andrade LG, Torres AA, De Sousa LP, Barcelos LS, Teixeira MM, Ferreira PC, Kroon EG, Souto-Padrón T, Bonjardim CA | display-authors = 6 | title = Activation of the PI3K/Akt pathway early during vaccinia and cowpox virus infections is required for both host survival and viral replication | journal = Journal of Virology | volume = 83 | issue = 13 | pages = 6883–6899 | date = July 2009 | pmid = 19386722 | pmc = 2698574 | doi = 10.1128/JVI.00245-09 }}</ref> Because of the large size of the genome, it makes the virus more likely and capable to fight back against the immunes system defenses. Out of all of the poxviruses, CPXV has the most cytokine responses that fight back against the immune system. It encodes cytokine receptors such as TNF, CrmB, CrmC, CrmD, and CrmE proteins. Another set of receptors that CPXV have are lymphotoxins such as IL-1ß, IFN-y, IFN 1, β-chemokines, and IL-18. However, not all of the receptors of CPXV are still not known. CPXV also encodes four tumor necrosis factors (TNF) and lymphotoxin which are the biggest group of homologous receptors for the virus. These receptors play a crucial role that are involved with the immune system.<ref>{{cite journal | vauthors = Panus JF, Smith CA, Ray CA, Smith TD, Patel DD, Pickup DJ | title = Cowpox virus encodes a fifth member of the tumor necrosis factor receptor family: a soluble, secreted CD30 homologue | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 12 | pages = 8348–8353 | date = June 2002 | doi = 10.1073/pnas.122238599 | pmid = 12034885 | pmc = 123070 | doi-access = free }}</ref>

CPXV has two different types of inclusion bodies. All of the poxviruses have basophilic inclusions also called B-type inclusion bodies. The B-type inclusion bodies contain the factory where the virus produces necessary elements for the replication and maturation of the virion. CPXV has another inclusion body that is unique to only some chordopoxviruses called acidophilic inclusion bodies also called A-type inclusion bodies (ATIs). The ATIs are encoded by the cpxv158 gene and is then made the protein ATIP which is a late protein. However, the importance of these ATIs in the life cycle are still not well known or understood and research is still being done to better understand them. It is known that replication can still continue without the cpxv158 gene, and that the replication cycle shows no difference between a fully encoded virion versus the virion that had deleted cwpx158 gene. However, with studies done on mice, the lesions that were caused by the CPXV-BR△ati were able to heal faster due to less tissue that was lost than the CPXV-BR lesions that took longer to heal and lost more tissue. This suggests that this gene helps supports the idea that ATIs are partly involved in how the host responds to the virus infection.<ref>{{cite journal | vauthors = Leite JA, da Fonseca FG, de Souza Trindade G, Abrahão JS, Arantes RM, de Almeida-Leite CM, dos Santos JR, Guedes MI, Ribeiro BM, Bonjardim CA, Ferreira PC, Kroon EG | display-authors = 6 | title = A-type inclusion bodies: a factor influencing cowpox virus lesion pathogenesis | journal = Archives of Virology | volume = 156 | issue = 4 | pages = 617–628 | date = April 2011 | doi = 10.1007/s00705-010-0900-0 | pmid = 21212997 }}</ref>

Another way that the virus is able to control and infect the host is by regulating cellular signaling pathways. During the infection, CPXV is known to use MEK/ERK/1/2/Egr-1, JNK1/2, and PI3K/Akt pathways. Some of these pathways are not unique only to CPXV, but how they function in response to the host is unique to this virus.<ref>{{cite journal | vauthors = Salgado AP, Soares-Martins JA, Andrade LG, Albarnaz JD, Ferreira PC, Kroon EG, Bonjardim CA | title = Study of vaccinia and cowpox viruses' replication in Rac1-N17 dominant-negative cells | journal = Memórias do Instituto Oswaldo Cruz | volume = 108 | issue = 5 | pages = 554–562 | date = August 2013 | pmid = 23903969 | pmc = 3970603 | doi = 10.1590/s0074-02762013000500004 }}</ref>

One notable protein in the CPXV is the p28 protein. It is made up of 242 amino acids and contains two domains, and N terminal KilA-N and a C-terminal RING domain. One of those domains, the N-terminal [[KilA-N domain]], allows for DNA to bind to it. The KilA-N domain facilitates this p28 protein that is translated early in the replication cycle in the cytoplasm and is then located in the cytoplasm for the rest of the life cycle of the virus. There is current research still being done to determine if the p28 protein could be a requital for an essential macrophage factor that is needed for the DNA replication.<ref>{{cite journal | vauthors = Bourquain D, Schrick L, Tischer BK, Osterrieder K, Schaade L, Nitsche A | title = Replication of cowpox virus in macrophages is dependent on the host range factor p28/N1R | journal = Virology Journal | volume = 18 | issue = 1 | pages = 173 | date = August 2021 | doi = 10.1186/s12985-021-01640-x | pmid = 34425838 | pmc = 8381512 | doi-access = free }}</ref>