Editing Plasmodium falciparum (section)

==Cancer==

The [[International Agency for Research on Cancer]] (IARC) has classified malaria due to ''P. falciparum'' as a Group 2A carcinogen, meaning that the parasite is probably a cancer-causing agent in humans.<ref>{{cite journal|last1=De Flora|first1=S|last2=La Maestra|first2=S|title=Epidemiology of cancers of infectious origin and prevention strategies|journal=Journal of Preventive Medicine and Hygiene|date=2015|volume=56|issue=1|pages=E15–20|doi=10.15167/2421-4248/jpmh2015.56.1.470|pmid=26789827|pmc=4718340}}{{open access}}</ref> Its association with a blood cell ([[lymphocyte]]) cancer called [[Burkitt's lymphoma]] is established. Burkitt's lymphoma was discovered by [[Denis Parsons Burkitt|Denis Burkitt]] in 1958 by African children, and he later speculated that the cancer was likely due to certain infectious diseases. In 1964, a virus, later called [[Epstein–Barr virus]] (EBV) after the discoverers, was identified from the cancer cells. The virus was subsequently proved to be the direct cancer agent and is now classified as [[List of IARC Group 1 carcinogens|Group 1 carcinogen]].<ref>{{cite journal|last1=Bouvard|first1=Véronique|last2=Baan|first2=Robert|last3=Straif|first3=Kurt|last4=Grosse|first4=Yann|last5=Secretan|first5=Béatrice|last6=Ghissassi|first6=Fatiha El|last7=Benbrahim-Tallaa|first7=Lamia|last8=Guha|first8=Neela|last9=Freeman|first9=Crystal|last10=Galichet|first10=Laurent|last11=Cogliano|first11=Vincent|title=A review of human carcinogens—Part B: biological agents|journal=The Lancet Oncology|date=2009|volume=10|issue=4|pages=321–322|doi=10.1016/S1470-2045(09)70096-8|pmid=19350698|url=https://eprints.whiterose.ac.uk/182093/1/mono100B.pdf|display-authors=8}}</ref>

In 1989, it was realised that EBV requires other infections such as malaria to cause lymphocyte transformation. It was reported that the incidence of Burkitt's lymphoma decreased with effective treatment of malaria over several years.<ref>{{cite journal|last1=Geser|first1=A.|last2=Brubaker|first2=G.|last3=Draper|first3=C.C.|title=Effect of a malaria suppression program on the incidence of African Burkitt's lymphoma|journal=American Journal of Epidemiology|date=1989|volume=129|issue=4|pages=740–752|doi=10.1093/oxfordjournals.aje.a115189|pmid=2923122}}</ref> The actual role played by ''P. falciparum'' remained unclear for the next two-and-half decades. EBV had been known to induce lymphocytes to become cancerous using its viral proteins (antigens such as [[EBNA-1]], [[EBNA-2]], [[Epstein–Barr virus latent membrane protein 1|LMP1]], and [[Epstein–Barr virus latent membrane protein 2|LMP2A]]).<ref>{{cite journal|last1=Rajcani|first1=Julius|last2=Szenthe|first2=Kalman|last3=Banati|first3=Ferenc|last4=Szathmary|first4=Susan|title=Survey of Epstein Barr Virus (EBV) Immunogenic Proteins and their Epitopes: Implications for Vaccine Preparation|journal=Recent Patents on Anti-Infective Drug Discovery|date=2014|volume=9|issue=1|pages=62–76|doi=10.2174/1574891X09666140828114812|pmid=25164057}}</ref><ref>{{cite journal|last1=Wang|first1=Yuyan|last2=Banerjee|first2=Shuvomoy|last3=Ding|first3=Ling|last4=Cai|first4=Cankun|last5=Wei|first5=Fang|last6=Cai|first6=Qiliang|title=The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers|journal=Virologica Sinica|date=2017|volume=32|issue=5|pages=357–368|doi=10.1007/s12250-017-4081-9|pmid=29116588|pmc=6704201|doi-access=free}}</ref> From 2014, it became clear that ''P. falciparum'' contributes to the development of the lymphoma. ''P. falciparum''-infected erythrocytes directly bind to [[B lymphocytes]] through the CIDR1α domain of PfEMP1. This binding activates [[toll-like receptors]] ([[TLR7]] and [[TLR10]]) causing continuous activation of lymphocytes to undergo proliferation and differentiation into [[plasma cells]], thereby increasing the secretion of [[IgM]] and [[cytokines]].<ref>{{cite journal|last1=van Tong|first1=Hoang|last2=Brindley|first2=Paul J.|last3=Meyer|first3=Christian G.|last4=Velavan|first4=Thirumalaisamy P.|title=Parasite Infection, Carcinogenesis and Human Malignancy|journal=eBioMedicine|date=2017|volume=15|pages=12–23|doi=10.1016/j.ebiom.2016.11.034|pmid=27956028|pmc=5233816}}{{open access}}</ref>  This, in turn, activates an enzyme called [[activation-induced cytidine deaminase]] (AID), which tends to cause mutation in the DNA (by [[double-strand break]]) of EBV-infected lymphocytes. The damaged DNA undergoes uncontrolled [[DNA replication|replication]], thus making the cell cancerous.<ref>{{cite journal|last1=Thorley-Lawson|first1=David|last2=Deitsch|first2=Kirk W.|last3=Duca|first3=Karen A.|last4=Torgbor|first4=Charles|last5=Knoll|first5=Laura J|title=The Link between ''Plasmodium falciparum'' Malaria and Endemic Burkitt's Lymphoma—New Insight into a 50-Year-Old Enigma|journal=PLOS Pathogens|date=2016|volume=12|issue=1|pages=e1005331|doi=10.1371/journal.ppat.1005331|pmid=26794909|pmc=4721646 |doi-access=free }}{{open access}}</ref>