Editing Leishmania (section)

==Biochemistry and cell biology==
The biochemistry and cell biology of ''Leishmania'' is similar to that of other [[Kinetoplastida|kinetoplastids]]. They share the same main morphological features: a single [[flagellum]] which has an invagination - the flagellar pocket - at its base; a [[kinetoplast]], which is found in the single [[mitochondrion]]; and a subpelicular array of microtubules, which make up the main part of the [[cytoskeleton]].

===Lipophosphoglycan coat===
''Leishmania'' possesses a [[lipophosphoglycan]] coat over the outside of the cell. Lipophosphoglycan is a trigger for [[TLR 2|toll-like receptor 2]], a signalling receptor involved in triggering an [[innate immune system|innate immune response]] in mammals.

The precise structure of lipophosphoglycan varies depending on the species and [[Biological life cycle|lifecycle]] stage of the parasite. The glycan component is particularly variable and different lipophosphoglycan variants can be used as a [[molecular marker]] for different lifecycle stages. [[Lectin]]s, a group of [[proteins]] which bind different glycans, are often used to detect these lipophosphoglycan variants. For example, [[peanut agglutinin]] binds a particular lipophosphoglycan found on the surface of the infective form of ''L. major''.

Lipophosphoglycan is used by the parasite to promote its survival in the host and the mechanisms by which the parasite does this center around modulating the immune response of the host. This is vital, as the ''Leishmania'' parasites live within [[macrophages]] and need to prevent the macrophages from killing them. Lipophosphoglycan has a role in resisting the [[complement system]], inhibiting the [[oxidative burst]] response, inducing an [[inflammation]] response and preventing [[Natural Killer T cell|natural killer T cells]] recognising that the macrophage is infected with the ''Leishmania'' parasite.

{| class="wikitable"
|-
! Type
! Pathogen
! Location
|-
| ''[[Cutaneous leishmaniasis]]'' (localised and diffuse) infections appear as obvious skin reactions.
| The most common is the ''Oriental Sore'' (caused by Old World species ''[[Leishmania major|L. major]]'', ''[[Leishmania tropica|L. tropica]]'', and ''[[Leishmania aethiopica|L. aethiopica]]'').  In the New World, the most common culprits is ''[[Leishmania mexicana|L. mexicana]]''.
| Cutaneous infections are most common in [[Afghanistan]], [[Brazil]], [[Iran]], [[Peru]], [[Saudi Arabia]] and [[Syria]].
|-
| ''[[Mucocutaneous leishmaniasis]]'' <!-- (Espundia or Uta) --> infections start off as a reaction at the bite, and can go by [[metastasis]] into the mucous membrane and become fatal.
| ''[[Leishmania braziliensis|L. braziliensis]]''
| Mucocutaneous infections are most common in [[Bolivia]], [[Brazil]] and [[Peru]]. Mucocutaneous infections are also found in [[Karamay]], China Xinjiang Uygur Autonomous Region.
|-
| ''[[Visceral leishmaniasis]]'' infections are often recognised by fever, swelling of the liver and spleen, and [[anemia]].  They are known by many local names, of which the most common is probably ''[[kala azar]]'',<ref name=humber>[http://homepages.uel.ac.uk/D.P.Humber/akhter/dis.htm Visceral leishmniasis: The disease] {{webarchive|url=https://web.archive.org/web/20050428075129/http://homepages.uel.ac.uk/D.P.Humber/akhter/dis.htm |date=2005-04-28 }}</ref><ref name=bartleby>[http://www.bartleby.com/61/51/K0005100.html kala-azar] {{webarchive|url=https://web.archive.org/web/20090210143548/http://www.bartleby.com/61/51/K0005100.html |date=2009-02-10 }}. The American Heritage Dictionary of the English Language</ref>
| Caused exclusively by species of the ''L. donovani'' complex (''[[Leishmania donovani|L. donovani]]'', ''[[Leishmania infantum|L. infantum]]'' syn. ''L. chagasi'').<ref name=Sherris />
| Found in tropical and subtropical areas of all continents except [[Australia]], visceral infections are most common in [[Bangladesh]], [[Brazil]], [[India]], [[Nepal]], and [[Sudan]].<ref name=Sherris /> Visceral leishmaniasis also found in part of China, such as Sichuan Province, Gansu Province, and Xinjiang Uygur Autonomous Region.
|}

===Intracellular mechanism of infection===
In order to avoid destruction by the [[immune system]] and thrive, the ''Leishmania'' 'hides' inside its host's cells. This location enables it to avoid the action of the [[humoral immune response]] (because the pathogen is safely inside a cell and outside the open bloodstream), and furthermore it may prevent the immune system from destroying its host through nondanger surface signals which discourage [[apoptosis]]. The primary cell types ''Leishmania'' infiltrates are [[phagocytosis|phagocytotic]] cells such as [[neutrophils]] and [[macrophages]].<ref>{{cite journal|last=Vannier-Santos|first=MA|author2=Martiny A |author3=de Souza W.|title=Cell biology of Leishmania spp.: invading and evading.|journal=Current Pharmaceutical Design|date=August 2002|pages=297–318|pmid=11860368|volume=8|issue=4|doi=10.2174/1381612023396230}}</ref>

Usually, a phagocytotic immune cell like a macrophage will ingest a pathogen within an enclosed [[endosome]] and then fill this endosome with enzymes which digest the pathogen. However, in the case of ''Leishmania'', these enzymes have no effect, allowing the parasite to multiply rapidly. This uninhibited growth of parasites eventually overwhelms the host macrophage or other immune cell, causing it to die.<ref>{{cite journal|last=Paul|first=William E.|title=Infectious Diseases and the Immune System|journal=Scientific American|volume=269|issue=3|date=September 1993|pages=94–95|bibcode=1993SciAm.269c..90P|doi=10.1038/scientificamerican0993-90|pmid=8211095}}</ref>

Transmitted by the [[sandfly]], the [[protozoan]] [[parasitism|parasites]] of ''L. major'' may switch the strategy of the first immune defense from eating/inflammation/killing to eating/no inflammation/no killing of their host [[phagocyte]] and corrupt it for their own benefit.{{Citation needed|date=December 2008}} They use the willingly phagocytosing polymorphonuclear neutrophil granulocytes (PMNs) rigorously as a tricky hideout, where they [[cell growth|proliferate]] unrecognized from the immune system and enter the long-lived [[macrophages]] to establish a "hidden" [[infection]].{{Citation needed|date=December 2008}}

===Uptake and survival===
[[File:Leishmaniasis life cycle diagram en.svg|thumb|579px|center|Lifecycle of ''Leishmania'']]

Upon [[microbial]] infection, PMNs move out from the bloodstream through the vessels' endothelial layer, to the site of the infected tissue (dermal tissue after fly bite). They immediately initiate the first immune response and phagocytize the invader by recognition of foreign and activating surfaces on the parasite. Activated PMN secrete [[chemokines]], [[Interleukin 8|IL-8]] particularly, to attract further [[granulocytes]] and stimulate phagocytosis. Further, ''L. major'' increases the secretion of IL-8 by PMNs. This mechanism is observed during infection with other [[obligate intracellular parasites]], as well. For microbes like these, multiple intracellular survival mechanisms exist. Surprisingly, the coinjection of apoptotic and viable pathogens causes by far a more fulminate course of disease than injection of only viable parasites. When the anti-inflammatory signal [[phosphatidylserine]] usually found on apoptotic cells, is exposed on the surface of dead parasites, ''L. major'' switches off the [[oxidative burst]], thereby preventing killing and degradation of the viable pathogen.

In the case of ''Leishmania'', progeny are not generated in PMNs, but in this way they can survive and persist untangled in the primary site of infection. The promastigote forms also release ''Leishmania'' chemotactic factor (LCF) to actively recruit neutrophils, but not other [[leukocytes]], for instance [[monocytes]] or [[NK cells]]. In addition to that, the production of [[interferon gamma]] (IFNγ)-inducible protein 10 (IP10) by PMNs is blocked in attendance of ''Leishmania'', what involves the shut down of inflammatory and protective immune response by NK and [[Th1 cell]] recruitment. The pathogens stay viable during phagocytosis since their primary hosts, the PMNs, expose apoptotic cell-associated molecular pattern (ACAMP) signaling "no pathogen".

===Persistency and attraction===
The lifespan of [[neutrophil granulocytes]] is quite short. They circulate in [[bloodstream]] for about 6 to 10 hours after leaving [[bone marrow]], whereupon they undergo spontaneous [[apoptosis]]. Microbial pathogens have been reported to influence cellular apoptosis by different strategies. Obviously because of the inhibition of [[caspase]]3-activation, ''L. major'' can induce the delay of neutrophils apoptosis and extend their lifespan for at least 2–3 days. The fact of extended lifespan is very beneficial for the development of infection because the final host cells for these parasites are macrophages, which normally migrate to the sites of infection within two or three days. The pathogens are not dronish; instead they take over the command at the primary site of infection. They induce the production by PMNs of the chemokines MIP-1α and MIP-1β ([[macrophage inflammatory protein]]) to recruit macrophages.<ref>{{cite journal |last1=Laskay |first1=Tamás |last2=van Zandbergen |first2=Ger |last3=Solbach |first3=Werner |title=Neutrophil granulocytes – Trojan horses for Leishmania major and other intracellular microbes? |journal=Trends in Microbiology |date=May 2003 |volume=11 |issue=5 |pages=210–214 |doi=10.1016/S0966-842X(03)00075-1}}</ref>

An important factor in prolonging infection is the inhibition of [[Adaptive immune system|the adaptive immune system]]. This occurs especially during the intercellular phases, when amastigotes search for new macrophages to infect and are more susceptible to immune responses. Nearly all types of [[phagocyte]]s are targeted.<ref>{{cite journal |last1=Martínez-López |first1=María |last2=Soto |first2=Manuel |last3=Iborra |first3=Salvador |last4=Sancho |first4=David |title=Leishmania Hijacks Myeloid Cells for Immune Escape |journal=Frontiers in Microbiology |date=7 May 2018 |volume=9 |doi=10.3389/fmicb.2018.00883 | pmid = 29867798 | pmc= 5949370 | doi-access= free }}</ref> For example, [[Mincle receptor|mincle]] has been shown to be targeted by ''L. major''. Interaction between mincle and a protein released by the parasite results in a weakened immune response in [[dendritic cell]]s.<ref>{{cite journal |last1=Iborra |first1=Salvador |last2=Martínez-López |first2=María |last3=Cueto |first3=Francisco J. |last4=Conde-Garrosa |first4=Ruth |last5=Del Fresno |first5=Carlos |last6=Izquierdo |first6=Helena M. |last7=Abram |first7=Clare L. |last8=Mori |first8=Daiki |last9=Campos-Martín |first9=Yolanda |last10=Reguera |first10=Rosa María |last11=Kemp |first11=Benjamin |last12=Yamasaki |first12=Sho |last13=Robinson |first13=Matthew J. |last14=Soto |first14=Manuel |last15=Lowell |first15=Clifford A. |date=October 2016 |title=Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection |journal=Immunity |volume=45 |issue=4 |pages=788–801 |doi=10.1016/j.immuni.2016.09.012 |pmc=5074365 |pmid=27742545 |last16=Sancho |first16=David}}</ref>

=== Silent phagocytosis theory ===
To save the integrity of the surrounding tissue from the [[toxic]] cell components and [[proteolysis|proteolytic]] [[enzyme]]s contained in neutrophils, the apoptotic PMNs are silently cleared by macrophages. Dying PMNs expose the "eat me"-signal [[phosphatidylserine]] which is transferred to the outer leaflet of the [[plasma membrane]] during apoptosis. By reason of delayed apoptosis, the parasites that persist in PMNs are taken up into macrophages, employing an absolutely [[physiology|physiological]] and nonphlogistic process. The strategy of this "silent phagocytosis" has the following advantages for the parasite:

* Taking up apoptotic cells silences macrophage killing activity leading to a survival of the pathogens.
* Pathogens inside of PMNs have no direct contact to the macrophage surface [[Receptor (biochemistry)|receptors]], because they can not see the parasite inside the apoptotic cell. So, the activation of the phagocyte for immune activation does not occur.

However, studies have shown this is unlikely, as the pathogens are seen to leave apoptopic cells and no evidence is known of macrophage uptake by this method.