Everything about Leishmania totally explained
Leishmania is a
genus of
trypanosome protozoa, and is the
parasite responsible for the disease
leishmaniasis. It is spread through
sandflies of the genus
Phlebotomus in the
Old World, and of the genus
Lutzomyia in the
New World. Their primary hosts are
vertebrates;
Leishmania commonly infects
hyraxes,
canids,
rodents, and
humans.
Leishmania currently affects 12 million people in 88 countries.
Origin
The origins of
Leishmania are unclear. One possible theory proposes an African origin, with migration to the Americas. Another migration from the Americas to the
Old World about 15 million years ago, across the
Bering Strait land bridge. Another proposes a
palearctic origin. Such migrations would entail migration of vector and reservoir or successive adaptations along the way. A more recent migration is that of
L. infantum from Mediterranean countries to
Latin America (there named
L. chagasi), since European colonization of the
New World, where the parasites picked up its current New World
vectors in their respective ecologies. This is the cause of the epidemics now evident. One recent New World epidemic concerns foxhounds in the USA.
Pathophysiology
Leishmania cells have two
morphological forms:
promastigote (with an anterior
flagellum) in the insect host, and
amastigote (without flagella) in the vertebrate host. Infections are regarded as cutaneous, mucocutaneous, or visceral.
Cutaneous (localized and diffuse) infections appear as obvious skin reactions. The most common is the
Oriental Sore (caused by Old World species
L. major,
L. tropica, and
L. aethiopica). In the New World, the most common culprits are
L. mexicana and
L. (Viannia) braziliensis. Cutaneous infections are most common in
Afghanistan,
Brazil,
Iran,
Peru,
Saudi Arabia and
Syria.
Mucocutaneous (espundia) infections will start off as a reaction at the bite, and can go via
metastasis into the mucous membrane and become fatal. Mucocutaneous infections are most common in
Bolivia,
Brazil and
Peru. Mucocutaneous infections are also found in
Karamay, China Xinjiang Uygur Autonomous Region.
Visceral infections are often recognized 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, and are caused exclusively by species of the
L. donovani complex (
L. donovani,
L. infantum syn.
L. chagasi).
Resistance to the antimonials is prevalent in some parts of the world, and the most common alternative is
amphotericin B (see
leishmaniasis for other treatment options). Paromomycin is an inexpensive alternative with fewer side effects than amphotericin that
The Institute for OneWorld Health has funded for production as an
orphan drug for use in treatment of leishmaniasis, starting in India.
Molecular biology
An important aspect of the
Leishmania protozoan is its
glycoconjugate layer of
lipophosphoglycan (LPG). This is held together with a phosphoinositide membrane anchor, and has a tripartite structure consisting of a lipid domain, a neutral hexasaccharide, and a phosphrorylated galactose-mannose, with a termination in a neutral cap. Not only do these parasites develop post-phlebotomus digestion but, it's thought to be essential to oxidative bursts, thus allowing passage for infection. Characteristics of intracellular digestion include an
endosome fusing with a
lysosome, releasing acid
hydrolases which degrade
DNA,
RNA, proteins and
carbohydrates.
Genomics
The genomes of three
Leishmania species (
L. major,
L. infantum and
L. braziliensis) have been sequenced, revealing more than 8300 protein-coding and 900
RNA genes. Almost 40% of protein-coding genes fall into 662 families containing between two and 500 members. Most of the smaller gene families are tandem arrays of one to three genes, while the larger gene families are often dispersed in tandem arrays at different
loci throughout the
genome. Each of the 35 or 36
chromosomes are organized into a small number of gene clusters of tens-to-hundreds of genes on the same DNA strand. These clusters can be organized in head-to-head (divergent) or tail-to-tail (convergent) fashion, with the latter often separated by
tRNA,
rRNA and/or
snRNA genes. Transcription of protein-coding genes initiates bi-directionally in the divergent strand-switch regions between gene clusters and extends poly
cistronically through each gene cluster before terminating in the strand-switch region separating convergent clusters.
Leishmania telomeres are usually relatively small, consisting of a few different types of repeat sequence. Evidence can be found for recombination between several different groups of telomeres. The
L. major and
L. infantum genomes contain only ~50 copies of inactive degenerated
Ingi/L1Tc-related elements (DIREs), while
L. braziliensis also contains several telomere-associated transposable elements (TATEs) and spliced leader-associated (SLACs) retroelements. The
Leishmania genomes share a conserved core proteome of ~6200 genes with the related trypanosomatids
Trypanosoma brucei and
Trypanosoma cruzi, but there are ~1000
Leishmania-specific genes (LSGs), which are mostly randomly distributed throughout the genome. There are relatively few (~200) species-specific differences in gene content between the three sequenced
Leishmania genomes, but ~8% of the genes appear to be evolving at different rates between the three species, indicative of different selective pressures that could be related to disease pathology. About 65% of protein-coding genes currently lack functional assignment.
Leishmania as component of CVBD
Canine Vector-borne Diseases (
CVBD) covers diseases caused by pathogens transmitted by ectoparasites as ticks, fleas, sand flies or mosquitoes.
Other microorganism-based diseases caused by ectoparasites include
Bartonella,
Borrelia,
Babesia, Dirofilaria, Ehrlichia, and Anaplasma.
Neutrophil granulocytes - the Trojan horses for Leishmania parasites
The strategy of the "Trojan horse" as a mechanism of
pathogenicity of
intracellular microorganisms is, to avoid the
immune system and its memory function cleverly, with
phagocytosis of infected and
apoptotic neutrophils by
macrophages, employing the non-danger surface signals of apoptotic cells.
Transmitted by the
sandfly, the
protozoan parasites of the genus
Leishmania 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. They use the willingly phagocytosing polymorphonuclear neutrophil granulocytes (PMN) rigorously as a tricky hideout, where they
proliferate unrecognized from the immune system and enter the long-lived
macrophages to establish a “hidden”
infection.
Uptake and survival
By a
microbial infection PMN move out from the bloodstream and through the vessels’ endothelial layer, to the site of the infected tissue (dermal tissue after fly bite). They immediately start their business there as the first immune response and phagocyte the invader because of the foreign and activating surfaces. In that processes an
inflammation emerges. Activated PMN secrete
chemokines,
IL-8 particularly, to attract further
granulocytes and stimulate them to phagocytosis. Furthermore
Leishmania major increases the secretion of IL-8 by PMN. In the parasites case, that may not sound reasonable at first. We can observe this mechanism on other
obligate intracellular parasites, too. For microbes like these, there are several ways to survive inside cells.
Surprisingly, the co-injection of apoptotic and viable pathogens causes by far a more fulminate course of disease than injection of only viable parasites. Exposing on the surface of dead parasites the anti-inflammatory signal
phosphatidylserine, usually found on apoptotic cells,
Leishmania major switches off the
oxidative burst, so killing and degradation of the co-injected viable pathogen isn't achieved.
In case of
Leishmania progeny isn't generated in PMN, but in this way they can survive and persist untangled on the primary site of infection. The
promastigote forms also release LCF (Leishmania chemotactic factor) to recruit actively 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 PMN 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 PMN, 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 or 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
caspase3-activation
Leishmania 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 2 or 3 days. The pathogens are not dronish; instead they take over the command at the primary site of infection. They induce the production by PMN of the chemokines MIP-1α and MIP-1β (
macrophage inflammatory protein) to recruit macrophages.
Silent phagocytosis
To save the integrity of the surrounding tissue from the
toxic cell components and
proteolytic enzymes contained in neutrophils, the apoptotic PMN are silently cleared by macrophages. Dying PMN 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 PMN are taken up into macrophages, employing an absolutely
physiological and non-phlogistic process.
The strategy of this "
silent phagocytosis" has following advantage for the parasite:
• Taking up apoptotic cells silences macrophage killing activity leading to a survival of the pathogens.
• Pathogens inside of PMN have no direct contact to the macrophage surface
receptors, because they can not see the parasite inside the apoptotic cell. So the activation of the phagocyte for immune activation doesn't occur.
Literature:
- Zandbergen et al. "Leishmania disease development depends on the presence of apoptotic promastigotes in the virulent inoculum", PNAS, Sept. 2006 (PDF
)
Laskay et al. "Neutrophil granulocytes - Trojan horses for "Leishmania major" and other intracellular microbes?", TRENDS in microbiology, May 2003
Shaw, J. J. (1969). The haemoflagellates of sloths. London, H. K. Lewis & Co. Ltd. (PDF)
Further Information
Get more info on 'Leishmania'.
|
External Link Exchanges
Do you know how hard it is to get a link from a large encyclopaedia? Well we're different and will prove it. To get a link from us just add the following HTML to your site on a relevant page:
<a href="http://leishmania.totallyexplained.com">Leishmania Totally Explained</a>
Then simply click through this link from your web page. Our crawlers will verify your link, extract the title of your web page and instantly add a link back to it. If you like you can remove the words Totally Explained and embed the link in article text.
As long as your link remains in place, we'll keep our link to you right here. Please play fair - our crawlers are watching. Your site must be closely related to this one's topic. Any kind of spamming, dubious practises or removing the link will result in your link from us being dropped and, potentially, your whole site being banned. |
