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). Found in tropical and subtropical areas of all continents except Australia, visceral infections are most common in Bangladesh, Brazil, India, Nepal and Sudan. Visceral leishmaniasis also found in part of China, such as Sichuan Province, Gansu Province and Xinjiang Uygur Autonomous Region.
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.
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 polycistronically 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.
Canine Vector-borne Diseases (CVBD) covers diseases caused by pathogens transmitted by ectoparasites as ticks, fleas, sand flies or mosquitoes.
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.
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 is not achieved.
In case of Leishmania progeny is not 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.”
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.
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 does not occur.