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Intracellular Protozoan Parasites: Trypanosoma cruzi and Leishmania

Transcript of Part 2: Leishmania spp and Leishmaniasis

00:00:02.04		My name is Norma Andrews, I'm a professor at Yale University,
00:00:05.18		and what I'm going to be talking to you about in this second part of my lecture
00:00:09.12		is about Leishmania, this parasite, and the disease that it causes in humans
00:00:15.00		which is called Leishmaniasis.
00:00:17.06		This is also a protozoan parasite from the order Kinetoplastida,
00:00:23.04		family Trypanosomatidae, and inside this family, we find several protozoan organisms,
00:00:30.09		and the two groups that are medically important because they cause serious diseases in man,
00:00:35.26		Trypanosoma which includes Trypanosoma cruzi that I already talked about
00:00:39.23		in the first part of this lecture.
00:00:42.03		And also the African trypanosome that causes sleeping sickness in Africa, Leishmania,
00:00:47.08		which I'm going to introduce to you now is closely related to trypanosomes,
00:00:53.09		and it's also an intracellular parasite.
00:00:58.12		So, here in the distribution of Leishmania throughout the world,
00:01:02.25		we can see that it's not only restricted to South America like Chagas' disease,
00:01:07.21		but is also found in many regions of Africa, the Middle East, and also around the Mediterranean.
00:01:15.09		So, similar to Chagas' disease, Leishmaniasis is also largely a disease of poverty.
00:01:21.07		It is mostly found in underdeveloped regions of the world,
00:01:27.22		but it has some characteristics that actually make it very serious in the sense that
00:01:34.17		development is proving not to be sufficient to stop transmission,
00:01:39.01		and actually there's several signs that the disease is recently moving
00:01:44.23		from rural areas to urban areas of the world.
00:01:48.18		So, this is a very serious development that indicates that this number of people
00:01:54.19		which are currently around 12 million that are already infected by this parasite...
00:01:58.15		There are 350 million people at risk worldwide.
00:02:02.17		So, the instance of Leishmaniasis may actually increase over time.
00:02:07.28		Here we see an example of one of the clinical manifestations of Leishmaniasis.
00:02:14.27		This is a child with a cutaneous lesion, which... The form of the disease in Leishmaniasis
00:02:22.10		is directly associated to the species of Leishmania that causes the infection.
00:02:27.07		So, these three species here, L. major, L. tropica, and L. mexicana
00:02:31.18		are frequently associated with the cutaneous form of the disease
00:02:35.07		which can be very disfiguring, although these lesions most of the time, they are self-healing.
00:02:41.10		There's a more serious form of this cutaneous disease
00:02:45.21		which is the form that attacks the mucosal membranes
00:02:49.06		in which this can really be seriously disfiguring and this is usually
00:02:53.09		associated with some of the species, for example Leishmania braziliensis.
00:02:58.06		The most severe form of Leishmaniasis is by far the visceral form
00:03:03.24		which is caused by these three species, mostly,
00:03:08.28		Leishmania donovani, Leishmania infantum, and Leishmania chagasi,
00:03:12.21		and this disease is characterized by periodic fever,
00:03:18.13		severe enlargement of the liver and the spleen, and also weight loss and anemia.
00:03:25.19		This is significant cause of morbidity and mortality
00:03:30.02		in the endemic areas for visceral Leishmaniasis.
00:03:33.27		This disease was already known to be present.
00:03:38.02		It was called early on Calazar, but what was not known is what was the organism causing it.
00:03:46.27		It was not even clear that it was an infectious disease.
00:03:49.10		So, it was this British physician, William Leishman
00:03:54.03		which analyzed the material from patients in India and also simultaneously,
00:04:01.26		by the Irish investigator Charles Donovan,
00:04:05.26		they realized that macrophages present in the spleen
00:04:10.11		of these patients were heavily loaded with these organisms
00:04:15.26		which they recognized as similar to trypanosomes.
00:04:19.13		So this was the first indication that this was a parasitic disease,
00:04:24.03		and another very important finding in the history of Leishmaniasis
00:04:29.00		was made by Rogers and Nicolle a few years later,
00:04:32.28		in which they took this material from the spleen of the patients and put it into culture
00:04:37.26		and they were able to show that a second form of the parasite appeared in these cultures
00:04:43.19		indicating directly the existence of a life cycle and most likely an insect vector.
00:04:49.17		So this actually was only decades later that the first hint for which could be
00:04:56.09		the insect involved in this transmission was made by John Sinton when he realized that
00:05:02.05		the incidence of visceral Leishmaniasis in Eastern India
00:05:05.01		actually coincided with the distribution
00:05:07.26		of a specific type of sandfly, the silvery sandfly.
00:05:12.05		This rapidly led to a lot of work in which this picture is what emerged
00:05:19.14		in which these regions that I already showed
00:05:22.08		that we can see Leishmaniasis transmitted to humans.
00:05:27.22		In each case, a specific species of Leishmania
00:05:30.05		is associated with a specific species of the sandfly
00:05:33.06		which is responsible for the transmission.
00:05:35.15		And it was only more recently, decades later after these original observations,
00:05:42.09		that there was a formal demonstration that sandflies
00:05:46.25		could transmit Leishmania to humans.
00:05:49.04		Although earlier, it had already been detected in sandflies
00:05:53.13		that had been feeding on an infected animal, but also in humans.
00:06:02.07		It was then only this time around the 40s that
00:06:08.01		the life cycle of Leishmania was really understood,
00:06:12.21		with this replication of the parasites happening inside the sandfly
00:06:17.14		and this is similar to Trypanosoma cruzi in the sense
00:06:23.03		that these parasites also don't gain access to the salivary gland.
00:06:25.23		They are transmitted in this case by regurgitation.
00:06:30.06		So, after a blood meal, this fly delivers these parasites
00:06:36.06		which replicate abundantly in its digestive tract,
00:06:40.06		and this is how they penetrate the mammalian host,
00:06:43.26		which in addition to humans, dogs, and rodents play a major role in this cycle,
00:06:49.17		and it is inside macrophages of the mammalian host that the intracellular replication occurs.
00:06:56.03		More recently, David Sacks at the NIH made another very important observation
00:07:02.23		and contribution to the understanding of the biology of Leishmania parasite
00:07:08.00		which was by identifying an infective stage.
00:07:10.26		So, similar to what I discussed in the first part of this lecture, for Trypanosoma cruzi,
00:07:16.00		Leishmania also has an infective stage, so the parasites that replicate inside the insect vector,
00:07:22.22		they replicate into these infective stages which David Sacks called metacyclic promastigotes.
00:07:29.07		During this differentiation, they also acquire that resistance to lysis by complement,
00:07:34.26		which allows them to survive inside the mammalian host.
00:07:38.01		David Sacks and other groups have made
00:07:42.13		very important contributions in linking this differentiation
00:07:46.13		into the metacyclic form to this surface molecule, LPG,
00:07:50.10		which is a major component of the surface coat of these parasites.
00:07:54.09		What is shown here in this immunogold electron microscopy,
00:07:59.23		these black dots that we can see here in this enlarged segment
00:08:03.20		represent antibodies reacting with this surface molecule
00:08:08.07		and what David Sacks and others showed
00:08:12.05		is that these molecules are lipid-anchored,
00:08:16.05		and they have these repeated disaccharide-phosphate units...
00:08:20.03		This molecule undergoes significant elongation during differentiation
00:08:25.11		and these side groups which are usually terminated in galactose
00:08:29.00		in the epimastigote insect form
00:08:31.13		acquire these side chains terminated by arabinose.
00:08:36.06		This is a key change in one of the specific species, Leishmania major
00:08:41.28		that David Sacks showed that is responsible
00:08:46.01		for a very important part of this transmission cycle,
00:08:48.24		which is the detachment of the parasites from the midgut of the insect,
00:08:54.04		allowing them to be delivered to the infected host.
00:08:57.12		So this change in the structure of this LPG molecule
00:09:01.22		is what mediates detachment and then facilitates transmission
00:09:07.10		during or after the blood meal by the sandfly.
00:09:11.10		Another very important point that emerged recently
00:09:16.13		also from the work of David Sacks at the NIH
00:09:18.28		is that the vectorial competence
00:09:21.06		--the ability of these sandflies to transmit specific species of Leishmania--
00:09:26.18		is related to polymorphisms on this LPG molecule, so only now, very recently,
00:09:33.25		a much more complete picture has emerged of what are the molecular properties of this parasite
00:09:40.16		that really create these very specific associations between vector
00:09:46.19		and cycles of transmission throughout the world.
00:09:50.24		What is the next frontier now, now that we really understand
00:09:55.20		quite well what is happening inside the sandfly
00:09:58.03		with the delivery of these infective stages,
00:10:00.17		the next frontier is understanding what's happening in the mammalian host.
00:10:04.15		We know that Leishmania mostly replicates inside macrophages,
00:10:08.14		since the original observations of Leishman and Donovan,
00:10:12.12		but we don't understand completely how the parasites actually survive in these cells.
00:10:18.10		Macrophages are cells that are actually designed to destroy intracellular pathogens,
00:10:23.01		and the entry of Leishmania into these macrophages
00:10:26.09		is known to be mediated by phagocytic receptors
00:10:29.01		so in this case, different from Trypanosoma cruzi.
00:10:32.11		There's no indication of an active mechanism of invasion,
00:10:35.26		but it is pretty clear that at least the complement receptors,
00:10:40.14		CR1 and CR3 play an important role
00:10:42.26		because these parasites are not lysed by complement,
00:10:46.06		but they are opsinized by complement,
00:10:48.05		which allows them to be efficiently internalized by macrophages.
00:10:52.03		Inside the macrophages, the really remarkable aspect of the life cycle of Leishmania
00:10:58.04		is that these parasites can survive in compartments
00:11:01.12		that have many properties of lysosomes.
00:11:03.26		They are acidic, they contain a full set of hydrolases
00:11:08.23		and also of lysosomal membrane proteins,
00:11:11.16		and we don't really understand how the parasites are able to spend their whole cycle
00:11:16.28		which also lasts several days--they have a doubling time of around 12 hours--
00:11:22.01		and what is indicated in this slide here is that even MHC class II,
00:11:27.02		which is a protein expressed by activated macrophages
00:11:31.01		is present on the membrane of these vacuoles containing the parasites
00:11:35.14		that replicate in spite of these harsh conditions.
00:11:40.09		In addition to this remarkable adaptation to survive inside cells of the immune system,
00:11:47.12		which in normal circumstances actually play a role in the elimination of pathogens,
00:11:51.19		another very challenging aspect of Leishmaniasis
00:11:56.22		is the difficulty in limiting exposure of humans to these insect vectors.
00:12:02.11		In this case, this is a very small insect.
00:12:06.16		What this picture here shows is one sandfly sitting on the knuckle of a finger,
00:12:11.24		just to give an idea of how small they are.
00:12:14.24		The simple measures that have been shown to be so effective
00:12:17.25		in containing malaria transmission, for example,
00:12:22.00		just bed nets, really are not effective
00:12:25.11		because these are very small flies that can go through these regular bed nets
00:12:30.15		that are normally used in these endemic areas.
00:12:33.23		What is very clear for Leishmaniasis is that there is a strong need
00:12:37.17		for development of new drugs
00:12:40.01		and new drugs with less toxicity, because again here the drugs currently in use
00:12:44.25		in large parts of the world are still very toxic.
00:12:49.19		The good news is that the recent developments are leading rapidly
00:12:54.19		to the identification, implementation,
00:12:57.10		and clinical trials of new and better drugs
00:13:00.25		with several philanthropic organizations and also non-profit institutions participating actively
00:13:08.00		in this concerted effort to make this very important need in public health met
00:13:17.21		by taking advantage of current state-of-the-art technology.
00:13:24.03		Thank you.  In the next segment, I'm going to discuss more the cell biology of infection
00:13:30.07		of both Trypanosoma cruzi and Leishmania.

This material is based upon work supported by the National Science Foundation and the National Institute of General Medical Sciences under Grant No. 2122350 and 1 R25 GM139147. Any opinion, finding, conclusion, or recommendation expressed in these videos are solely those of the speakers and do not necessarily represent the views of the Science Communication Lab/iBiology, the National Science Foundation, the National Institutes of Health, or other Science Communication Lab funders.

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