MINIREVIEW
Leishmania : origin, evolution and future since the Precambrian
Felipe Francisco Tuon1, Vicente Amato Neto2 & Valdir Sabbaga Amato3
1
Department of Infectious Diseases, University of São Paulo, Medical School, São Paulo, Brazil; 2Laboratory of Medical Investigation – Parasitology (LIM
46), Hospital das Clı́nicas, Medical School, University of São Paulo, São Paulo, Brazil; and 3Infectious and Parasitic Diseases Clinic, Hospital das Clinicas,
Medical School, University of São Paulo, São Paulo, Brazil
Correspondence: Valdir Sabbaga Amato,
Infectious and Parasitic Diseases Clinic,
Hospital das Clı́nicas, Faculdade de Medicina
da Universidade de São Paulo, Avenida Dr.
Enéas de Carvalho Aguiar 255, 4o andar. Sala
4028 – ICHC, Cerqueira César, ZIP code
05403-010, São Paulo, Brazil. Tel.: 155 11
30696530; fax: 155 11 30697508; e-mail:
[email protected]
Received 13 May 2008; revised 7 June 2008;
accepted 9 June 2008.
First published online 10 July 2008.
DOI:10.1111/j.1574-695X.2008.00455.x
Abstract
This brief review discusses the history of leishmaniasis, considering its origin from
the Paleoartic, Neoartic or Neotropic. We reassess some of the theories of the likely
origin of this protozoan since the beginning of life on Earth, passing through the
Mesozoic and continuing to the appearance of humans. The relationship between
this parasite or its ancestors, possible vectors and hosts with regard to ecological
modifications is discussed. Recent molecular techniques have helped to elucidate
some of the evolutionary questions regarding Leishmania, but have also brought
doubts about the origin and evolution of this human parasite. PCR has been used
for studies in the new discipline of paleoparasitology, helping to elucidate some of
the remaining evolutionary questions. Understanding of this global condition is
fundamental in determining the best approach to use against the parasite,
specifically for the development of an efficient vaccine.
Editor: Willem van Leeuwen
Keywords
American tegumentary leishmaniasis;
leishmaniasis; PCR; vaccine; immune response;
history.
Introduction
Leishmaniasis is an ancient disease that may have been
historically portrayed in figures, papyrus, statues and ceramics, and has been discussed from analysis of mummified
human remains and archaeological findings (AltamiranoEnciso et al., 2003). The discovery of a chronic ulcer that heals
over time has been cited under several names among the wider
population of the Asian continent. However, the description
of visceral leishmaniasis from historical papers is absent.
Nevertheless, the identification of New World leishmaniasis
was facilitated by descriptions of a typical mucosa lesion,
which was common among pre-Colombian inhabitants.
Reconstruction of the history of this disease has been
facilitated by the collection of DNA and amplification of
nucleic acids (PCR) from the mummies of Ancient Egypt in
the region of Nubia. Several studies have also been performed using PCR to identify protozoan material from
paleontological fossils (Zink et al., 2006).
Molecular trees, fossil records, historical events and
discoveries associated with biogeographical, entomological
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and ecological evidence need to be consolidated to support
some of the hypotheses regarding the origin of Leishmania
and the resulting human disease.
In this review, several theories are unified and divergent
aspects are discussed based on previous studies and our own
experience. The review discusses some aspects of the possible origin and evolution of the parasite. The term ‘possible’
is used here because no single theory has yet been confirmed. Noyes et al. (2000) suggested an association between
historical biogeography, including fossil records, ecology
and phylogeny of the organisms (Leishmania and sand fly),
constructing a large number of scenarios to explain the data,
limited by insufficient research about this parasite. The main
focus of the present review is discussion of the New World
origin of leishmaniasis, including a brief review about the
origin of the parasite.
Origin of Leishmania
Radiometric dates indicate that deposition of the Ruyang
sediments, coastal marine shales of the Ruyang Group,
FEMS Immunol Med Microbiol 54 (2008) 158–166
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History and Leishmania
northern China which contains Shuiyousphaeridium sp.,
occurred between 1600 and 1000 Mya. Carbon isotopic
stratigraphy, in turn, suggests an age greater than 1250 Mya.
Thus, the possible first protist appeared during the Mesoproterozoic (Xiao et al., 1997; Knoll et al., 2006).
Leishmania belongs to the phylum Kinetoplastida, which
lacks a fossil record. Molecular studies have shown that
kinetoplastids are probably related to the euglenids (Dooijes
et al., 2000). Both belong to the eukaryote supergroup
Excavata, whose fossils suggest their appearance during the
Ordovician (Roger & Hug, 2006).
The association between the evolution of parasites with
their host appearance appears to be weak. However, molecular, vector evolution, ecology and geographical evolution
data have improved our knowledge (Kerr, 2006). The
definition of a digenetic parasite makes it difficult to
consider the emergence of the current genus Leishmania
before the emergence of two adequate hosts (definitive
and intermediary), one of them a vector. Considering
Leishmania as an evolutionary form of a primitive protozoan present since the origin of the Protozoa, the first host
could have been a primitive water-dwelling animal. The
kingdom Animalia appeared 700 Mya, and it is possible that
the first host for the Leishmania descendant appeared at this
time, when the Earth was covered by water with a lower
concentration of oxygen (Scamardella, 1999; CavalierSmith, 2006). This descendant could be one of several fossils
described recently, dated from the Proterozoic, but is
difficult to associate one of them with Leishmania without
molecular evaluation (Xiao et al., 1997). Structural evaluation of these primitive protists is complex and it will be to
understand the link between Proterozoic and Phanerozoic
forms (Knoll et al., 2006).
Parasitism: hosts and vectors
Kerr (2006) proposed that the descendant of Leishmania
appeared during the Ordovician. The theory of digenetic life
needing a host (vertebrate and invertebrate) goes back to the
origin of fish in the Ordovician, followed by the radiation of
fish and amphibians, with leeches as common vectors of
digenetic trypanosomes among both groups (Molyneux,
1977).
Winged insects appeared around 300 Mya, during the
Carboniferous. The first hematophagous winged insect was
recorded from the Lower Cretaceous, 140 Mya (Azar & Nel,
2003). The separation of primitive winged insects within the
Diptera (Phlebotomus and Lutzomyia) occurred during the
Triassic, more than 200 Mya (Gullan & Cranston, 2000).
The first fossil member of the genus Leishmania was the
Paleoleishmania proterus, recently described by Poinar &
Poinar (2004a). This fossil dates from the Early Cretaceous
(100 Mya) and brought new insights regarding transmission. This discovery revealed an Early Cretaceous sand fly
FEMS Immunol Med Microbiol 54 (2008) 158–166
larvae which developed in habitats containing free-living
flagellates with the characteristics of trypanosomatids and
suggested that these flagellates were ingested by and probably multiplied inside sand fly larvae (Poinar & Poinar,
2004a, b; Poinar, 2007). Once in an adult sand fly, the
flagellates could be transmitted to a vertebrate, thus establishing a continuing cycle between vectors and vertebrates.
This was before the appearance of placental mammals
during the Paleocene.
It was after this that the current vector of Leishmania
appeared, namely Phlebotomus. Given that the vector,
mammal host and fossil suggest a Leishmania descendant
two epochs previously, leishmaniasis may have been established 50 Mya, during the Paleogene.
Nevertheless, this association of hosts and parasite was
questioned by Maslov et al. (1996), who evaluated the link
between Trypanosoma and several hosts.
Spread of Leishmania
The concept of a spreading host–vector complex is more
likely than simultaneous origins of the parasite from
different areas. Known vectors appeared before leishmaniasis. The emergence of winged insects promoted the
development of the phlebotomine sand fly lineage. After
several million years, this ancestry was probably separated by the break-up of Pangea with the formation of
Gondwana, allowing the evolution of two genera, Phlebotomus and Lutzomyia, the latter being responsible for
the transmission of leishmaniasis in the New World
(Killick-Kendrick, 1990, 1999).
Although certain primitive insects would have been able
to migrate over large distances, this is not the case for
current sand flies, which also have a short life cycle. We thus
cannot consider the sand fly as responsible for the spread of
ancient Leishmania (Kerr, 2000; Kerr et al., 2000).
The origin of Leishmania is controversial, some authors
considering that it originated from the Neotropic, others from
the Paleoartic or Neoartic (Noyes, 1998; Kerr, 2000; Lukes
et al., 2007). Independent of its origin, the dissemination of
Leishmania followed the migration of vectors and hosts
together (Perrotey et al., 2005). The definitive host of primitive Leishmania may have been reptiles or primitive mammals.
It was initially suggested that the genus Leishmania
appeared during the period Paleogene or Paleocene, following the extinction of the dinosaurs and the emergence of the
first placental mammals. These animals are the current
definitive hosts of Leishmania. At this time, the ancestor of
Leishmania was separated into Sauroleishmania, which infected reptiles such as lizards, and the current Leishmania,
which infects mammals (Momen & Cupolillo, 2000). Geologically, it is interesting to note that, at that time, the Earth
warmed and tropical climates appeared, an important
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160
condition for the multiplication of the parasite independent
from the host as cold-blooded vectors.
It is possible to create several theories regarding the
dissemination of Leishmania based on separation of the
continents. These vector–parasite–host theories of dissemination are summarized in Fig. 1 and are discussed according
to period below (Table 1).
Triassic
During the Triassic, there was a single landmass, Pangea.
Primitive mammals and reptiles (hosts) and Diptera (primitive vector) were present during this period, allowing the
dissemination of primitive Leishmania throughout the
world. Dinosaurs living in the area of South America,
associated with the description of Sauroleishmania as a
reptile-associated Leishmania, support this theory.
A molecular tree indicates that Sauroleishmania diverged
from L. (Leishmania) in the Paleartic prior to the migration
of the latter through the Bering Straits (Croan et al., 1997).
However, alternative explanations for the origin of Sauroleishmania, which are not supported by current molecular
phylogeny, have been proposed (Momen & Cupolillo, 2000).
These generally place the Sauroleishmania at the root of the
tree based on development in vectors similar to that of
F.F. Tuon et al.
primitive insect trypanosomatids and the ancient origins of
lizards (Lainson & Shaw, 1987).
The earliest fossil sand flies (120 Mya) have been reported from Lebanon, which formed part of Gondwana
(Lewis, 1982). Members of the Phlebotominae had probably lived for a long time in Pangea from where separate
sand fly faunas could have developed in the Neotropics and
Paleoartic (Noyes et al., 2000). These limited data support
a Triassic period and Pangea for the dissemination of
Leishmania.
Jurassic
Gondwana separated from Pangea during the Jurassic. The
Leishmania, vector (primitive Diptera) and hosts (reptiles or
primitive mammals) disseminated throughout the world,
except for the Neoartic. Leishmania arrived in the Neoartic
region after the formation of the isthmus of Panama during
the Neocene.
The formation of Laurasia and Gondwana suggest
the separation of the vector into two genera, namely
Phlebotomus and Lutzomyia (Killick-Kendrick, 1990, 1999).
Additional studies are needed to confirm the presence of
Lutzomyia in the New World. This theory awaits confirmation, mainly on the basis of paleoparasitology.
Fig. 1. Possible dissemination of Leishmania based on movement of the continents.
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FEMS Immunol Med Microbiol 54 (2008) 158–166
161
History and Leishmania
Cretaceous
The first Leishmania fossil occurs in the Cretaceous Paleoartic. Given this origin, Leishmania may have been brought to
the Neortic by primitive mammals through the Bering
Straits.
Recent studies by Kerr et al. have suggested that the most
acceptable theory for the entrance of Leishmania into
America is through the Bering Straits. During the Miocene,
a primitive mammal, probably an infected rodent, brought
the parasite into the New World (Noyes, 1998; Kerr, 2000,
2006; Kerr et al., 2000). The origin of Leishmania has
also been suggested to have been in the Neoartic (North
America) (Noyes et al., 1997). This same author considered
the spread of the parasite from North America to Asia,
Europe and Africa by this route. However, several strong
lines of evidence run counter to this and humans cannot
have brought the disease south from Alaska (Noyes et al.,
1997; Noyes, 1998; Yurchenko et al., 2006; Lukes et al.,
2007).
The theory of Leishmania in the Neotropics has been
considered and some molecular studies and findings regarding vectors support this idea. An origin in the Neotropics
with migration to the Neoartic and further Paleoartic is
currently accepted (Yurchenko et al., 2006; Lukes et al.,
2007).
Species of Leishmania
The genus Leishmania has two subgenera, L. (Leishmania)
and L. (Viannia). Considering an origin in the Paleoartic,
the current distribution of species and molecular trees,
L. (Leishmania) appeared first. The origin of the subgenus
L. (Viannia) is controversial.
L. (Viannia) lack the GP46/M-2 gene family found in
L. (Leishmania) (Cupolillo et al., 2000). Kerr explains this
deletion as a consequence of the time since the entry of
L. (Leishmania) into the Neotropic during the Pliocene. If
murid rodents first carried Leishmania to the Neotropic, the
deletion occurred after murid rodents appeared there in the
Pliocene (Kerr et al., 2000; Kerr, 2006, 2000).
Trees resulting from molecular studies should not be used
in isolation for the evaluation of ancestors; evolution of
hosts and vectors, as well as climatic and geographical
aspects need to be taken into account (Kerr, 2006). This
concept of careful interpretation of molecular data was
emphasized by Cavalier-Smith (Cavalier-Smith, 2006). He
advocated the use of transition analyses of complex cellular
and molecular characters to provide polarizations that can
then be used to infer ancestor–descendant relationships and
thus the adequate ‘root’ (Cavalier-Smith, 2006).
Another interesting question has emerged regarding the
evolution of the visceralizing/disseminating phenotype
of certain species (e.g. Leishmania donovani, Leishmania
FEMS Immunol Med Microbiol 54 (2008) 158–166
braziliensis) vs. the localized phenotype of others (e.g.
Leishmania major). The complex interaction between
host–parasite and immune response suggest an antigendependent pattern of disease, which is associated with the
species. Thus, the visceral form of the disease depends on
an immune response against some antigens, receptors
(e.g. Toll-like), coreceptor (e.g. CD40) and parasite tropism
(e.g. reticuloendothelial system). This interaction is
complex.
Old World leishmaniasis
In the Old World, the species of visceral leishmaniasis was
probably dichotomized into L. donovani and Leishmania
infantum about 1 Mya (Lukes et al., 2007). This theory was
proposed based on the evaluation of molecular trees (Mauricio et al., 2007). Leishmania donovani thus seems to have
originated in Eastern Africa, the same region as the origin of
humans. The presence of Leishmania in Asia may have
occurred along with the expansion of the human population, as some authors do not consider animal dynamics
(other mammals) to have been likely (Nozais, 2003). These
concepts of dichotomies of species based on only molecular
trees are controversial. Unfortunately, there are insufficient
data to determine the dissemination of leishmaniasis
through Asia as well as an origin in Africa.
Nevertheless, L. major (cutaneous leishmaniasis) could
have originated in North Africa when the Saharan region
was humid and covered by woodland. We do not known
whether humans brought the disease to the Middle East or
whether it was acquired from other reservoirs. Interestingly,
the vectors (phlebotomine sand flies) were already present
long before the arrival of humans in Europe and Asia, which
ensures the wild cycle for some species in Africa. Part of the
spread of the disease could have occurred by precursors
of modern rodents. Again, the disease, according to
D.H. Molyneux and R.W. Ashford, was once thought to
have originated in Central Asia in zoonotic reservoirs, and
around the 14th century to have spread to India, the
Mediterranean and eventually to western Africa (Oumeish,
1999). The appearance of the first phlebotomine fossils in
the Lebanon also argues for an origin of Leishmania in the
Middle East.
New World tegumentary leishmaniasis
Recent discoveries regarding the history of New World
leishmaniasis, in terms of both their tegumentary and their
visceral origin, have been made. It has been suggested that
the disease was brought by the Phoenicians and Syrians into
the Brazilian northeast (Altamirano-Enciso et al., 2003).
However, such early oceanic travels have not been proven.
These assumptions were made based on the characteristics
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162
of reported skin lesions, which were similar to the disease of
the Old World.
Another possibility is the existence of Leishmania during
the Mesozoic. Considering the genetic polymorphism and
clonality of Leishmania, the parasite might have already made its way to America before the separation of
Gondwana, 100 Mya. The separation of Gondwana led to
the development of the subgenera Viannia (New World) and
Leishmania (Old World). The vast distribution of species of
Leishmania could only have occurred after the appearance of
rodents in the Paleogene after the emergence of primitive
mammals. These dynamics are difficult to understand due
to a lack of evidence from this parasite and due to its
possible ancestral species, as Sauroleishmania, which appeared in the Cretaceous period and infected reptiles but not
mammals. We consider this theory to be plausible but
lacking confirmatory data. A more acceptable theory is of
L. (Viannia) following the break-up of Gondwana and of
L. (Leishmania) arriving in America through the Bering
Straits from the Paleoartic, as proposed by other researches
(Kerr, 2000). However, the closest known relative of
Leishmania (Leptomonas costaricensis) suggests that the
initial transition to dixenous parasitism pre-dated the
continental split and that subsequently the Neotropical and
the Old World Leishmania descendant evolved independently (Yurchenko et al., 2006).
The theory of an Andean region (American origin) origin
of American leishmaniasis has gained popularity with recent
studies of paleoparasitology. Prior to this, though, PreColombian ceramic pieces revealed deformities in the region
of the face that are suggestive of injuries from mucosal
leishmaniasis (Fig. 2) (Altamirano-Enciso et al., 2003;
Altamirano et al., 2005). The mucosal form is caused mainly
by L. braziliensis, a species that is present only in America
Fig. 2. ‘Huaco mochica’ showing mutilation of the nose and upper lip
suggestive of mucosal leishmaniasis (Altamirano-Enciso et al., 2003).
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F.F. Tuon et al.
(Shaw et al., 1987; Shaw, 1994; Ishikawa et al., 2002). It is
thought that population dynamics in Latin America among
Amazonian and Interandean regions has been important for
the dissemination of the disease (Altamirano-Enciso et al.,
2003). If this theory is confirmed, then the Andes could be
the cradle of New World leishmaniasis (Altamirano-Enciso
et al., 2003).
New World visceral leishmaniasis
Visceral leishmaniasis in the New World is of unknown
origin. Current studies cannot confirm the human disease
prior to European invasion of South America (Momen et al.,
1993). These findings suggest that Leishmania chagasi
arrived from Europe, and that this species is very similar to
L. infantum (Shaw, 2006). Furthermore, considering the
theory of clonality, it is difficult to justify sufficient mutations in less than 500 years, the time frame since the
discovery of America. Leishmania chagasi shares clinical
and molecular aspects with L. infantum (Pratlong et al.,
2001). If we consider L. infantum as having a Paleoartic
origin, another theory would be the spread of the parasite to
the northeast region of Brazil prior to the separation of
Gondwana.
Unfortunately, there are differences between L. chagasi
and other species of Leishmania in Latin America, and the
genetic profile of this species suggests a more recent parasite
than the subgenus Viannia. The formation of the isthmus
between North America and South America should have
occurred before the spread of Leishmania to the Amazon
region and the northeast of Brazil, the current endemic area
of L. chagasi (Abramson et al., 1995). Thus, we consider that
this strengthens the theory that L. chagasi was brought by
Europeans during the 15th century.
The current name of the etiological agent of visceral
leishmaniasis in the New World has been changed. The
name ‘L. chagasi’ has been progressively changed by several
authors to ‘L. infantum chagasi’, representing a subspecies of
a different species. Leishmania chagasi shows several similarities to L. infantum, but molecular studies have showed
sufficient differences to create a subspecies, L. infantum
chagasi (Shaw, 2006). By contrast, there is also strong genetic
evidence that these species are indistinguishable (Momen
et al., 1993). This question remains.
Shaw (2007) has discussed this taxonomic update and our
suggestion is to include this problem within historical evolutionary theories. First, structural and biochemical characteristics indicate close similarities between the two agents, but
which are not identical based on molecular studies. Second,
the geographical distance between human cases from each
species (or subspecies) always suggests a separation of the two.
We are currently studying vector evolution, mainly in the New
World, which might provide an explanation for the
FEMS Immunol Med Microbiol 54 (2008) 158–166
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History and Leishmania
Table 1. Geological timescale and the theory of the evolution of Leishmania
Eon
Era
Period
Phanerozoic Cenozoic
Mesozoic
Paleozoic
Proterozoic
Neoproterozoic
Mesoproterozoic
Paleoproterozoic
Archean
Neogene
Epoch
Duration
Evolution
Holocene
0–11.5 ty
Leishmania (L) spread to Neotropic through
primitive rodents from Neoartic or the
migration to this region from Neotropic
Pleistocene 11.5–1.806 ty
Pliocene
1.8–5.3 my
Isthmus of Panama formation and physical
unification between Neoartic and Neotropic
allowing further spread of Leishmania to
South America
Miocene 5.3–23.0 my
Leismania (L) into Neoartic after Bering Strait
formation by primitive rodents from
Paleoartic or migration to this ecozone from
Neotropic
Paleogene
Oligocene 23.0–33.9 my
Eocene
33.9–55.8 my Appearance of genus Phlebotomus,
confirmed vector of Leishmania
Paleocene 55.8–65.5 my Placental mammals, ancestral hosts of
Leishmania
Cretaceous
Upper
65.5–100 my First Leishmania descendant in a reptile host
First hematophagous winged insect
Lower
100–145 my Separation of Africa and South America
Jurassic
145–199 my The first digenetic protozoan, a possible
ancestor of Leishmania
Triassic
199–251 my
Permian
251–299 my Division of Trypanosomatidae following the
evolution of Hemiptera and Diptera (vector of
the Leishmania)
Carboniferous
299–360 my First winged insect
Devonian
360–416 my Formation of first digenetic protozoan,
ancestror of other Trypanosoma, not
Leishmania. Parasite of a primitive fish
Silurian
416–444 my
Ordovician
444–488 my
Cambrian
488–542 my
542–1000 my
1–1.6 by
Possible origin of the Phylum Protista
1.6–2.5 by
3.5–2.5 by
by, billions of years; my, millions of years; ty, thousand of years.
appearance of this strain [L. (L.) i. chagasi] in the last
millennium (Shaw, 2006). The interaction of Leishmania with
several proteins in the gut of phlebotomine sand flies may be
sufficient to explain the selection of different strains in the
New World as well as to maintain a significant variability over
the continent (Shaw, 2006).
New paleoparasitologial studies
Significant improvements in paleoparasitology have been
made following archaeological excavations and the implementation of techniques for nucleic acid amplification and
the recognition of parasitic residues.
Samples of more than 90 mummies from Egypt’s preDynasty to the Dynasty of Abydos (3500–2800 BC) and the
Western empire (2050–1650 BC) were analyzed for the
FEMS Immunol Med Microbiol 54 (2008) 158–166
identification of mtDNA from Leishmania (Zink et al.,
2006). Analysis found parasite DNA in mummies that was
compatible with L. donovani, suggesting the visceral form. A
similar study was conducted in northern Sudan, and
preliminary results showed the presence of DNA from
Leishmania in this population as early as 1500 BC (Braunstein et al., 1988; Vray, 2002; Chastel, 2004).
Subsequently, study of lytic lesions on 241 skulls from the
Department of Physical Anthropology of the National
Museum of Anthropology, Lima, Peru, showed that about
2% of these lesions were highly suggestive of mucosal
leishmaniasis (Altamirano et al., 2005). In Chile, another
study with skulls featuring the same characteristics suggested the presence of L. donovani, but these studies have not
yet been completed (Table 1).
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164
The most important piece of information from these
studies determined was that leishmaniasis existed before the
arrival of Europeans in America (Guillen & Allison, 2005).
The study showed a mummy of a 6-year-old girl dated
to 800 BC that revealed macrophages with Leishmania based
on immunohistological examination (Guillen & Allison,
2005).
Following traffic between major settlements the disease
spread, although it remained in specific locations restricted
by the availability of a favorable ecosystem and the presence
of a vector and reservoir, which may or may not have been
human.
Paleoparasitology, especially focused as an interdisciplinary science, is certainly contributing to this new history of
leishmaniasis, and primarily to the history of New World
leishmaniasis.
Anthropological aspects and population
dynamics
The following gives some brief background to Leishmania
and the evolution of modern human (Nozais, 2003). Seven
million years ago, according to our best theories and
paleontological evidence, primates became separated into
two groups (Benton & Donoghue, 2007). A contingent of
primates remained in tropical forests with wild habitats,
collecting fruits; these animals have maintained their lives in
this mode to date, leading to the chimpanzees and gorillas.
Another population of primates, for various reasons that are
beyond the scope of this work, migrated to open lands.
Living in areas of savannas and fields promoted the development of an upright position. This ‘upright’ population
formed the australopithecines 3 Mya, which later differentiated to Homo habilis (Spoor et al., 2007). Two hundred
thousand years ago, the development of this primate allowed
for the evolution of Homo erectus, our next ancestor.
Even before the evolution of H. erectus, ancestors of
humans with characteristics of hunters and predators left
the savannas of East Africa, the likely birthplace of humanity, and migrated to the Middle East, Asia and Europe. This
dynamic occurred with a migration of 50 km for each
generation, explaining the spread of our ancestors to the
Old World (Blanc, 1984). Fifty thousand years ago, Homo
sapiens dominated the region of East Africa, and only 35 000
years ago, the Neanderthals of Europe were replaced by
H. sapiens coming from Asia, rather than by the development of H. erectus in that region (Leakey & Levin, 1985).
Population dynamics were thus very important to the global
development of humans, the host of Leishmania.
It is possible that this population dynamic has been
responsible for the spread of various parasitic diseases, including leishmaniasis. Leishmaniasis is inextricably linked to
primitive humans, given that the wild cycle of the disease was
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F.F. Tuon et al.
part of the landscape at that time (Nozais, 2003). Considering
this, population dynamics may have been responsible for
parasitic diseases that were restricted to a region.
We cannot disregard the possibility that some diseases
may have decimated populations and delayed the development of villages in certain regions of the world. It is curious
to note that humans have continually adapted to diseases.
Furthermore, some generations of people may have been
sensitive to leishmaniasis while others may have been
resistant. This occurs even today, and we do not know if
this also happened in ancient times or if leishmaniasis did
actually decimate some human populations. Current paleoparasitological studies suggest that no decimation occurred
via leishmaniasis, indicating a parasitic disease that followed
human development. This theory of maintenance of the
host by the parasite is called the Red Queen Theory, and
explains the maintenance of several parasites (Ochoa & Jaffe,
1999). However, we await further studies about this parasite
and human civilization. If data confirm that leishmaniasis
decimated previous civilizations or villages, the Red Queen
Theory cannot be applied to Leishmania and we must be
alert to the current increase in mortality, as witnessed in
Brazil, following urbanization of the disease (Arias et al.,
1996).
Future research needs
We await future findings from studies of paleoparasitology,
which has developed further to include an understanding of the
phylogeny of several parasitic agents and, consequently, an
understanding of the history of human diseases (Vray, 2002).
Much of the data mentioned in this review should soon be
updated, and it is possible that we will have new information on
this historic illness, which has been associated with humans
since its origin and has continued throughout human history.
The origin and evolution of human Leishmania seems to be
linked to human origins in Africa and followed the population
dynamics throughout the Paleoartic (Asia, Africa and Europe).
From the Paleoartic, the formation of the Bering Straits allowed
the dissemination of Leishmania into the New World. In
America, species variability was able to occur, given the polymorphism of vectors, hosts, climate and humidity from the
Amazon region, while preserving other species in the Andean
region. The probable cradle of this parasite in Latin America
is confirmed by mummies showing mucosal lesions from
L. braziliensis.
More studies are needed, evaluating Brazilian Indians and
dinosaur fossils, to understand the dynamics of the parasite
in the New World. Several studies of New World Leishmania
await publication, and their appearance should help the
progress of other researchers.
This parasite has survived over many millions of years
under selective pressures that depended on natural
FEMS Immunol Med Microbiol 54 (2008) 158–166
165
History and Leishmania
ecological changes (storms, floods, hurricanes, volcanic
eruptions, etc.) that disrupted host–vector relationships.
Previous climatic changes, ice ages and the formation of
arid regions, as well as enormous land mass disruptions have
not devastated Leishmania. We must be alert to further
relationships with this parasite because many ecological
changes are accelerating (deforestation, global warming,
armed conflicts, immunodeficiency, etc.) (Shaw, 2007). If
you consider the mathematical model of adaptation of the
parasite to the host, the recent increase in the incidence of
leishmaniasis could be sufficient to indicate an adaptation.
The development of vaccines is increasing and we must be
ready for new information; we believe that vaccination will be
the most probable method of elimination of the human disease
and will redirect this parasite to its zoonotic cycle. Reducing this
burden will perhaps be by providing an antipoverty vaccine to
all those at risk of acquiring leishmaniasis, thereby consigning
the disease to a Natural History Museum.
Acknowledgements
We thank Ruth B. Martins for preparation of Fig. 2.
Statement
The authors were not part of any associations or commercial
relationships that might represent conflicts of interest (e.g.
pharmaceutical stock ownership, consultancy, advisory board
membership, relevant patents, or research funding); no financial support was received for the preparation of this article.
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