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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 104, Num. 2, 2009, pp. 129-131
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Memórias do Instituto Oswaldo Cruz, Vol. 104, No. 2, March, 2009, pp. 129-131
EDITORIAL
Lílian
MG Bahia-Oliveira, Marie-Laure
Dardé, Maria
Regina Reis Amendoeira
Code Number : oc09022
Toxoplasma
gondii centennial anniversary: 100 years of research to celebrate all over
the world
In May 2006, researchers
participating in the International Toxoplasma and Food Congress, hosted
by the Instituto Zooprofilattico Sperimentale della Sicilia in the city of Palermo,
Italy, expressed their support for an international congress to celebrate the
100th anniversary of the discovery of the parasite Toxoplasma gondii in Brazil. The idea rapidly gained the worldwide support of prominent scientists
working in the field. The Congress, entitled "Toxoplasma Centennial Congress:
From Discovery to Public Health Management" was held in Brazil last year.
The quality and
diversity of studies presented in this meeting prompted us to organise the information
presented at the meeting, with the aim of bringing together original articles
and reviews that will be important for future advances in this field. We consider
this endeavour a success. The present issue of Memórias do Instituto
Oswaldo Cruz is a collection of 37 articles covering a wide array of research,
ranging from basic cell biology, immunology, proteomics and genome projects
to studies on clinical management, public health control through screening programmes,
diagnosis and environmental control. It also presents two historical reviews.
The first, entitled "Toxoplasma gondii: 1908-2008, homage to Nicolle,
Manceaux and Splendore", was written by David Ferguson. The author describes
historical advances in understanding the basic biology of the parasite. The
second, "Brazilian contribution for a better knowledge on the biology of Toxoplasma
gondii", was written by Wanderley de Souza and describes the importance
of the works of Herta Meyer, who established the first reproducible studies
on the cultivation of T. gondii (Guimarães & Meyer 1942) and
in the 1950s was among the first to use transmission electron microscopy to
analyze the fine structure of T. gondii.
The original works
of Splendore, published in 1908 and 1909, and of Nicolle and Manceaux, published
in 1909, are reprinted with permission in the supplementary electronic version
of this issue in their respective original languages, Italian and French. An
English translation is also available. We invite you to explore these works,
which will certainly please and surprise you when you discover the richly detailed
descriptions of the parasite that were made using microscopes with inconceivable
resolutions for that day's technology. The skill of those scientists was impressive
for proposing such accurate hypotheses on the mode of infection and by the challenges
that loomed on the horizon for future researchers who dedicated and still dedicate
their lives to investigating the many aspects of T. gondii and the relationship
with its hosts.
The challenges
of understanding T. gondii still arise today and will certainly pave
the way for scientific research throughout this century. Splendore and Nicolle
exchanged slides with preparations from infected rabbits and gundis, respectively,
and were convinced that the new protozoa belonged to the same genus. They independently
described the parasite dividing by "longitudinal bipartition" (currently known
as endodyogeny). This form of asexual multiplication is illustrated in the electron
micrograph used on the cover of this issue. Splendore also suggested schizogony
as a form of division, but Nicolle believed that it probably represented repeated
cycles of "longitudinal bipartition" (repeated endodyogeny). However, a specific
form of schizogony (Toxoplasma endopolygeny) occurring during coccidian
development in the gut of the cat was identified 60 years later.
In the second publication
on the subject (1909), Splendore describes three very important aspects of the
biology of Toxoplasma cuniculi (as he named the new parasite on that
occasion) and the signs of the disease it caused: (i) "In a new group of cases
occurring in the same period last year, microscopic examination revealed the
same anatomic and parasitic situation. I am of the opinion that seasonal variation
must be taken into consideration in a transmission study, as constant transmission
has never been possible." (ii) "A dog injected with emulsified tissues extracted
from a rabbit showing a high number of parasites suffered from bloody diarrhoea
in the first few days, and two months later was suffering from severe progressive
wasting disease and loss of sight due to ocular turbidity." (iii) "Surprisingly,
rabbit parasites can reproduce in birds, as shown last year with two sparrows
(Zonotrichia pileata) that died five days after subcutaneous injection
of two spleen drops extracted from an infected rabbit."
Those three aspects
mentioned by Splendore were shown to have the following important public health
impacts several years later: (i) seasonal weather variations, for instance,
have been considered an important factor in toxoplasmosis outbreaks where oocysts
are implicated as the life cycle stage responsible for infection dissemination
(Bowie et al. 1997, DeMoura et al. 2006); (ii) the ocular involvement of toxoplasmosis,
which was definitively recognised in the late 1940s and early 1950s (Wilder
1952, Feldman 1953, Frenkel & Jacobs 1958 and Ferguson, in this issue);
and (iii) the diversity of T. gondii intermediate hosts; namely, the
fact that any warm-blooded animal - bird or mammal - is a potential intermediate
host (Dubey & Beatie 1988) was highlighted by Splendore when he noted that
the new disease of rabbits could be reproduced in birds.
The concomitant
discovery of the parasite in South America and North Africa raised the question:
is it exactly the same parasite? One of the major findings of the past 25 years
concerns the genetic diversity of T. gondii and the geographical distribution
of genotypes, South American genotypes being different from European or North
American ones. Other continents are still relatively unexplored.
Substantial advancements
in Toxoplasma molecular and cell biology research have also occurred
in the past 20 years. This issue includes three critical reviews and viewpoints
on specific topics in those areas written by distinguished senior and young
scientists who propose ideas that certainly will stimulate new directions for
research for the next 100 years. In his article, Boothroyd explores the hypothesis
that a combination of sexual recombination and host range expansion may be the
major driving force in the evolution of some gene families and the specific
genes they encompass. The author proposes central questions that remain to be
investigated, such as: "Might some strains of Toxoplasma be adapted to
sexual replication in non-feline hosts? How many strains have actually been
tested for their ability to infect non-felines?" He concludes, stating: "Perhaps
it is time to revisit the 'felines-only' dogma". Sullivan et al. discuss the
evidence that shows how the clinically relevant process of bradyzoite differentiation
is regulated at both transcriptional and post-transcriptional levels and pose
some questions for future research. In the article entitled "What new cell biology
findings could bring to therapeutics: is it time for a phenome project in Toxoplasma
gondii?" Meissner and Klaus argue that in the absence of a powerful high-throughput
technology for the characterization of essential genes of interests, a coordinated
effort should be undertaken to convert the knowledge of the genome into that
of the phenome.
The impact of the
development on Toxoplasma genetics research can be evaluated in the articles
presented in this issue by Jamielson et al., who tested the hypothesis that
propensity for T. gondii to cause eye disease is associated with genes
previously implicated in congenital or juvenile onset ocular disease, and by
Dubey and Su, who compared Toxoplasma strains from United States and
Brazil and concluded that different population structures of T. gondii
between these countries may be shaped by different transmission routes. On the
topics of molecular cell biology research and the host-parasite relationship,
the articles published by Guimarães and Ferreira-da-Silva provide new
data on the potential use of primary cultures of skeletal muscle cells as a
cellular model for in vitro differentiation of the RH strain. Milovanovi et
al. present a set of data showing that significant lipid metabolism alterations,
including a decrease in reverse cholesterol transport, are observed during acute
Toxoplasma infection.
Substantial advances
have also been achieved over the past 15 years in basic and applied research
on the host immune response against Toxoplasma. Nine articles on this
subject are published in the present issue. Five excellent reviews are presented.
Hunter and Tait explore the development of a working model to study immunity
to T. gondii, Garweg and Candolf discuss current facts and possible clues
on the immunopathology of ocular toxoplasmosis and Subauste proposes that cell-mediated
immunity through CD40 reroutes the parasitophorous vacuoles (PVs) to the lysosomal
compartment by a process called autophagy, resulting in the death of T. gondii
and thus challenging the dogma that the non-fusogenic nature of the PV is irreversible.
Zaho et al. present a review on the immunity-related GTPase resistance system
in mice. Schreiner and Liesenfeld present a review entitled "Small intestinal
inflammation following oral infection with Toxoplasma gondii does not
occur exclusively in C57BL/6 mice: review of 70 reports from the literature",
in which the authors review the common features of small intestinal immunopathology
in the animal kingdom and speculate on its consequences for immunopathology
in humans. Two articles present data on the immune response of hosts. Brandão
et al. report the immune response of experimental reinfection of BALB/c mice
to different recombinant type I/III strains of T. gondii, and Bahia-Oliveira
et al. describe the evidence for the role of cross-immunomodulation in the outcome
of ocular toxoplasmosis in areas endemic for T. gondii and Ascaris
lumbricoides. In the area of vaccinology, two reviews are presented. Innes
et al. report some of the history, challenges and progress in the development
of veterinary vaccines against T. gondii, Jongert et al. propose that
future studies should use animal models other than rodents and that goals such
as the prevention of maternal-foetal transmission and eye disease are as important
as the traditional goals of survival or reduction in brain cyst numbers.
Environmental research
on toxoplasmosis fortunately has gained even more importance. Three articles
are presented on this subject: Villena et al. report methods for the detection
of Toxoplasma oocysts in water and their application in the Champagne-Ardenne
Region of France, Forman et al. describe the seroprevalence of T. gondii
in British marine mammals and Mai et al. present an important review on oocyst
wall formation and composition in coccidian parasites, factors that contribute
to oocyst resistance to a variety of environmental and chemical insults.
Due to the effectiveness
of sulphonamides against murine toxoplasmosis, reported by Sabin and Warren
(1942), and the synergistic effect of combined therapy with sulphonamides and
pyrimethamine, described by Eyles and Coleman (1953), these drugs form the basis
for the standard therapy regimens for toxoplasmosis in humans (Remington et
al. 2005). However, more than 50 years after the first assays on drug management
of toxoplasmosis, drug efficacy in the prevention of congenital toxoplasmosis
and the treatment of ocular disease is still a matter for debate, as reported
in five articles in this issue: (Chêne & Thiébaut, Gilbert,
McLeod et al., Stanford & Gilbert and Peyron). Research on drugs should
be one of the major goals of the next century, as emphasized in the presentations
of several delegates at the meeting. This is the ultimate goal of cell biology
studies, according to Sullivan et al. Development of a vaccine is another approach,
both to reducing Toxoplasma burden in animals destined for meat production
and to preventing human infection (Innes et al., Jongert et al.).
We can only honour
the legacy of the scientists awarded with the first edition of the Splendore
and Nicolle Medal (see the foreword of this issue) on the progress of research
in parasitology clinical management, diagnostics, immunology and molecular biology
of T. gondii. Their works have directed efforts not only on the basic
biology of the parasite but also in clinical management and public health areas
of Toxoplasma research worldwide. In the field of public health, there
are one review written by Tenter discussing the routes that are most important
from a public health point of view, considering the transmission of the parasite
to humans. It is also presented four articles in this issue with data from The
Netherlands (Kortbeek et al.), Italy (Stagni et al.) and Brazil, where infection
is a major health problem (Lopes et al., Varella et al.). On the topic of diagnosis,
articles are presented by Bessières et al., on congenital toxoplasmosis
in France, by Neves et al., on acute acquired toxoplasmosis, and by Mesquita
et al., on cerebral toxoplasmosis in peripheral blood samples from HIV-infected
patients in Brazil. G Holland presents an article on clinical management of
ocular disease entitled "Ocular toxoplasmosis: the influence of patient age",
in which the author discusses the influence of patient age on ocular toxoplasmosis,
concluding that it should be studied systematically in order to provide both
a better understanding of disease mechanisms and clinical information that may
be used to establish better treatment and prevention strategies. Comodaro et
al. present an overview and update on ocular toxoplasmosis, addressing many
misconceptions still found in the medical literature and Melamed presents a
history of the ocular toxoplasmosis knowledge gained from studies and observations
performed in Southern Brazil over the past 30 years.
Sadly, two months
prior to the meeting held last September, Dr. George Desmonts, one of scientist
who received the Splendore and Nicolle medal, died. However, his contribution
to toxoplasmosis research is immortalised in the literature. One example is
his and Jacques Couvreur's 1974 publication in the New England Journal of
Medicine (Desmonts & Courvreur 1974). This major publication revealed
the importance of maternal-foetal transmission of T. gondii and its devastating
consequences. This paper still remains a basic reference for anyone working
on toxoplasmosis.
In our opinion,
however, the major contribution by George Desmonts and his contemporary colleagues
was their effort to have congenital toxoplasmosis included in the list of diseases
that deserved special attention from the French public health authorities. The
inclusion of congenital toxoplasmosis in such a list resulted in the establishment
of a special programme to prevent, diagnose and treat congenital infections,
an example to be followed by many countries.
The present issue
of Memórias do Instituto Oswaldo Cruz is an homage not only to
the pioneers Alfonso Splendore, Charles Nicolle and Luis Manceaux, but also
to all the researchers and students who dedicated, continue to dedicate and
shall dedicate their efforts to understanding the fascinating biology of this
parasite and its relationships with hosts. This applies especially to those
who have fought relentlessly to include toxoplasmosis, particularly congenital
toxoplasmosis, in the list of diseases that are neglected and that deserve special
attention from public health authorities worldwide, especially in places with
alarming levels of infection. Finally, we extend this homage to toxoplasmosis
victims, many of whom will never see or benefit from the success of these research
efforts.
REFERENCES
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toxoplasmosis associated with municipal drinking water. The BC Toxoplasma
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LMG, Wada MY, Jones JL, Tuboi SH, Carmo EH, Ramalho WM, Camargo NJ, Trevisan
R, Graça, RMT, da Silva AJ, Moura I, Dubey JP, Garrett DO 2006. Waterborne
outbreak of toxoplasmosis, Brazil, from field to gene. Emerg Infect Dis 12:
326-329.
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J 1974. Congenital toxoplasmosis. A prospective study of 378 pregnancies. N
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pp.
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