Trypanosoma cruzi

Trypanosoma cruzi

Introduction

Trypanosoma cruzi is a protozoan parasite and the agent of human Chagas disease. Chagas disease is the highest impact infectious disease in Latin America and the most common cause of infectious myocarditis in the world ( Feldman and McNamara, 2000 ). Although human Chagas disease is a huge public health problem, humans are in fact only incidental hosts for T. cruzi. Trypanosoma cruzi is very widely distributed in many wild and domestic mammals and thus will never be eradicated. However, there is one major benefit to zoonotic infections like T. cruzi: the many hosts that T. cruzi infects besides humans, including rodents, canines, and nonhuman primates, make outstanding models for studying the immunology of T. cruzi infection, providing highly reliable information relevant to the human infections. Descriptions of the immune response to T. cruzi are all over the map, from suppressed and ineffective to overexuberant and disease promoting. However, the wealth of evidence shows that immunity to T. cruzi is generally highly effective, resulting in excellent control of parasite load and, occasionally, complete pathogen clearance. Unfortunately the consequence of the more common ‘control without elimination’ outcome is the cumulative tissue damage and increasing chances of clinical disease that become more severe with increasing length of infection. The mechanisms associated with effective control of T. cruzi infection are discussed more fully below.

Trypanosoma cruzi, is a parasitic protozoan that is the causative agent of Chagas disease (American trypanosomiasis). Currently, six distinct lineages of T. cruzi are classified into discrete typing units (TcI-VI), which vary in their geographic occurrence, host specificity, and pathogenicity.

Life Cycle

An infected triatomine insect vector (or “kissing” bug) takes a blood meal and releases trypomastigotes in its feces near the site of the bite wound. Trypomastigotes enter the host through the bite wound or intact mucosal membranes, such as the conjunctiva . Inside the host, the trypomastigotes invade cells near the site of inoculation, where they differentiate into intracellular amastigotes . The amastigotes multiply by binary fission and differentiate into trypomastigotes, and then are released into the circulation as bloodstream trypomastigotes . Trypomastigotes infect cells from a variety of tissues and transform into intracellular amastigotes in new infection sites. Clinical manifestations can result from this infective cycle. The bloodstream trypomastigotes do not replicate (different from the African trypanosomes). Replication resumes only when the parasites enter another cell or are ingested by another vector. The “kissing” bug becomes infected by feeding on human or animal blood that contains circulating parasites . The ingested trypomastigotes transform into epimastigotes in the vector’s midgut . The parasites multiply and differentiate in the midgut and differentiate into infective metacyclic trypomastigotes in the hindgut . Other less common routes of transmission include blood transfusions, organ transplantation, transplacental transmission, and foodborne transmission (via food/drink contaminated with the vector and/or its feces).

Hosts/Vectors

Apart from humans, a number of mammals serve as reservoir hosts for T. cruzi, e.g. armadillos, opossums, raccoons, woodrats, some other rodents, and domestic dogs. Common triatomine vector species for trypanosomiasis belong to the genera Triatoma, Rhodnius, and Panstrongylus.

Geographic Distribution

T. cruzi is endemic in vectors and wildlife reservoirs throughout the Americas from the southern half of the United States down to Argentina. Chagas disease cases have been reported from South and Central American countries, particularly in rural, impoverished areas. There have been a small number of autochthonous cases of Chagas disease in the United States.

Clinical Presentation

Chagas disease has an acute phase and chronic phase. The acute phase is usually asymptomatic, but can present with nonspecific somatic symptoms. Rarely, the acute phase may be more severe with potential cardiac or neurologic symptoms and signs. Nodular lesions or furuncles, usually called chagomas, may develop around the vector’s feeding site. Chagomas occurring on the on the eyelids are commonly referred to as palpebral and periocular firm swelling. Most acute cases resolve over a period of a few weeks or months into a subclinical chronic form of the disease (“indeterminate form”). Reactivation of Chagas disease from this asymptomatic form may occur in patients with HIV or those receiving immunosuppressive drugs.

The symptomatic chronic form (“determinate form”) may not occur for years or even decades after initial infection. This may include cardiac or gastrointestinal involvement, which occasionally occur together. The many complications of chronic Chagas disease can be fatal. Amastigote invasion of smooth muscle can lead to megaesophagus, megacolon, and dilated cardiomyopathy.

Reservoirwirte für Trypanosoma cruzi sind ca. 150 Haus- und Wildsäugetiere sowie der Mensch. Vektoren sind Raubwanzen wie z.B. Triatoma infestans. Raubwanzen meiden das Licht und nehmen die Erreger nachts mit ihrer Blutmahlzeit in ihrer trypomastigoten Form von infizierten Wirten auf.

Im Mittel- und Enddarm der Arthropoden (Gliederfüßer) wandeln sich die Trypomastigoten zunächst in Epimastigoten um, bei denen ein Replikationsprozess einsetzt. Geißelbasis und der Kinetoplast liegen beim Epimastigoten anterior vom Zellkern. Die Trypanosomen liegen in den Insekten in allen morphologischen Formen extrazellulär vor. Nach einer erneuten Wandlung werden sie als metazyklische, infektiöse Trypomastigoten über den Verdauungskanal des Insekts mit der Fäzes ausgeschieden.

Hinterlässt das Insekt seine Ausscheidungen auf der Haut, dringen die Trypomastigoten durch Mikroverletzungen in den Körper des Menschen oder eines anderen Wirts ein oder werden vom Wirt transkonjunktival eingebracht. Über das Blutgefäßsystem befallen die zirkulierenden Trypomastigoten dann glatte Muskelzellen, Zellen des retikuloendothelialen Systems und der Neuroglia. In den Zellen mutieren die Trypomastigoten zu unbegeißelten Amastigoten, bei denen eine ca. 4-tägige Vermehrungsphase einsetzt. Besonders in glatten Muskelzellen und Histiozyten können unter dem Mikroskop von Amastigoten geformte Pseudozysten beobachtet werden. Anschließend erfolgt eine erneute Umwandlung in die trypomastigote Form, die freigesetzt wird und extrazellulär durch hämatogene und lymphogene Streuung die Zellen weiterer Gewebe befällt, in denen der Umwandlungsprozess in die amastigote Form ein weiteres Mal einsetzt.

Morfologia

Durante o seu ciclo de vida, o T. cruzi pode apresentar três formas morfológicas: amastigota, epimastigota e tripomastigota.

  • Amastigota: apresenta forma arredondada. O núcleo e o cinetoplasto não são observados com microscópios ópticos. Não possui flagelos. Presente na fase intracelular, durante a fase crônica da doença.
  • Epimastigota: apresenta tamanho variável com formato alongado e núcleo semi-central. Representa a forma encontrada no tubo digestivo do barbeiro, o vetor da doença de chagas.
  • Tripomastigota: apresenta formato alongado e fusiforme em forma de “c” ou “s”. É a forma presente na fase extracelular, que circula no sangue, na fase aguda da doença. É a forma infectante para os vertebrados.

Trypanossoma cruzi em sua forma tripomastigota no sangue

Trattamento

Al momento non esiste un vaccino per la malattia di Chagas, ma sono disponibili due approcci terapeutici:

  • Trattamento antiparassitario, per eliminare o ridurre il numero di parassiti nel corpo;
  • Trattamento sintomatico, per gestire i sintomi e i segni di infezione.

La terapia con farmaci antiparassitari è più efficace se somministrata subito dopo l’infezione, al momento della comparsa della fase acuta. La malattia di Chagas può essere trattata con il benznidazole ed il nifurtimox; entrambi sono limitati nella capacità di garantire la guarigione parassitologica (cioè la completa eliminazione di T. cruzi dal corpo), specialmente nei pazienti con infezione cronica. Il trattamento eziologico è raccomandato per le persone in fase acuta e per i neonati con infezione congenita; può essere efficace anche per evitare la riattivazione della malattia (per esempio, in condizioni di immunosoppressione) e per i pazienti in fase cronica precoce. Le principali controindicazioni per il benznidazole ed il nifurtimox sono la gravidanza e l’insufficienza renale o epatica. Inoltre, il nifurtimox è controindicato per le persone con disturbi neurologici o psichiatrici.

La scelta dell’approccio terapeutico della malattia di Chagas spesso dipende dalla fase della malattia e dall’età del paziente. La prevalenza di effetti collaterali è inferiore se il paziente è di giovane età. Negli adulti infetti, soprattutto quelli con forma indeterminata, il trattamento eziologico può essere indicato, ma i potenziali benefici del farmaco — nel prevenire o ritardare lo sviluppo della malattia di Chagas — devono essere valutati rispetto alla lunga durata del protocollo terapeutico (fino a 2 mesi) e alle possibili reazioni avverse (che si verificano nel 40% dei pazienti trattati). Una volta che la tripanosomiasi americana raggiunge la fase cronica, i farmaci non sono efficaci nel curare la malattia.

Il trattamento sintomatico dipende dai segni e sintomi specifici e può aiutare le persone con manifestazioni cardiache o intestinali conseguenti alla malattia di Chagas.
Circa il 30% delle persone infette che non sono sottoposte a trattamento svilupperanno la forma cronica o sintomatica della tripanosomiasi americana. Dal momento del contagio iniziale, possono essere necessari più di 20 anni per sviluppare problemi cardiaci o la malattia chagasica digestiva. Le anomalie del ritmo cardiaco (aritmie, tachicardia ventricolare ecc.) possono causare la morte improvvisa. Se si sviluppa insufficienza cardiaca, la malattia di Chagas è fatale entro alcuni anni.

The protozoan Trypanosoma cruzi almost invariably establishes life-long infections in humans and other mammals, despite the development of potent host immune responses that constrain parasite numbers. The consistent, decades-long persistence of T. cruzi in human hosts arises at least in part from the remarkable level of genetic diversity in multiple families of genes encoding the primary target antigens of anti-parasite immune responses. However, the highly repetitive nature of the genome-largely a result of these same extensive families of genes-have prevented a full understanding of the extent of gene diversity and its maintenance in T. cruzi. In this study, we have combined long-read sequencing and proximity ligation mapping to generate very high-quality assemblies of two T. cruzi strains representing the apparent ancestral lineages of the species. These assemblies reveal not only the full repertoire of the members of large gene families in the two strains, demonstrating extreme diversity within and between isolates, but also provide evidence of the processes that generate and maintain that diversity, including extensive gene amplification, dispersion of copies throughout the genome and diversification via recombination and in situ mutations. Gene amplification events also yield significant copy number variations in a substantial number of genes presumably not required for or involved in immune evasion, thus forming a second level of strain-dependent variation in this species. The extreme genome flexibility evident in T. cruzi also appears to create unique challenges with respect to preserving core genome functions and gene expression that sets this species apart from related kinetoplastids.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 2. An example of homologous chromosomes…

Fig 2. An example of homologous chromosomes with large allelic variations.

(A) Synteny between two…

Fig 3. Protein best match analysis of…

Fig 3. Protein best match analysis of gene families between Brazil A4 and Y C6.

Fig 4. Gene amplification events in members…

Fig 4. Gene amplification events in members of large gene families.

(A) Tandem arrays of…

Fig 5. Examples of relocations of TS…

Fig 5. Examples of relocations of TS genes in Y C6.

(A) Tight clusters of…

Fig 6. The combination of gene amplification,…

Fig 6. The combination of gene amplification, relocation, recombination and in situ diversification of members…

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