Las Enfermedades Emergentes Desatendidas. Situación Nacional e Internacional

Las Enfermedades Desatendidas (ED) son un grupo de enfermedades infecciosas y parasitarias que secaracterizan por una inversión históricamente baja del sector farmacéutico y que afectan principalmente a laspoblaciones que viven en condiciones socioeconómicas de pobreza, con bajos ingresos y nivel educativo,vivienda precaria, carencia de acceso a servicios básicos como agua potable y saneamiento básico, en zonasde conflicto o en condiciones ambientales deterioradas, con escaso acceso a los servicios de salud. LaOrganización Mundial de la Salud (OMS) ha clasificado a 17 enfermedades infecciosas dentro de este grupo,donde cuatro de ellas, son consideradas, además, como Enfermedades Emergentes y Re-emergentes. Estasson: cisticercosis, rabia, enfermedad de Chagas y dengue. La OMS recomienda cinco estrategias de SaludPública para prevenir y controlar este grupo de enfermedades. Estos son: quimioterapia preventiva, manejointensificado de los casos, control de vectores, provisión de agua segura y estrategias de Salud Pública. Chileha logrado controlar algunas de estas enfermedades, a través de la implementación de algunas o varias deestas estrategias. Es así como, en el caso de la enfermedad de Chagas nuestro país ha logrado la interrupciónde la transmisión vectorial, a nivel domiciliario en el año 1999 y en el caso de la rabia, el último casoregistrado en humanos data del año 1996.  

Las Enfermedades Emergentes Desatendidas. Situación Nacional e Internacional

Las Enfermedades Desatendidas (ED) son un grupo de enfermedades infecciosas y parasitarias que secaracterizan por una inversión históricamente baja del sector farmacéutico y que afectan principalmente a laspoblaciones que viven en condiciones socioeconómicas de pobreza, con bajos ingresos y nivel educativo,vivienda precaria, carencia de acceso a servicios básicos como agua potable y saneamiento básico, en zonasde conflicto o en condiciones ambientales deterioradas, con escaso acceso a los servicios de salud. LaOrganización Mundial de la Salud (OMS) ha clasificado a 17 enfermedades infecciosas dentro de este grupo,donde cuatro de ellas, son consideradas, además, como Enfermedades Emergentes y Re-emergentes. Estasson: cisticercosis, rabia, enfermedad de Chagas y dengue. La OMS recomienda cinco estrategias de SaludPública para prevenir y controlar este grupo de enfermedades. Estos son: quimioterapia preventiva, manejointensificado de los casos, control de vectores, provisión de agua segura y estrategias de Salud Pública. Chileha logrado controlar algunas de estas enfermedades, a través de la implementación de algunas o varias deestas estrategias. Es así como, en el caso de la enfermedad de Chagas nuestro país ha logrado la interrupciónde la transmisión vectorial, a nivel domiciliario en el año 1999 y en el caso de la rabia, el último casoregistrado en humanos data del año 1996.  

Trypanosoma cruzi Evades the Complement System as an Efficient Strategy to Survive in the Mammalian Host: The Specific Roles of Host/Parasite Molecules and Trypanosoma cruzi Calreticulin

American Trypanosomiasis is an important neglected reemerging tropical parasitism, infecting about 8 million people worldwide. Its agent, Trypanosoma cruzi, exhibits multiple mechanisms to evade the host immune response and infect host cells. An important immune evasion strategy of T. cruzi infective stages is its capacity to inhibit the complement system activation on the parasite surface, avoiding opsonizing, immune stimulating and lytic effects. Epimastigotes, the non-infective form of the parasite, present in triatomine arthropod vectors, are highly susceptible to complement-mediated lysis while trypomastigotes, the infective form, present in host bloodstream, are resistant. Thus T. cruzi susceptibility to complement varies depending on the parasite stage (amastigote, trypomastigotes or epimastigote) and on the T. cruzi strain. To avoid complement-mediated lysis, T. cruzi trypomastigotes express on the parasite surface a variety of complement regulatory proteins, such as glycoprotein 58/68 (gp58/68), T. cruzi complement regulatory protein (TcCRP), trypomastigote decay-accelerating factor (T-DAF), C2 receptor inhibitor trispanning (CRIT) and T. cruzi calreticulin (TcCRT). Alternatively, or concomitantly, the parasite captures components with complement regulatory activity from the host bloodstream, such as factor H (FH) and plasma membrane-derived vesicles (PMVs). All these proteins inhibit different steps of the classical (CP), alternative (AP) or lectin pathways (LP). Thus, TcCRP inhibits the CP C3 convertase assembling, gp58/68 inhibits the AP C3 convertase, T-DAF interferes with the CP and AP convertases assembling, TcCRT inhibits the CP and LP, CRIT confers ability to resist the CP and LP, FH is used by trypomastigotes to inhibit the AP convertases and PMVs inhibit the CP and LP C3 convertases. Many of these proteins have similar molecular inhibitory mechanisms. Our laboratory has contributed to elucidate the role of TcCRT in the host-parasite interplay. Thus, we have proposed that TcCRT is a pleiotropic molecule, present not only in the parasite endoplasmic reticulum, but also on the trypomastigote surface, participating in key processes to establish T. cruzi infection, such as inhibition of the complement system and serving as an important virulence factor. Additionally, TcCRT interaction with key complement components, participates as an anti-angiogenic and anti-tumor molecule, inhibiting at least in important part, tumor growth in infected animals

Trypanosoma cruzi evades the complement system as an efficient strategy to survive in the Mammalian host: the specific roles of host/parasite molecules and Trypanosoma cruzi Calreticulin

American Trypanosomiasis is an important neglected reemerging tropical parasitism, infecting about 8 million people worldwide. Its agent, Trypanosoma cruzi, exhibits multiple mechanisms to evade the host immune response and infect host cells. An important immune evasion strategy of T. cruzi infective stages is its capacity to inhibit the complement system activation on the parasite surface, avoiding opsonizing, immune stimulating and lytic effects. Epimastigotes, the non-infective form of the parasite, present in triatomine arthropod vectors, are highly susceptible to complement-mediated lysis while trypomastigotes, the infective form, present in host bloodstream, are resistant. Thus T. cruzi susceptibility to complement varies depending on the parasite stage (amastigote, trypomastigotes or epimastigote) and on the T. cruzi strain. To avoid complement-mediated lysis, T. cruzi trypomastigotes express on the parasite surface a variety of complement regulatory proteins, such as glycoprotein 58/68 (gp58/68), T. cruzi complement regulatory protein (TcCRP), trypomastigote decay-accelerating factor (T-DAF), C2 receptor inhibitor trispanning (CRIT) and T. cruzi calreticulin (TcCRT). Alternatively, or concomitantly, the parasite captures components with complement regulatory activity from the host bloodstream, such as factor H (FH) and plasma membrane-derived vesicles (PMVs). All these proteins inhibit different steps of the classical (CP), alternative (AP) or lectin pathways (LP). Thus, TcCRP inhibits the CP C3 convertase assembling, gp58/68 inhibits the AP C3 convertase, T-DAF interferes with the CP and AP convertases assembling, TcCRT inhibits the CP and LP, CRIT confers ability to resist the CP and LP, FH is used by trypomastigotes to inhibit the AP convertases and PMVs inhibit the CP and LP C3 convertases. Many of these proteins have similar molecular inhibitory mechanisms. Our laboratory has contributed to elucidate the role of TcCRT in the host-parasite interplay. Thus, we have proposed that TcCRT is a pleiotropic molecule, present not only in the parasite endoplasmic reticulum, but also on the trypomastigote surface, participating in key processes to establish T. cruzi infection, such as inhibition of the complement system and serving as an important virulence factor. Additionally, TcCRT interaction with key complement components, participates as an anti-angiogenic and anti-tumor molecule, inhibiting at least in important part, tumor growth in infected animals.CONICYT-CHILE grants: FONDECYT regular 1130099 (AF), FONDECYT-Iniciación 11110251 (GR-T) and URC-024/16 (GR-T

Is the anti-tumor property of Trypanosoma cruzi infection mediated by its Calreticulin?

Eight to 10 million people in 21 endemic countries are infected with Trypanosoma cruzi. However, only 30% of those infected develop symptoms of Chagas’ disease, a chronic, neglected tropical disease worldwide. Similar to other pathogens, T. cruzi has evolved to resist the host immune response. Studies, performed 80 years ago in the Soviet Union, proposed that T. cruzi infects tumor cells with similar capacity to that displayed for target tissues such as cardiac, aortic or digestive. An antagonistic relationship between T. cruzi infection and cancer development was also proposed, but the molecular mechanisms involved have remained largely unknown. Probably, a variety of T. cruzi molecules is involved. This review focuses on how T. cruzi calreticulin (TcCRT), exteriorized from the endoplasmic reticulum, targets the first classical complement component C1 and negatively regulates the Classical Complement activation cascade, promoting parasite infectivity. We propose that this C1-dependent TcCRT-mediated virulence is critical to explain, at least an important part, of the parasite capacity to inhibit tumor development. We will discuss how TcCRT, by directly interacting with venous and arterial endothelial cells, inhibits angiogenesis and tumor growth. Thus, these TcCRT functions not only illustrate T. cruzi interactions with the host immune defensive strategies, but also illustrate a possible co-evolutionary adaptation to privilege a prolonged interaction with its host

The Interactions of Parasite Calreticulin With Initial Complement Components: Consequences in Immunity and Virulence

Because of its capacity to increase a physiologic inflammatory response, to stimulate phagocytosis, to promote cell lysis and to enhance pathogen immunogenicity, the complement system is a crucial component of both the innate and adaptive immune responses. However, many infectious agents resist the activation of this system by expressing or secreting proteins with a role as complement regulatory, mainly inhibitory, proteins.Trypanosoma cruzi, the causal agent of Chagas disease, a reemerging microbial ailment, possesses several virulence factors with capacity to inhibit complement at different stages of activation.T. cruzicalreticulin (TcCalr) is a highly-conserved, endoplasmic reticulum-resident chaperone that the parasite translocates to the extracellular environment, where it exerts a variety of functions. Among these functions, TcCalr binds C1, MBL and ficolins, thus inhibiting the classical and lectin pathways of complement at their earliest stages of activation. Moreover, the TcCalr/C1 interaction also mediates infectivity by mimicking a strategy used by apoptotic cells for their removal. More recently, it has been determined that these Calr strategies are also used by a variety of other parasites. In addition, as reviewed elsewhere, TcCalr inhibits angiogenesis, promotes wound healing and reduces tumor growth. Complement C1 is also involved in some of these properties. Knowledge on the role of virulence factors, such as TcCalr, and their interactions with complement components in host-parasite interactions, may lead toward the description of new anti-parasite therapies and prophylaxis.University of Toledo Biomedical Research Innovation Program, Toledo, Ohio, USA VID, University of Chile Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 1130099 CONICYT-REDES 17012

Trypanosoma cruzi calreticulin: immune evasion, infectivity, and tumorigenesis

To successfully infect, Trypanosome cruzi evades and modulates the host immune response. T. cruzi calreticulin (TcCalr) is a multifunctional, endoplasmic reticulum (ER)-resident chaperone that, translocated to the external microenvironment, mediates crucial host-parasite interactions. TcCalr binds and inactivates C1 and mannose-binding lectin (MBL)/ficolins, important pattern- recognition receptors (PRRs) of the complement system. Using an apoptotic mimicry strategy, the C1-TcCalr association facilitates the infection of target cells. T. cruzi infection also seems to confer protection against tumorigenesis. Thus, recombinant TcCalr has important antiangiogenic properties, detected in vitro, ex vivo, and in ovum, most likely contributing at least in part, to its antitumor properties. Consequently, TcCalr is useful for investigating key issues of host-parasite interactions and possible new immunological/pharmacological interventions in the areas of Chagas' disease and experimental cancer.Chilean FONDECYT/CONICYT 1050133 1095095 1130099 11110251 VID-Universidad de Chile FIV-FAVET 12101701-9102-181 URC-024/1

Molecular mechanisms involved in the inactivation of the first component of human complement by Trypanosoma cruzi calreticulin

Trypanosoma cruzi (T. cruzi), the agent of Chagas’ disease, the sixth most important neglected tropical disease worldwide, causes 50,000 deaths per year in Latin America. T. cruzi calreticulin (TcCRT), a highly pleiotropic chaperone molecule, plays important roles in several host/parasite interactions. Among other functions,wehave previously shown that TcCRT, translocated from the endoplasmic reticulum to the area of flagellar emergence, binds human C1q and inhibits activation of the classical pathway in vitro. Based on a series of in vitro experiments, we propose here two mechanisms to explain how TcCRT inhibits the classical pathway at the initial stages of C1 (q, r, s) activation. First, TcCRT interacts in vitro with both solid phase bound active C1s and C1, but impairment of C4 activating capacity is evident only when the serine proteases are within the structural context of the macromolecular first component. Although C1s activity, in this context, is inhibited by TcCRT, the serine protease is not displaced from the C1 complex. Second, TcCRT prevents C1 formation, by interfering with the ability of the (C1r–C1s)2 tetramer to bind C1q. These complement inhibitory effects are better explained by direct interaction of the parasite protein with C1, rather than by the TcCRT capacity to bind calcium, an essential element for the functional integrity of C1.Thisworkwassupported by Chilean Public Grants 1095095 from FONDECYT, and ACT-29 Bicentenial Research Project from CONICYT. C. Valck received a CONICYT Fellowship for Doctoral Training