Host-parasite dynamics in Chagas disease from systemic to hyper-local scales

Trypanosoma cruzi is a remarkably versatile parasite. It can parasitize almost any nucleated cell type and naturally infects hundreds of mammal species across much of the Americas. In humans it is the cause of Chagas disease, a set of mainly chronic conditions predominantly affecting the heart and gastrointestinal tract that can progress to become life threatening. Yet around two thirds of infected people are long-term asymptomatic carriers. Clinical outcomes depend on many factors, but the central determinant is the nature of the host-parasite interactions that play out over the years of chronic infection in diverse tissue environments. In this review, we aim to integrate recent developments in the understanding of the spatial and temporal dynamics of T. cruzi infections with established and emerging concepts in host immune responses in the corresponding phases and tissues

Distinct monocyte subset phenotypes in patients with different clinical forms of chronic Chagas disease and seronegative dilated cardiomyopathy

BACKGROUND: Chronic infection with Trypanosoma cruzi leads to a constant stimulation of the host immune system. Monocytes, which are recruited in response to inflammatory signals, are divided into classical CD14hiCD16-, non-classical CD14loCD16+ and intermediate CD14hiCD16+ subsets. In this study, we evaluated the frequencies of monocyte subsets in the different clinical stages of chronic Chagas disease in comparison with the monocyte profile of seronegative heart failure subjects and seronegative healthy controls. The effect of the anti-parasite drug therapy benznidazole on monocyte subsets was also explored. METHODOLOGY/PRINCIPAL FINDINGS: The frequencies of the different monocyte subsets and their phenotypes were measured by flow cytometry. Trypanosoma cruzi-specific antibodies were quantified by conventional serological tests. T. cruzi-infected subjects with mild or no signs of cardiac disease and patients suffering from dilated cardiomyopathy unrelated to T. cruzi infection showed increased levels of non-classical CD14loCD16+ monocytes compared with healthy controls. In contrast, the monocyte profile in T. cruzi-infected subjects with severe cardiomyopathy was skewed towards the classical and intermediate subsets. After benznidazole treatment, non-classical monocytes CD14loCD16+ decreased while classical monocytes CD14hiCD16-increased. CONCLUSIONS/SIGNIFICANCE: The different clinical stages of chronic Chagas disease display distinct monocyte profiles that are restored after anti-parasite drug therapy. T. cruzi-infected subjects with severe cardiac disease displayed a profile of monocytes subsets suggestive of a more pronounced inflammatory environment compared with subjects suffering from heart failure not related to T. cruzi infection, supporting that parasite persistence might also alter cell components of the innate immune system

Variación geróntica intraespecífica en el bivalvo Antártico Retrotapes antarcticus

Retrotapes antarcticus, del Eoceno de Antártida, presenta dos morfotipos diferentes, uno con valvas planas y otro con valvas globosas. Autores previos propusieron que la especie actual Retrotapes exalbidus muestra los mismos morfotipos. Este trabajo evalúa el morfotipo globoso versus el plano, comparando ambas especies a través de un análisis de Contornos Elípticos de Fourier utilizando 17 valvas de R. antarcticus y 40 valvas de R. exalbidus. Luego se realizó un análisis de componentes principales y la edad de ambos morfotipos fue estimada a través del conteo de las líneas de crecimiento en la dirección del mismo. Varios autores argumentaron que las diferencias genéticas entre ambos morfotipos de R. exalbidus no permiten considerarlos como especies distintas y plantearon que tal vez los morfotipos globosos se correspondan con especímenes gerontes. Nuestros resultados demuestran que la variación registrada en R. antarcticus es igual a la observada en R. exalbidus. El análisis de las líneas de crecimiento confirma que el morfotipo globoso corresponde a especímenes gerontes en ambas especies. Esto constituye un ejemplo de variación intraespecífica geróntica. Además, esta contribución nos permite conocer más acerca del modo de vida del bivalvo fósil R. antarcticus, debido a que presentan un patrón de crecimiento similar al de la especie viviente.The bivalve Retrotapes antarcticus, from the Eocene of Antarctica, includes two different morphotypes of which one presents flat valves while the other one exhibits globoid valves. Previous authors have identified the same two morphotypes in the extant species Retrotapes exalbidus. This paper assesses the flat versus globoid morphotypes via comparing the two species by analyzing Elliptic Fourier Contours of 17 valves of R. antarcticus and 40 valves of R. exalbidus. A principal component analysis was performed and the age of both morphotypes was estimated by way of counting growth lines. Several authors have argued that genetic differences between the two forms of R. exalbidus are not sufficient to separate them into two distinct species and suspected that the globoid morphotype may correspond to gerontic specimens. Our results demonstrate that the morphological transformation detected in R. antarcticus is similar to that observed in R. exalbidus. The analysis of growth lines confirms that the globoid morphotype corresponds to gerontic specimens in both species. This constitutes an example of gerontic intraspecific variation. Additionally, this contribution allows us to further understand the life-history of the fossil bivalve R. antarcticus for it presents a growth pattern akin to that of the living species.Fil: Alvarez, Maximiliano Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; ArgentinaFil: Pérez Mazliah, Damián Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentin

New Record of a Phocid (Mammalia, Carnivora, Phocidae) in the Late Miocene of Patagonia, Argentina

South American Fossil records of seals is restricted to a few locations in Peru, Chile and Argentina. In the Late Miocene of Argentina, two species has been reported: Kawas benegasorum (Puerto Madryn Fm.), known only for postcranial remains; and Properiptychus argentinus (Parana Fm.). We describe a new record from Puerto Madryn Fm. MACN-Pv 20064 corresponds to a fragment of right hemimandible without teeth. It is assigned to the Phocidae and differs from P. argentinus by being more robust, slightly more convex and presenting a smooth texture. A more precise identification is not possible, leaving this new record as Phocidae indet.Fil: Echarri, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; ArgentinaFil: Pérez Mazliah, Damián Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Geología y Paleontología; ArgentinaFil: Miñana, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; ArgentinaFil: Lucero, Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentin

Allopurinol reduces antigen-specific and polyclonal activation of human T cells

Allopurinol is the most popular commercially available xanthine oxidase inhibitor and it is widely used for treatment of symptomatic hyperuricaemia, or gout. Although, several anti-inflammatory actions of allopurinol have been demonstrated in vivo and in vitro, there have been few studies on the action of allopurinol on T cells. In the current study, we have assessed the effect of allopurinol on antigen-specific and mitogen-driven activation and cytokine production in human T cells. Allopurinol markedly decreased the frequency of IFN-γ and IL-2-producing T cells, either after polyclonal or antigen-specific stimulation with Herpes Simplex virus 1, Influenza (Flu) virus, tetanus toxoid and Trypanosoma cruzi-derived antigens. Allopurinol attenuated CD69 upregulation after CD3 and CD28 engagement and significantly reduced the levels of spontaneous and mitogen-induced intracellular reactive oxygen species in T cells. The diminished T cell activation and cytokine production in the presence of allopurinol support a direct action of allopurinol on human T cells, offering a potential pharmacological tool for the management of cell-mediated inflammatory diseases

Changes in Trypanosoma cruzi-specific immune responses after treatment: surrogate markers of treatment efficacy

Fil: Laucella, Susana A. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Mazliah, Damián Pérez. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Bertocchi, Graciela. Hospital Interzonal General de Agudos "Eva Perón"; Argentina.Fil: Alvarez, María G. Hospital Interzonal General de Agudos "Eva Perón"; Argentina.Fil: Cooley, Gretchen. Center for Tropical and Emerging Global Diseases; Estados Unidos.Fil: Viotti, Rodolfo. Hospital Interzonal General de Agudos "Eva Perón"; Argentina.Fil: Albareda, María Cecilia. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Lococo, Bruno. Hospital Interzonal General de Agudos "Eva Perón"; Argentina.Fil: Postan, Miriam. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Armenti, Alejandro. Hospital Interzonal General de Agudos "Eva Perón"; Argentina.Fil: Tarleton, Rick L. Center for Tropical and Emerging Global Diseases; Estados Unidos.Background: As many as 20 million people are living with Trypanosoma cruzi infection in Latin American, yet few receive any treatment. The major limitation in developing and evaluating potential new drugs for their efficacy is the lack of reliable tests to assess parasite burden and elimination. Methods: Adults volunteers with chronic T. cruzi infection were evaluated clinically and stratified according to the Kuschnir classification. Individuals with group 0 and group 1 clinical status were treated with benznidazole (5 mg/kg per day for 30 days). The changes in T. cruzi-specific T cell and antibody responses, as well as in clinical status, were measured periodically over the 3-5-year follow-up period and were compared with pretreatment conditions and with values in an untreated control group. Results: The frequency of peripheral interferon (IFN)-gamma-producing T cells specific for T. cruzi declined as early as 12 months after benznidazole treatment and subsequently became undetectable in a substantial proportion of treated subjects. In addition, decreases in antibody responses to a pool of recombinant T. cruzi proteins also decreased in many of these same subjects. The shift to negative IFN-gamma T cell responses was highly associated with an early increase in IFN-gamma-producing T cells with phenotypic features of effector/effector memory cells in a subset of subjects. Benznidazole treatment also resulted in an increase in naive and early differentiated memory-like CD8(+) T cells in a majority of subjects. Conclusions: Benznidazole treatment during chronic Chagas disease has a substantial impact on parasite-specific immune response that is likely indicative of treatment efficacy and cure

Perturbed T cell IL-7 receptor signaling in chronic Chagas disease

Fil: Albareda, María Cecilia. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Pérez-Mazliah, Damián E. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Natale, M. Ailén. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Castro Eiro, Melisa D. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Alvarez, María G. Hospital Interzonal General de Agudos Eva Perón; Argentina.Fil: Viotti, Rodolfo. Hospital Interzonal General de Agudos Eva Perón; Argentina.Fil: Bertocchi, Graciela. Hospital Interzonal General de Agudos Eva Perón; Argentina.Fil: Lococo, Bruno. Hospital Interzonal General de Agudos Eva Perón; Argentina.Fil: Tarleton, Rick L. enter for Tropical and Emerging Global Diseases, Athens, Georgia; Estados Unidos.Fil: Laucella, Susana A. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.We have previously demonstrated that immune responses in subjects with chronic Trypanosoma cruzi infection display features common to other persistent infections with signs of T cell exhaustion. Alterations in cytokine receptor signal transduction have emerged as one of the cell-intrinsic mechanisms of T cell exhaustion. In this study, we performed an analysis of the expression of IL-7R components (CD127 and CD132) on CD4(+) and CD8(+) T cells and evaluated IL-7-dependent signaling events in patients at different clinical stages of chronic chagasic heart disease. Subjects with no signs of cardiac disease showed a decrease in CD127(+)CD132(+) cells and a reciprocal gain of CD127(-)CD132(+) in CD8(+) and CD4(+) T cells compared with either patients exhibiting heart enlargement or uninfected controls. T. cruzi infection, in vitro, was able to stimulate the downregulation of CD127 and the upregulation of CD132 on T cells. IL-7-induced phosphorylation of STAT5 as well as Bcl-2 and CD25 expression were lower in T. cruzi-infected subjects compared with uninfected controls. The serum levels of IL-7 were also increased in chronic chagasic patients. The present study highlights perturbed IL-7/IL-7R T cell signaling through STAT5 as a potential mechanism of T cell exhaustion in chronic T. cruzi infection

Disruption of IL-21 Signaling Affects T Cell-B Cell Interactions and Abrogates Protective Humoral Immunity to Malaria

<div><p>Interleukin-21 signaling is important for germinal center B-cell responses, isotype switching and generation of memory B cells. However, a role for IL-21 in antibody-mediated protection against pathogens has not been demonstrated. Here we show that IL-21 is produced by T follicular helper cells and co-expressed with IFN-γ during an erythrocytic-stage malaria infection of <i>Plasmodium chabaudi</i> in mice. Mice deficient either in IL-21 or the IL-21 receptor fail to resolve the chronic phase of <i>P</i>. <i>chabaudi</i> infection and <i>P</i>. <i>yoelii</i> infection resulting in sustained high parasitemias, and are not immune to re-infection. This is associated with abrogated <i>P</i>. <i>chabaudi</i>-specific IgG responses, including memory B cells. Mixed bone marrow chimeric mice, with T cells carrying a targeted disruption of the <i>Il21</i> gene, or B cells with a targeted disruption of the <i>Il21r</i> gene, demonstrate that IL-21 from T cells signaling through the IL-21 receptor on B cells is necessary to control chronic <i>P</i>. <i>chabaudi</i> infection. Our data uncover a mechanism by which CD4+ T cells and B cells control parasitemia during chronic erythrocytic-stage malaria through a single gene, <i>Il21</i>, and demonstrate the importance of this cytokine in the control of pathogens by humoral immune responses. These data are highly pertinent for designing malaria vaccines requiring long-lasting protective B-cell responses.</p></div