Oral Route Driven Acute Trypanosoma cruzi Infection Unravels an IL-6 Dependent Hemostatic Derangement

Oral transmission of Trypanosoma cruzi, the etiologic agent of Chagas disease, is presently the most important route of infection in Brazilian Amazon. Other South American countries have also reported outbreaks of acute Chagas disease associated with food consumption. A conspicuous feature of this route of transmission is presenting symptoms such as facial and lower limbs edema, in some cases bleeding manifestations and risk of thromboembolism are evident. Notwithstanding, studies that address this route of infection are largely lacking regarding its pathogenesis and, more specifically, the crosstalk between immune and hemostatic systems. Here, BALB/c mice were orally infected with metacyclic trypomastigotes of T. cruzi Tulahuén strain and used to evaluate the cytokine response, primary and secondary hemostasis during acute T. cruzi infection. When compared with control uninfected animals, orally infected mice presented higher pro-inflammatory cytokine (TNF-α, IFN-γ, and IL-6) serum levels. The highest concentrations were obtained concomitantly to the increase of parasitemia, between 14 and 28 days post-infection (dpi). Blood counts in the oral infected group revealed concomitant leukocytosis and thrombocytopenia, the latter resulting in increased bleeding at 21 dpi. Hematological changes paralleled with prolonged activated partial thromboplastin time, Factor VIII consumption and increased D-dimer levels, suggest that oral T. cruzi infection relies on disseminated intravascular coagulation. Remarkably, blockade of the IL-6 receptor blunted hematological abnormalities, revealing a critical role of IL-6 in the course of oral infection. These results unravel that acute T. cruzi oral infection results in significant alterations in the hemostatic system and indicates the relevance of the crosstalk between inflammation and hemostasis in this parasitic disease

The BINGO Project IX: Search for Fast Radio Bursts -- A Forecast for the BINGO Interferometry System

The Baryon Acoustic Oscillations (BAO) from Integrated Neutral Gas Observations (BINGO) radio telescope will use the neutral Hydrogen emission line to map the Universe in the redshift range $0.127 \le z \le 0.449$, with the main goal of probing BAO. In addition, the instrument optical design and hardware configuration support the search for Fast Radio Bursts (FRBs). In this work, we propose the use of a BINGO Interferometry System (BIS) including new auxiliary, smaller, radio telescopes (hereafter \emph{outriggers}). The interferometric approach makes it possible to pinpoint the FRB sources in the sky. We present here the results of several BIS configurations combining BINGO horns with and without mirrors ($4$ m, $5$ m, and $6$ m) and 5, 7, 9, or 10 for single horns. We developed a new {\tt Python} package, the {\tt FRBlip}, which generates synthetic FRB mock catalogs and computes, based on a telescope model, the observed signal-to-noise ratio (S/N) that we used to compute numerically the detection rates of the telescopes and how many interferometry pairs of telescopes (\emph{baselines}) can observe an FRB. FRBs observed by more than one baseline are the ones whose location can be determined. We thus evaluate the performance of BIS regarding FRB localization. We found that BIS will be able to localize 23 FRBs yearly with single horn outriggers in the best configuration (using 10 outriggers of 6 m mirrors), with redshift $z \leq 0.96$; the full localization capability depends on the number and the type of the outriggers. Wider beams are best to pinpoint FRB sources because potential candidates will be observed by more baselines, while narrow beams look deep in redshift. The BIS can be a powerful extension of the regular BINGO telescope, dedicated to observe hundreds of FRBs during Phase 1. Many of them will be well localized with a single horn + 6 m dish as outriggers.(Abridged)Comment: 12 pages, 9 figures, 5 tables, submitted to A&

The BINGO Project VI: HI Halo Occupation Distribution and Mock Building

BINGO (Baryon Acoustic Oscillations from Integrated Neutral Gas Observations.) is a radio telescope designed to survey from 980 MHz to 1260 MHz, observe the neutral Hydrogen (HI) 21-cm line and detect BAO (Baryon Acoustic Oscillation) signal with Intensity Mapping technique. Here we present our method to generate mock maps of the 21-cm Intensity Mapping signal covering the BINGO frequency range and related test results. (Abridged)Comment: 16 pages, 20 figures, 1 table. Accepted for publication in A&

The BINGO Project IV: Simulations for mission performance assessment and preliminary component separation steps

The large-scale distribution of neutral hydrogen (HI) in the Universe is luminous through its 21 cm emission. The goal of the Baryon Acoustic Oscillations from Integrated Neutral Gas Observations -- BINGO -- radio telescope is to detect baryon acoustic oscillations (BAOs) at radio frequencies through 21 cm intensity mapping (IM). The telescope will span the redshift range 0.127 $< z <$ 0.449 with an instantaneous field-of-view of $14.75^{\circ} \times 6.0^{\circ}$. In this work we investigate different constructive and operational scenarios of the instrument by generating sky maps as they would be produced by the instrument. In doing this we use a set of end-to-end IM mission simulations. The maps will additionally be used to evaluate the efficiency of a component separation method (GNILC). We have simulated the kind of data that would be produced in a single-dish IM experiment such as BINGO. According to the results obtained, we have optimized the focal plane design of the telescope. In addition, the application of the GNILC method on simulated data shows that it is feasible to extract the cosmological signal across a wide range of multipoles and redshifts. The results are comparable with the standard principal component analysis method.Comment: 16 pages. Version to appear in A&

Avaliação da subpopulação celular CD8+ expandida durante a fase aguda da infecção por Trypanosoma cruzi após tratamento com benznidazol

A infecção pelo Trypanosoma cruzi é sistêmica e induz importantes alterações em órgãos linfoides e na dinâmica de distribuição das subpopulações celulares envolvidas na resposta imunológica. Através do presente trabalho demonstramos que o modelo experimental utilizando camundongos C57BL/6 infectados pela cepa Y de Trypanosoma cruzi apresentou importantes alterações na distribuição linfocitária esplênica após tratamento com benznidazol (Bz). Através de análises por citometria de fluxo, constatamos que o grupo infectado (I) apresenta diminuição simultânea da frequência de células B, células T CD4+ e células T CD8+ em relação aos grupos normal (N) e infectado e tratado com Bz (IBz). Por outro lado, neste último, evidenciamos que o tratamento atenuou a diminuição de células T CD4+ e de células B ocasionada pela infecção e, mais importante, expandiu a subpopulação de células T CD8+. Nestas, detectamos menor estado de ativação recente frente ao grupo I, porém, ambos os grupos apresentaram menor frequência de células T CD8+CD44LowCD62L High e similar frequência de células T CD8+CD44LowCD62LHigh, em comparação ao grupo controle. A avaliação ex vivo da produção de IFN- por células T CD8 revelou que os grupos I e IBz apresentaram maior produção de IFN- em relação ao grupo N; entretanto, não houve diferença de produção de IFN- entre os grupos I e IBz. Em contraposição, após a separação de céluals T CD8+ e estimulação in vitro com anti-CD3 e anti-CD28 durante 36 horas, detectamos que as células dos animais do grupo IBz manifestaram maior produção de IFN- em relação aos outros grupos experimentais. A análise do perfil fenotípico de celulas T CD8 de animais dos grupos I e IBz revelou uma alta frequência de células T com baixa expressão da molécula CD8 (fenótipo CD8low) e, particularmente, dentro da subpopulação de células T CD8+ produtoras de IFN-. Nesse sentido, observamos um aumento importante da frequência de células T CD8Low dentro da subpopulação de linfócitos CD3+ no baço desses animais. Nossos resultados revelaram ainda que a subpopulação de células com fenótipo CD8+CD44LowCD62LHigh apresentam baixa frequência de células com o perfil CD8Low. É importante salientar que, embora a diminuição da expressão de CD8 (definida pela mediana da intensidade de fluorescência) tenha sido maior no grupo IBz quando comparado ao grupo I, não constatamos diferença na proporção de células CD8Low quando analisamos a partição entre CD8Low/CD8 nestes dois grupos. Visto que o potencial de resposta de células T CD8Low pode ser importante para o controle de infecções virais e parasitárias, a investigação do significado biológico/funcional da modulação negativa da molécula CD8 podem ser necessários para a efetiva compreensão da participação destas células na resposta imune antígeno específicaWe present herein a Trypanosoma cruzi infection model focusing in changes of splenic lymphocyte distribution following benznidazol (Bz) treatment. Our evaluation indicates that the infected group (I) presents decrease in the relative frequency of B cells and both CD4+ and CD8+ T cells as compared with control group (N) and infected and Bz treated (IBZ) groups. Furthermore, we observed that treatment attenuated the decrease in CD4+ T cells and B cells caused by infection, and expanded the subpopulation of CD8+ T cells. This subset also showed decrease state of recent activation, as compared to group I, but both groups showed lower frequency of CD8+CD44LowCD62LHigh and similar frequency CD8+CD44LowCD62LHigh, when compared to N group. Ex vivo evaluation of IFN- by CD8 T cells revealed that either I and IBZ groups produced similarly increased levels compared to the control group N. In contrast, in vitro stimulation of CD8+ T cells from infected and Bz treated mice showed increased production of IFN- when compared to either control and infected groups. Interestingly, phenotypical analysis of of CD8+ T cells from I and IBz groups revealed a high frequency of low CD8-expressor cells. Moreover, we observed a significant increase in the frequency of CD8Low T cells within the splenic subpopulation of CD3+ lymphocytes from these animals. Our results also showed that a low frequency of CD8Low cells was found within the subset of effector/memory cells. Importantly, although the lowest CD8 expression (defined by median of fluorescence intensity) was seen in IBz group, no difference in the proportion of CD8Low/CD8 cells between these two groups. Since the potential of CD8Low T cells response may be important in the control of viral and parasitic infections, investigation of the biological/ functional significance of the negative modulation of the CD8 molecule may be required to effectively understand the role of these cells in antigen specific immune response58f

CD8low T cells expanded following acute Trypanosoma cruzi infection and benznidazole treatment are a relevant subset of IFN-γ producers.

CD8 T cells are regarded as pivotal players in both immunoprotection and immunopathology following Trypanosoma cruzi infection. Previously, we demonstrated the expansion of CD8+ T lymphocytes in the spleen of T. cruzi-infected mice under treatment with benznidazole (N-benzyl-2-nitroimidazole acetamide; Bz), a drug available for clinical therapy. This finding underlies the concept that the beneficial effects of Bz on controlling acute T. cruzi infection are related to a synergistic process between intrinsic trypanocidal effect and indirect triggering of the active immune response. In the present study, we particularly investigated the effect of Bz treatment on the CD8+ T cell subset following T. cruzi infection. Herein we demonstrated that, during acute T. cruzi infection, Bz treatment reduces and abbreviates the parasitemia, but maintains elevated expansion of CD8+ T cells. Within this subset, a remarkable group of CD8low cells was found in both Bz-treated and non-treated infected mice. In Bz-treated mice, early pathogen control paralleled the lower frequency of recently activated CD8low cells, as ascertained by CD69 expression. However, the CD8low subset sustains significant levels of CD44highCD62Llow and CD62LlowT-bethigh effector memory T cells, in both Bz-treated and non-treated infected mice. These CD8low cells also comprise the main group of spontaneous interferon (IFN)-γ-producing CD8+ T cells. Interestingly, following in vitro anti-CD3/CD28 stimulation, CD8+ T cells from Bz-treated T. cruzi-infected mice exhibited higher frequency of IFN-γ+ cells, which bear mostly a CD8low phenotype. Altogether, our results point to the marked presence of CD8low T cells that arise during acute T. cruzi infection, with Bz treatment promoting their significant expansion along with a potential effector program for high IFN-γ production

Oral Route Driven Acute Trypanosoma cruzi Infection Unravels an IL-6 Dependent Hemostatic Derangement

Submitted by Sandra Infurna ([email protected]) on 2019-07-04T15:19:44Z No. of bitstreams: 1 WilsonSavino_DinaAntunes_etal_IOC_2019.pdf: 2958086 bytes, checksum: 06fc5810e00b55cc4b92335c1120548b (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2019-07-04T15:30:53Z (GMT) No. of bitstreams: 1 WilsonSavino_DinaAntunes_etal_IOC_2019.pdf: 2958086 bytes, checksum: 06fc5810e00b55cc4b92335c1120548b (MD5)Made available in DSpace on 2019-07-04T15:30:53Z (GMT). No. of bitstreams: 1 WilsonSavino_DinaAntunes_etal_IOC_2019.pdf: 2958086 bytes, checksum: 06fc5810e00b55cc4b92335c1120548b (MD5) Previous issue date: 2019Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Instituto Nacional de CIência e Tecnologia em NeuroimunoModulação. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Instituto Nacional de CIência e Tecnologia em NeuroimunoModulação. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Instituto Nacional de CIência e Tecnologia em NeuroimunoModulação. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Instituto Nacional de CIência e Tecnologia em NeuroimunoModulação. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Doenças Parasitárias. Rio de Janeiro, RJ. Brasil.undação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Instituto Nacional de CIência e Tecnologia em NeuroimunoModulação. Rio de Janeiro, RJ, Brasil.undação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Instituto Nacional de CIência e Tecnologia em NeuroimunoModulação. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica Leopoldo de Meis. Rio de Janeiro, RJ, Brasil.undação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Instituto Nacional de CIência e Tecnologia em NeuroimunoModulação. Rio de Janeiro, RJ, Brasil.Oral transmission of Trypanosoma cruzi, the etiologic agent of Chagas disease, is presently the most important route of infection in Brazilian Amazon. Other South American countries have also reported outbreaks of acute Chagas disease associated with food consumption. A conspicuous feature of this route of transmission is presenting symptoms such as facial and lower limbs edema, in some cases bleeding manifestations and risk of thromboembolism are evident. Notwithstanding, studies that address this route of infection are largely lacking regarding its pathogenesis and, more specifically, the crosstalk between immune and hemostatic systems. Here, BALB/c mice were orally infected with metacyclic trypomastigotes of T. cruzi Tulahuén strain and used to evaluate the cytokine response, primary and secondary hemostasis during acute T. cruzi infection. When compared with control uninfected animals, orally infected mice presented higher pro-inflammatory cytokine (TNF-α, IFN-γ, and IL-6) serum levels. The highest concentrations were obtained concomitantly to the increase of parasitemia, between 14 and 28 days post-infection (dpi). Blood counts in the oral infected group revealed concomitant leukocytosis and thrombocytopenia, the latter resulting in increased bleeding at 21 dpi. Hematological changes paralleled with prolonged activated partial thromboplastin time, Factor VIII consumption and increased D-dimer levels, suggest that oral T. cruzi infection relies on disseminated intravascular coagulation. Remarkably, blockade of the IL-6 receptor blunted hematological abnormalities, revealing a critical role of IL-6 in the course of oral infection. These results unravel that acute T. cruzi oral infection results in significant alterations in the hemostatic system and indicates the relevance of the crosstalk between inflammation and hemostasis in this parasitic disease

The BINGO Project VII: Cosmological Forecasts from 21cm Intensity Mapping

The 21cm line of neutral hydrogen (HI) opens a new avenue in our exploration of the structure and evolution of the Universe. It provides complementary data to the current large-scale structure observations with different systematics, and thus it will be used to improve our understanding of the $\Lambda$CDM model. Among several radio cosmological surveys designed to measure this line, BINGO is a single-dish telescope mainly designed to detect baryon acoustic oscillations (BAOs) at low redshifts ($0.127< z<0.449$). Our goal is to assess the fiducial BINGO setup and its capabilities of constraining the cosmological parameters, and to analyze the effect of different instrument configurations. We used the Phase 1 fiducial configuration of the BINGO telescope to perform our cosmological forecasts. In addition, we investigated the impact of several instrumental setups, taking into account some instrumental systematics, and different cosmological models. Combining BINGO with Planck temperature and polarization data, the projected constraint improves from a $13\%$ and $25\%$ precision measurement at the $68\%$ confidence level with Planck only to $1\%$ and $3\%$ for the Hubble constant and the dark energy equation of state (EoS), respectively, within the wCDM model. Assuming a Chevallier-Polarski-Linder parameterization, the EoS parameters have standard deviations given by $\sigma_{w_0} = 0.30$ and $\sigma_{w_a} = 1.2$, which are improvements on the order of $30\%$ with respect to Planck alone. Also, we can access information about the HI density and bias, obtaining $\sim 8.5\%$ and $\sim 6\%$ precision, respectively, assuming they vary with redshift at three independent bins. The fiducial BINGO configuration will be able to extract significant cosmological information from the HI distribution and provide constraints competitive with current and future cosmological surveys. (Abridged)Comment: 22 pages, accepted for publication in A&

Testing synchrotron models and frequency resolution in BINGO 21 cm simulated maps using GNILC

To recover the 21 cm hydrogen line, it is essential to separate the cosmological signal from the much stronger foreground contributions at radio frequencies. The BINGO radio telescope is designed to measure the 21 cm line and detect BAOs using the intensity mapping technique. This work analyses the performance of the GNILC method, combined with a power spectrum debiasing procedure. The method was applied to a simulated BINGO mission, building upon previous work from the collaboration. It compares two different synchrotron emission models and different instrumental configurations, in addition to the combination with ancillary data to optimize both the foreground removal and recovery of the 21 cm signal across the full BINGO frequency band, as well as to determine an optimal number of frequency bands for the signal recovery. We have produced foreground emissions maps using the Planck Sky Model, the cosmological Hi emission maps are generated using the FLASK package and thermal noise maps are created according to the instrumental setup. We apply the GNILC method to the simulated sky maps to separate the Hi plus thermal noise contribution and, through a debiasing procedure, recover an estimate of the noiseless 21 cm power spectrum. We found a near optimal reconstruction of the Hi signal using a 80 bins configuration, which resulted in a power spectrum reconstruction average error over all frequencies of 3%. Furthermore, our tests showed that GNILC is robust against different synchrotron emission models. Finally, adding an extra channel with CBASS foregrounds information, we reduced the estimation error of the 21 cm signal. The optimisation of our previous work, producing a configuration with an optimal number of channels for binning the data, impacts greatly the decisions regarding BINGO hardware configuration before commissioning