Chagas disease (CD), caused by the protozoan Trypanosoma cruzi ( T. cruzi ), is the main parasitic disease in the Western Hemisphere. Unfortunately, its physiopathology is not completely understood, and cardiomegaly development is hard to predict. Trying to explain tissue lesion and the fact that only a percentage of the infected individuals develops clinical manifestations, a variety of mechanisms have been suggested as the provokers of CD, such as parasite persistence and autoimmune responses. However, holistic analysis of how parasite and host-related elements may connect to each other and influence clinical outcome is still scarce in the literature. Here, we investigated murine models of CD caused by three different pathogen strains: Colombian, CL Brener and Y strains, and employed parasitological and immunological tests to determine parasite load, antibody reactivity, and cytokine production during the acute and chronic phases of the disease. Also, we developed a quantitative PCR (qPCR) protocol to quantify T. cruzi kDNA minicircle integration into the mammalian host genome. Finally, we used a correlation analysis to interconnect parasite- and host-related factors over time. Higher parasite load in the heart and in the intestine was significantly associated with IgG raised against host cardiac proteins. Also, increased heart and bone marrow parasitism was associated with a more intense leukocyte infiltration. kDNA integration rates correlated to the levels of IgG antibodies reactive to host cardiac proteins and interferon production, both influencing tissue inflammation. In conclusion, our results shed light into how inflammatory process associates with parasite load, kDNA transfer to the host, autoreactive autoantibody production and cytokine profile. Altogether, our data support the proposal of an updated integrative theory regarding CD pathophysiology.

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BACKGROUND Studies aimed at validating canine visceral leishmaniasis diagnostic tests present heterogeneous results regarding test accuracy, partly due to divergences in reference standards used and different infection evolution periods in animals. OBJECTIVE This study aimed to evaluate the accuracy of the rapid test-dual path platform (TR-DPP) (Biomanguinhos®), EIE-Leishmaniose-Visceral-Canina-Biomanguinhos (EIE-LVC) (Biomanguinhos®), enzyme-linked immunosorbent assay (ELISA) rK39 (in-house), and the direct agglutination test (DAT- Canis ) against a reference standard comprising parasitological and molecular techniques. METHODS A phase II/III validation study was carried out in sample sera from 123 predominantly asymptomatic dogs living in an area endemic for visceral leishmaniasis. FINDINGS Sixty-nine (56.1%) animals were considered infected according to the reference standard. For each test, the sensitivity and specificity, respectively, were as follows: TR-DPP, 21.74% [confidence interval (CI)95% 13.64% to 32.82%] and 92.59% (CI95% 82.45% to 97.08%); EIE-LVC, 11.59% (CI95% 5.9% to 21.25%) and 90.74% (CI95% 80.09% to 95.98%); ELISA rK39, 37.68% (CI95% 27.18% to 49.48%) and 83.33% (CI95% 71.26% to 90.98%); and DAT- Canis , 18.84% (CI95% 11.35% to 29.61%) and 96.30% (CI95% 87.46% to 98.98%). CONCLUSION We concluded that improving the sensitivity of serum testing for diagnosing asymptomatic dogs must constitute a priority in the process of developing new diagnostic tests to be used in the visceral leishmaniasis control program in Brazil.

The proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but are completely silenced after differentiation to macrophages. The molecular mechanisms of the extraordinarily dynamic transcriptional regulation of S100a8 and S100a9 genes, however, are only barely understood. Using an unbiased genome-wide CRISPR/Cas9 knockout based screening approach in immortalized murine monocytes we identified the transcription factor C/EBPδ as a central regulator of S100a8 and S100a9 expression. We showed that S100A8/A9 expression and thereby neutrophil recruitment and cytokine release were decreased in C/EBPδ KO mice in a mouse model of acute lung inflammation. S100a8 and S100a9 expression was further controlled by the C/EBPδ-antagonists ATF3 and FBXW7. We confirmed the clinical relevance of this regulatory network in subpopulations of human monocytes in a clinical cohort of cardiovascular patients. Moreover, we identified specific C/EBPδ-binding sites within S100a8 and S100a9 promoter regions, and demonstrated that C/EBPδ-dependent JMJD3-mediated demethylation of H3K27me3 is indispensable for their expression. Overall, our work uncovered C/EBPδ as a novel regulator of S100a8 and S100a9 expression. Therefore, C/EBPδ represents a promising target for modulation of inflammatory conditions that are characterised by S100a8 and S100a9 overexpression.

Introduction: Chagas disease (CD), a neglected endemic disease in Latin America, has acquired new epidemiological characteristics with an increase in the importance of alternative transmission routes such as congenital transmission. We evaluated the scientific research on this subject. Methods: We searched the Scielo, BVS, and PubMed databases from 2006 to 2017. Results: We identified a small number of published articles, mostly in journals with an impact factor less than 3.0. Studies on human congenital transmission of CD were carried out in only seven different countries. Conclusions: Our data highlight the lack of research on congenital CD.