The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

Leishmaniasis is a vector-borne infectious disease caused by different species of protozoa from the Leishmania genus. Classically, the disease can be classified into two main clinical forms: Visceral (VL) and Tegumentary (TL) leishmaniasis. TL is a skin/mucosal granulomatous disease that manifests mainly as cutaneous localized or disseminated ulcers, papules diffusely distributed, mucosal lesions or atypical lesions. Once the etiology of the infection is confirmed, treatment can take place, and different drugs can be administered. It has already been shown that, even when the scar is clinically evident, inflammation is still present in the native tissue, and the decrease of the inflammatory process occurs slowly during the 1st years after clinical healing. The maintenance of residual parasites in the scar tissue is also well documented. Therefore, it is no longer a surprise that, under some circumstances, therapeutic failure and/or lesion reactivation occurs. All over the years, an impressive amount of data on relapses, treatment resistance and lesion reactivation after healing has been collected, and several factors have been pointed out as having a role in the process. Different factors such as Leishmania species, parasite variability, Leishmania RNA virus 1, parasite load, parasite persistence, age, nutritional status, gender, co-morbidities, co-infection, pregnancy, immunosuppression, lesion duration, number and localization of lesions, drug metabolism, irregular treatment and individual host cellular immune response were described and discussed in the present review. Unfortunately, despite this amount of information, a conclusive understanding remains under construction. In addition, multifactorial influence cannot be discarded. In this context, knowing why leishmaniasis has been difficult to treat and control can help the development of new approaches, such as drugs and immunotherapy in order to improve healing maintenance. In this sense, we would like to highlight some of the findings that may influence the course of Leishmania infection and the therapeutic response, with an emphasis on TL

Trans-Atlantic spill over: deconstructing the ecological adaptation of Leishmania infantum in the Americas

Pathogen fitness landscapes change when transmission cycles establish in non-native environments or spill over into new vectors and hosts. The introduction of Leishmania infantum in the Americas into the Neotropics during European colonization represents a unique case study to investigate the mechanisms of ecological adaptation of this important parasite. Defining the evolutionary trajectories that drive L. infantum fitness in this new environment are of great public health importance as they will allow unique insight into pathways of host/pathogen co-evolution and their consequences for region-specific changes in disease manifestation. This review summarizes current knowledge on L. infantum genetic and phenotypic diversity in the Americas and its possible role in the unique epidemiology of visceral leishmaniasis (VL) in the New World. We highlight the importance of appreciating adaptive molecular mechanisms in L. infantum to understand the parasites’ successful establishment on the continent

Colonization and genetic diversification processes of Leishmania infantum in the Americas

Leishmania infantum causes visceral leishmaniasis, a deadly vector-borne disease introduced to the Americas during the colonial era. This non-native trypanosomatid parasite has since established widespread transmission cycles using alternative vectors, and human infection has become a significant concern to public health, especially in Brazil. A multi-kilobase deletion was recently detected in Brazilian L. infantum genomes and is suggested to reduce susceptibility to the anti-leishmanial drug miltefosine. We show that deletion-carrying strains occur in at least 15 Brazilian states and describe diversity patterns suggesting that these derive from common ancestral mutants rather than from recurrent independent mutation events. We also show that the deleted locus and associated enzymatic activity is restored by hybridization with non-deletion type strains. Genetic exchange appears common in areas of secondary contact but also among closely related parasites. We examine demographic and ecological scenarios underlying this complex L. infantum population structure and discuss implications for disease control

Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders: findings from the ENIGMA ADHD, ASD, and OCD Working Groups

Objective Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders

Infectious Diseases and the Lymphoid Extracellular Matrix Remodeling: A Focus on Conduit System

The conduit system was described in lymphoid organs as a tubular and reticular set of structures compounded by collagen, laminin, perlecan, and heparin sulfate proteoglycan wrapped by reticular fibroblasts. This tubular system is capable of rapidly transport small molecules such as viruses, antigens, chemokines, cytokines, and immunoglobulins through lymphoid organs. This structure plays an important role in guiding the cells to their particular niches, therefore participating in cell cooperation, antigen presentation, and cellular activation. The remodeling of conduits has been described in chronic inflammation and infectious diseases to improve the transport of antigens to specific T and B cells in lymphoid tissue. However, malnutrition and infectious agents may induce extracellular matrix remodeling directly or indirectly, leading to the microarchitecture disorganization of secondary lymphoid organs and their conduit system. In this process, the fibers and cells that compound the conduit system may also be altered, which affects the development of a specific immune response. This review aims to discuss the extracellular matrix remodeling during infectious diseases with an emphasis on the alterations of molecules from the conduit system, which damages the cellular and molecular transit in secondary lymphoid organs compromising the immune response

Is There Any Difference between the In Situ and Systemic IL-10 and IFN-γ Production when Clinical Forms of Cutaneous Sporotrichosis Are Compared?

Submitted by Sandra Infurna ([email protected]) on 2016-12-15T11:14:37Z No. of bitstreams: 1 fernanda_morgado_etal_IOC_2016.pdf: 4768094 bytes, checksum: 5ab755cd6bdf28be44e74b4620b05950 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2016-12-15T11:30:54Z (GMT) No. of bitstreams: 1 fernanda_morgado_etal_IOC_2016.pdf: 4768094 bytes, checksum: 5ab755cd6bdf28be44e74b4620b05950 (MD5)Made available in DSpace on 2016-12-15T11:30:54Z (GMT). No. of bitstreams: 1 fernanda_morgado_etal_IOC_2016.pdf: 4768094 bytes, checksum: 5ab755cd6bdf28be44e74b4620b05950 (MD5) Previous issue date: 2016Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunoparasitologia. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmaniose. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz, Instituto Nacional de Infectologia Evandro Chagas. Serviço de Infectologia - VigLeish. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz, Instituto Nacional de Infectologia Evandro Chagas. Serviço de Infectologia - VigLeish. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz, Instituto Nacional de Infectologia Evandro Chagas. Serviço de Infectologia - VigLeish. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz, Instituto Nacional de Infectologia Evandro Chagas. Serviço de Infectologia - VigLeish. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz, Instituto Nacional de Infectologia Evandro Chagas. Serviço de Infectologia - VigLeish. Rio de Janeiro, RJ, Brasil / New University of Lisbon (UNL). Hygiene and Tropical Medicine Institute (IHMT). Lisboa, Portugal.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunoparasitologia. Rio de Janeiro, RJ. Brasil.Fungus of the Sporothrix schenckii complex can produce skin lesions in humans, commonly lymphocutaneous (LC) and fixed (F) forms of sporotrichosis. Some authors have suggested that clinical forms are influenced by differences in virulence and genetic profile of isolates. But little is known about the role of immune response in determining the clinical outcome of sporotrichosis. To verify the profile of systemic and in situ IFN-γ and IL-10 expression in sporotrichosis patients, and consequently to detect any difference between the two compartments and/or clinical presentation, we quantified the number of IFN-γ and IL-10 producer peripheral blood mononuclear cells stimulated with S. schenckii antigen (Ss-Ag) by Elispot, and quantified cytokines expression by in situ immunohistochemistry in the same patient. Three groups were formed: 1- LC (n = 9); 2- F (n = 10); 3- healthy individuals (n = 14). All sporotrichosis patients produced high amounts of systemic IFN- γ when compared to uninfected individuals. No differences were observed between LC and F groups. Regarding in situ IL-10 expression, a difference between LC and F groups was observed: LC lesions presented higher amounts of IL-10 than F lesions differently from systemic IL-10 which showed similarities. Our data suggests that LC lesions present higher IL-10 expression which could be related to regulatory mechanisms for compensating the tissue injury, however favoring fungal persistence in the lesions. Surprisingly, there were no differences in systemic and in situ IFN- γ expression between CL and F patients, although it was significantly higher expressed in these patients than in healthy individuals

Protein malnutrition promotes dysregulation of molecules involved in T cell migration in the thymus of mice infected with Leishmania infantum

Erratum: Protein malnutrition promotes dysregulation of molecules involved in T cell migration in the thymus of mice infected with Leishmania infantum Monica Losada-Barragán, Adriana Umaña-Pérez, Sergio Cuervo-Escobar, Luiz Ricardo Berbert, Renato Porrozzi, Fernanda N. Morgado, Daniella Areas Mendes-da-Cruz, Wilson Savino, Myriam Sánchez-Gómez & Patricia Cuervo Scientific Reports 7:45991; published online 11 April 2017; updated on 25 September 2017 In this Article, Figure 4 is incorrect. The correct Figure 4 appears below as Figure 1. The legend of Figure 4 was correct from the time of publication.Submitted by Sandra Infurna ([email protected]) on 2017-05-06T14:31:05Z No. of bitstreams: 1 fernanda_morgado_etal_IOC_2017.pdf: 1948820 bytes, checksum: 2f6cb145e6c680b0fd96fcf54446a3e2 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2017-05-06T14:50:06Z (GMT) No. of bitstreams: 1 fernanda_morgado_etal_IOC_2017.pdf: 1948820 bytes, checksum: 2f6cb145e6c680b0fd96fcf54446a3e2 (MD5)Made available in DSpace on 2017-05-06T14:50:06Z (GMT). No. of bitstreams: 1 fernanda_morgado_etal_IOC_2017.pdf: 1948820 bytes, checksum: 2f6cb145e6c680b0fd96fcf54446a3e2 (MD5) Previous issue date: 2017Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmaniose. Rio de Janeiro, RJ, Brasil.Universidad Nacional de Colombia. Sede Bogotá. Facultad de Ciencias. Departamento de Química. Grupo de Investigación en Hormonas. Bogotá, Colombia.Universidad Nacional de Colombia. Sede Bogotá. Facultad de Ciencias. Departamento de Química. Grupo de Investigación en Hormonas. Bogotá, Colombia.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmaniose. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmaniose. 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. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Universidad Nacional de Colombia. Sede Bogotá. Facultad de Ciencias. Departamento de Química. Grupo de Investigación en Hormonas. Bogotá, Colombia.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmaniose. Rio de Janeiro, RJ, Brasil.Protein malnutrition, the most deleterious cause of malnutrition in developing countries, has been considered a primary risk factor for the development of clinical visceral leishmaniasis (VL). Protein malnutrition and infection with Leishmania infantum leads to lymphoid tissue disorganization, including changes in cellularity and lymphocyte subpopulations in the thymus and spleen. Here we report that protein malnutrition modifies thymic chemotactic factors by diminishing the CCL5, CXCL12, IGF1, CXCL9 and CXCL10 protein levels in infected animals. Nevertheless, T cells preserve their migratory capability, as they were able to migrate ex vivo in response to chemotactic stimuli, indicating that malnutrition may compromise the thymic microenvironment and alter in vivo thymocyte migration. Decrease in chemotactic factors protein levels was accompanied by an early increase in the parasite load of the spleen. These results suggest that the precondition of malnutrition is affecting the cell-mediated immune response to L. infantum by altering T cell migration and interfering with the capacity of protein-deprived animals to control parasite spreading and proliferation. Our data provide evidence for a disturbance of T lymphocyte migration involving both central and peripheral T-cells, which likely contribute to the pathophysiology of VL that occurs in malnourished individuals

<i>In situ</i> IFN-γ and IL-10 expression in lymphocutaneous and fixed lesions of sporothrichosis.

<p>The <i>in situ</i> IFN-γ and IL-10 expression was detected by immunohistochemistry. The arrows point positive areas (red/AEC– 3-amino-9-ethylcarbazole). The intensity of staining was scored in ten microscopic fields (200x magnification) as rare (at least 1 positive area / field), discrete (2–3 positive areas / field), moderate (4–5 positive areas / field) and intense (>5 positive areas / field). Scale bar = 10μm.</p

Clinical data of patients with lymphocutaneous (LC) and fixed (F) forms of sporothrichosis.

<p>Clinical data of patients with lymphocutaneous (LC) and fixed (F) forms of sporothrichosis.</p