Frontiers in Cellular and Infection Microbiology, 2020
Cutaneous leishmaniasis (CL) is caused by the bite of the infected sand fly, which inoculates par... more Cutaneous leishmaniasis (CL) is caused by the bite of the infected sand fly, which inoculates parasites of Leishmania spp and triggers an immune response. An exacerbated cutaneous inflammatory response is crucial for controlling parasite burden but can also promote tissue damage. This study aimed to characterize the populations of natural killer (NK), CD57 + , CD4 + , and CD8 + T cells, CD20 + B cells, as well as CD68 + macrophages, in biopsies of ulcerated CL lesions, and quantify the production of perforin + , grazyme B + , interleukin 1 beta (IL-1β + ) and Tumor Necrosis Factor (TNF-α + cells). We then correlated these parameters with necrosis, inflammation and the number of amastigotes. CD4 + T cells were positively correlated to the extent of inflammation, B cells and IL-1β + were associated with the extent of necrosis, CD68 + macrophages and perforin were correlated with the number of amastigotes, and CD57 + NK cells was correlated to CD68 + macrophages and amastigotes. In sum, the finding suggests that the production of cytotoxic granules and cytokines by inflammatory cells contributes to tissue damage in CL lesions.
Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operatin... more Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operating synergistically with Toll-Like Receptors (TLRs) in the production of inflammatory mediators. TREM-1 signaling depends on the adapter protein DAP12, which results in the activation of NFkB, the expression of inflammatory genes, and the release of antimicrobial peptides, such as Beta-defensin 2. We evaluated the activation of the TREM-1 signaling pathways in Cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis and linage human keratinocytes exposed to these parasites since the host immune response against Leishmania plays a critical role in promoting parasite killing but also participates in inflammation and tissue damage. We analyzed publicly available transcriptome data from the lesions of CL patients. In the CL biopsies, we found increased expression of the molecules involved in the TREM-1 pathway. We then validated these findings with RT-qPCR and immunohistochemistry in new...
Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operatin... more Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operating synergistically with Toll-Like Receptors (TLRs) in the production of inflammatory mediators. TREM-1 signaling depends on the adapter protein DAP12, which results in the activation of NFkB, the expression of inflammatory genes, and the release of antimicrobial peptides, such as Beta-defensin 2. We evaluated the activation of the TREM-1 signaling pathways in Cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis and linage human keratinocytes exposed to these parasites since the host immune response against Leishmania plays a critical role in promoting parasite killing but also participates in inflammation and tissue damage. We analyzed publicly available transcriptome data from the lesions of CL patients. In the CL biopsies, we found increased expression of the molecules involved in the TREM-1 pathway. We then validated these findings with RT-qPCR and immunohistochemistry in new...
Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patie... more Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis treated at a referral center in the state of Bahia, Brazil. Methods: A cross-sectional study, with prospective data collection, carried out at the Cystic Fibrosis Referral Center of Bahia of the Octavio Mangabeira Specialized Hospital. We evaluated 74 patients diagnosed with cystic fibrosis, older than
Cutaneous leishmaniasis (CL), caused by Leishmania braziliensis, is the most important presentati... more Cutaneous leishmaniasis (CL), caused by Leishmania braziliensis, is the most important presentation of tegumentary leishmaniasis (TL) in Latin American. While the role of dogs as reservoirs of Leishmania infantum, and the clinic features of canine visceral leishmanisis are well described, little is known about the importance of dogs in the transmission of L. braziliensis to humans. In the present study, we determine the frequency of L. braziliensis infection in dogs with cutaneous and mucosal ulcers in an endemic area of CL. We also describe the clinical manifestations and histopathologic features, and determine if the parasites isolated from dogs are genetically similar to those found in humans. This is a cross sectional study in which 61 dogs living in an endemic area of CL and presenting ulcerated lesions were evaluated. Detection of L. braziliensis DNA by polymerase chain reaction (PCR) in skin biopsies, serology and leishmania skin test (LST) with soluble L. braziliensis antigen were performed. The clinical and histopathologic features were described, and we compared the genotypic characteristics of isolates obtained from dogs and humans. The sensitivity of the three tests together to detect exposure was 89% and the concordance between the tests was high. The skin lesions were most frequent in the ears, followed by scrotal sac. The PCR was positive in 41 (67%) of animals, and the lesions in the snout, followed by the scrotal sac and ears were the sites where parasite DNA was most detected. There were genotype similarities between L.braziliensis isolates from dogs and humans.
Despite highly variable efficacy, BCG (Bacillus Calmette-Guérin) is the only vaccine available to... more Despite highly variable efficacy, BCG (Bacillus Calmette-Guérin) is the only vaccine available to prevent the tuberculosis (TB). Genomic heterogeneity between attenuated BCG strains and virulent Mycobacterium tuberculosis might help to explain this vaccine's impaired capacity to induce long-term protection. Here, we investigate the lipid-related genes absent in attenuated BCG strains in order to correlate changes in both lipid metabolism and cell-wall lipid content to vaccine impairment. Whole genome sequences of M. tuberculosis H37Rv and the six most used BCG strains worldwide were aligned and the absent regions functionally categorized. Genomes of the BCG strains showed a total of 14 non-homologous lipid-related genes, including those belonging to mce3 operon, as well as the gene echaA1, which encodes an enoyl-CoA hydratase, and the genes encoding phospholipases PlcA, PlcB and PlcC. Taken together, the depletion of these M. tuberculosis H37Rv genomic regions were associated with marked alterations in lipid-related genes of BCG strains. Such alterations may indicate a dormant-like state and can be determining factors to the vaccine's inability to induce long-term protection. These lipids can be further evaluated as an adjuvant to boost the current BCG-based vaccine.
Psoriasis is a chronic, inflammatory disease affecting the skin and joints. The pathogenesis of t... more Psoriasis is a chronic, inflammatory disease affecting the skin and joints. The pathogenesis of this disease is associated with genetic, environmental and immunological factors, especially unbalanced T cell activation and improper keratinocyte differentiation. Psoriatic lesion infiltrate is composed of monocytes and T cells, and most studies have focused on the participation of T cells in the pathogenesis of this disease. Here we investigated the contribution of mononuclear phagocytes in the immunopathology observed in psoriatic patients. Significant increases in the levels of TNF, IL-1β, CXCL9, as well as the soluble forms of CD14 and CD163, were observed within the lesions of psoriatic patients compared to skin biopsies obtained from healthy individuals. Moreover, we found an association between the levels of CCL2, a monocyte attractant chemokine, and disease severity. In conclusion, our findings suggest a potential role for mononuclear phagocytes in the pathogenesis of psoriasis.
IFN-γ and TNF play critical roles in the control of Mycobacterium tuberculosis infection. Despite... more IFN-γ and TNF play critical roles in the control of Mycobacterium tuberculosis infection. Despite leading to an exaggerated production of inflammatory cytokines, HTLV-1 infection increases the risk of developing tuberculosis (TB). However, the immune mechanisms accounting for this phenomenon are still unclear. The aim of this study was to evaluate immunological aspects of the HTLV-1/M. tuberculosis co-infection. In this cross-sectional study, the levels of TNF, IL-1β, and IL-17 were determined by ELISA in the supernatants of either unstimulated or tuberculin purified protein derivative (PPD) stimulated peripheral blood mononuclear cells. Cells from HTLV-1 infected individuals produced lower levels of TNF following PPD stimulation compared to unstimulated cells. IL-1β and IL-17 production by cells from HTLV-1/M. tuberculosis co-infected individuals was lower than in cells from patients with TB. Impairment in TNF, IL-1β, and IL-17 production upon stimulation with mycobacterial antigen...
Leprosy is a chronic infectious disease caused by the obligate intracellular bacillus Mycobacteri... more Leprosy is a chronic infectious disease caused by the obligate intracellular bacillus Mycobacterium leprae. Because leprosy diagnosis is complex and requires professional expertise, new tools and methodologies are needed to detect cases in early stages and prevent transmission. The M. leprae genome contains mce1A, which encodes a putative mammalian cell entry protein (Mce1A). We hypothesised that the presence of Mce1A on the cell surface could be detected by the host's immune system. The aim of this study was to evaluate antibody responses against the Mce1A protein in leprosy patients, household contacts of patients, and the general population to present an addition tool for leprosy diagnosis. A cross-sectional study involving 89 volunteers [55 leprosy cases, 12 household contacts (HHC) and 22 endemic controls (EC)] was conducted at Couto Maia Hospital, in Salvador, Bahia (BA), Brazil. The median anti-Mce1A IgA was significantly higher in multibacillary (MB) and paucibacillary (...
The Journal of investigative dermatology, Jan 12, 2017
Cutaneous leishmaniasis due to Leishmania braziliensis infection is an inflammatory disease which... more Cutaneous leishmaniasis due to Leishmania braziliensis infection is an inflammatory disease which skin ulcer development is associated with mononuclear cells infiltrate and high levels of inflammatory cytokines production. Recently, NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and IL-1β production has been associated with increased pathology in murine cutaneous leishmaniasis. We hypothesized that cutaneous leishmaniasis patients have increased expression of NLRP3 leading to high levels of IL-1β production. In this work we show high production of IL-1β in biopsies and Leishmania antigen-stimulated peripheral blood mononuclear cells (PBMC) from patients infected with L. braziliensis, and reduced IL-1β levels after cure. IL-1β production positively correlated with the area of necrosis in lesions and duration of the lesions. The main source of IL-1β was intermediate monocytes (CD14++CD16+). Furthermore, our murine experiments show that IL-1β produc...
AIDS research and human retroviruses, Jan 26, 2017
The human T cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of HTLV-1-associated m... more The human T cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infected individuals have increased susceptibility to Mycobacterium tuberculosis infection but the influence of tuberculosis (TB) on the course of HTLV-1 infection is unknown. The aim of this study was to evaluate the influence of TB on immunological, virologic, and neurologic features of HTLV-1 infection. This is a retrospective analysis of individuals enrolled in a cohort study from an HTLV-1 clinic who were evaluated for past or latent tuberculosis (LTB) and classified clinically as HTLV-1 carriers, probable HAM/TSP and definite HAM/TSP. Spontaneous cytokine production (interferon-gamma [IFN-γ], tumor necrosis factor [TNF], and interleukin[IL]-10), serum chemokines (CXCL9 and CXCL10) and HTLV-1 proviral load were evaluated. Of 172 participants, 64 did not have histories of TB (TB- group), 81 had LTB and 27 had TB in the past (TB...
The American journal of tropical medicine and hygiene, Mar 23, 2017
Cutaneous leishmaniasis (CL), characterized by an ulcerated lesion, is the most common clinical f... more Cutaneous leishmaniasis (CL), characterized by an ulcerated lesion, is the most common clinical form of human leishmaniasis. Before the ulcer develops, patients infected with Leishmania (Viannia) braziliensis develop a small papule at the site of the sandfly bite, referred to as early cutaneous leishmaniasis (E-CL). Two to four weeks later the typical ulcer develops, which is considered here as late CL (L-CL). Although there is a great deal known about T-cell responses in patients with L-CL, there is little information about the in situ inflammatory response in E-CL. Histological sections of skin biopsies from 15 E-CL and 28 L-CL patients were stained by hematoxilin and eosin to measure the area infiltrated by cells, as well as tissue necrosis. Leishmania braziliensis amastigotes, CD4(+), CD8(+), CD20(+), and CD68(+) cells were identified and quantified by immunohistochemistry. The number of amastigotes in E-CL was higher than in L-CL, and the inflammation area was larger in classic...
A hipótese da higiene teoriza que diversos aspectos relacionados ao modo de vida moderna contribu... more A hipótese da higiene teoriza que diversos aspectos relacionados ao modo de vida moderna contribuem para o aumento nos últimos anos da incidência das doenças alérgicas. Segundo essa hipótese, a ausência de infecções que induzem uma resposta imune Th1 levaria ao desenvolvimento da resposta imune Th2 associada com as doenças alérgicas. No nosso meio, a tuberculose apresenta destaque e a BCG (Bacilo Calmette-Guérin) é uma vacina utilizada logo após o nascimento sendo eficaz para prevenir contra as formas graves da tuberculose e induzindo a ativação da resposta imune Th1. Estudos em animais experimentais demonstram a modulação da resposta imune Th2 com o uso da BCG. Dessa forma diversos trabalhos em diferentes populações humanas têm sido realizados avaliando a possível modulação das doenças alérgicas induzida pela vacinação com BCG com resultados variáveis. Alguns desses estudos avaliam apenas os parâmetros de natureza clínica associados com a expressão das doenças alérgicas enquanto em outros se compara a resposta tuberculínica cutânea ou a cicatriz da BCG entre indivíduos vacinados ou não com a BCG. Uma abordagem importante para esclarecer melhor essa controvérsia da influência da vacina BCG sobre a atopia seria através do estudo do efeito da revacinação BCG sobre a resposta imune em adultos atópicos. Palavras-chave: BCG, asma, alergia, tuberculose, resposta imune. The hygiene hypothesis states that some aspects related to the modern way of life contribute to the increase of allergic disease incidence in the last years. According to this hypothesis, the absence of infections that lead towards a Th1 immune response would induce the development of a Th2 immune response associated with allergic diseases. In our environment, the tuberculosis infection shows relevance and BCG (Bacille Calmette-Guérin) is a vaccine used soon after birth being efficacious against the severe forms of tuberculosis and inducing a Th1 immune response activation. Studies in animal experimental models have shown the down-modulation of Th2 immune response after BCG. Therefore, a lot of studies in different human population have been done to evaluate the possible modulation of allergic diseases induced by BCG vaccination with conflicting results. Some of these studies evaluate only the clinical aspects associated with the expression of allergic diseases whereas others compare the skin tuberculin response or the BCG scar between BCG vaccinated or non-vaccinated individuals. An important approach to solve the current controversy over BCG vaccination and allergy would be through studying the effects of BCC revaccination over the immune response in atopic adults.
The International Journal of Tuberculosis and Lung Disease the Official Journal of the International Union Against Tuberculosis and Lung Disease, Jun 1, 2009
Although treatment of latent tuberculosis infection (LTBI) is an essential component of tuberculo... more Although treatment of latent tuberculosis infection (LTBI) is an essential component of tuberculosis (TB) control in countries such as the United States, it is not widely practiced in most TB-endemic countries. O B J E C T I V E : To examine the practice of and adherence to LTBI treatment in a high-risk population in Brazil. D E S I G N : We followed household contacts (HHCs) of patients hospitalized with pulmonary TB in Salvador, Brazil, for 6 months after they initiated LTBI treatment with isoniazid (INH). HHCs were asked to return to the hospital once a month for 6 months for follow-up visits and INH refi lls. R E S U LT S : Of 101 HHCs who initiated LTBI treatment, 54 (53.5%) completed the 6-month regimen. The risk of treatment non-completion was signifi cantly higher in HHCs who reported side effects to INH (RR 2.69, 95%CI 1.3-5.8, P = 0.01), and in those who had to take two buses for a one-way trip to the hospital (RR 1.8, 95%CI 1.01-3.3, P = 0.04). Of the 101 HHCs, 29 (28.7%) did not return for any follow-up visits; these HHCs were signifi cantly more likely to have a 2-bus commute to the hospital compared to HHCs who completed treatment (OR 20.69, 95%CI 2.1-208.4, P = 0.01). C O N C L U S I O N : Nearly 50% of HHCs at high risk for developing TB completed a 6-month course of LTBI treatment. Completion of LTBI treatment was most affected by medication intolerance and commuting difficulties for follow-up visits.
Hemoglobinopathies are the most common genetic disorders in the world and include sickle cell ane... more Hemoglobinopathies are the most common genetic disorders in the world and include sickle cell anemia (SCA), which is a public health problem in Brazil. Nevertheless, the disease is highly unknown among health professionals, and delayed diagnosis constitutes an important cause of concern for caretakers of SCA patients. The purpose of this study was to compare the clinical and laboratory history of SCA patients whose diagnosis was established during the first year of life to those of other SCA patients who had delayed SCA diagnosis. Demographic, clinical, and laboratory data were all reviewed from 99 steady-state SCA patients who were followed in a public hematology and hemotherapy clinic in Salvador, Brazil. The patients were aged > or = 12 years and attended the outpatient unit at least once from November 2008 to June 2009. The data were analyzed in 2010. For all patients, the mean age (+/- SD) at diagnosis was 12.7(+/- 12.1) years, ranging from 0 to 47 years. Mean age was higher in patients whose SCA diagnosis was established after age 5 (32.9 +/- 11.9 years, P = .005). Increased unconjugated bilirubin, stroke and splenic sequestration were more prevalent in patients who were diagnosed in the first year of life (P = .043, .024 and .026 respectively). The data suggest that stroke, splenic sequestration and unconjugated bilirubin level may be influenced by age at SCA diagnosis.
Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patie... more Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis treated at a referral center in the state of Bahia, Brazil. Methods: A cross-sectional study, with prospective data collection, carried out at the Cystic Fibrosis Referral Center of Bahia of the Octávio Mangabeira Specialized Hospital. We evaluated 74 patients diagnosed with cystic fibrosis, older than six years of age, treated between December 9, 2003 and March 7, 2005. We analyzed the following variables: gender, age, forced vital capacity, forced expiratory volume in one second, pharmacodynamic response, chest X-ray findings, facial sinus X-ray findings, wheezing, cultures for Aspergillus spp., total immunoglobulin E (IgE), specific IgE for Aspergillus fumigatus and immediate skin test reactivity to A. fumigatus antigen. Results: Of the 74 patients, 2 were diagnosed with ABPA. We found total IgE levels > 1,000 IU/mL in 17 (23%), positive immediate skin reactivity to A. fumigatus antigen in 19 (25.7%) and wheezing in 60 (81.1%). Conclusions: The prevalence of ABPA was 2.7%. The high levels of total IgE, high incidence of wheezing and high rate of immediate skin test reactivity to A. fumigatus antigen suggest that these patients should be carefully monitored due to their propensity to develop ABPA.
The American journal of tropical medicine and hygiene, Jan 19, 2015
Skin ulcer development in cutaneous leishmaniasis due to Leishmania braziliensis infection is ass... more Skin ulcer development in cutaneous leishmaniasis due to Leishmania braziliensis infection is associated with a mononuclear cell infiltrate and high levels of tumor necrosis factor (TNF). Herein, we show that despite the absence of Leishmania-driven TNF, a cutaneous leishmaniasis patient with acquired immunodeficiency syndrome developed a skin ulcer. The presence of mononuclear phagocytes and high levels of TNF, chemokine (C-C motif) ligand 2 (CCL2), and metalloproteinase-9 in tissue are identified as potential contributors to immunopathology observed in L. braziliensis-infected patients.
The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases
The formula proposed by Rich in 1951 explained the formation in a tuberculous lesion in a period ... more The formula proposed by Rich in 1951 explained the formation in a tuberculous lesion in a period that was unknown cellular functions, cytokines and other immunological aspects involved in granuloma formation by tuberculosis; its components are assembled conceptually to explain the pathogenic mechanisms involved in the granulomatous lesion in tuberculosis. In this manuscript, we report an update of Rich's formula based on the new and old concepts about pathogenic mechanisms involved in the granulomatous lesion in tuberculosis. Current knowledge allows us to conclude that the balance between the characteristics of the bacillus and host protective response is necessary to indicate the outcome of pathogenesis, infection or active disease and the necrosis degree of the tuberculosis lesion.
Objectives. We investigated IFN-γ levels before and after a six month course of isoniazid among i... more Objectives. We investigated IFN-γ levels before and after a six month course of isoniazid among individuals with latent tuberculosis infection (LTBI) in a high-transmission setting. Design. A total of 26 household contacts of pulmonary tuberculosis patients who were positive for LTBI by tuberculin skin test completed six months of treatment and submitted a blood sample for a follow-up examination. The IFN-γ response to Mycobacterium tuberculosis-specific antigens was measured, and the results before and after the completion of LTBI treatment were compared. Results. Of the 26 study participants, 25 (96%) showed an IFN-γ level higher than their baseline level before treatment (P ≤ 0.001). Only one individual had a decreased IFN-γ level after treatment but remained positive for LTBI. Conclusion. In a high-transmission setting, the IFN-γ level has increased after LTBI treatment. Further studies must be undertaken to understand if this elevation is transient.
Frontiers in Cellular and Infection Microbiology, 2020
Cutaneous leishmaniasis (CL) is caused by the bite of the infected sand fly, which inoculates par... more Cutaneous leishmaniasis (CL) is caused by the bite of the infected sand fly, which inoculates parasites of Leishmania spp and triggers an immune response. An exacerbated cutaneous inflammatory response is crucial for controlling parasite burden but can also promote tissue damage. This study aimed to characterize the populations of natural killer (NK), CD57 + , CD4 + , and CD8 + T cells, CD20 + B cells, as well as CD68 + macrophages, in biopsies of ulcerated CL lesions, and quantify the production of perforin + , grazyme B + , interleukin 1 beta (IL-1β + ) and Tumor Necrosis Factor (TNF-α + cells). We then correlated these parameters with necrosis, inflammation and the number of amastigotes. CD4 + T cells were positively correlated to the extent of inflammation, B cells and IL-1β + were associated with the extent of necrosis, CD68 + macrophages and perforin were correlated with the number of amastigotes, and CD57 + NK cells was correlated to CD68 + macrophages and amastigotes. In sum, the finding suggests that the production of cytotoxic granules and cytokines by inflammatory cells contributes to tissue damage in CL lesions.
Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operatin... more Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operating synergistically with Toll-Like Receptors (TLRs) in the production of inflammatory mediators. TREM-1 signaling depends on the adapter protein DAP12, which results in the activation of NFkB, the expression of inflammatory genes, and the release of antimicrobial peptides, such as Beta-defensin 2. We evaluated the activation of the TREM-1 signaling pathways in Cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis and linage human keratinocytes exposed to these parasites since the host immune response against Leishmania plays a critical role in promoting parasite killing but also participates in inflammation and tissue damage. We analyzed publicly available transcriptome data from the lesions of CL patients. In the CL biopsies, we found increased expression of the molecules involved in the TREM-1 pathway. We then validated these findings with RT-qPCR and immunohistochemistry in new...
Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operatin... more Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operating synergistically with Toll-Like Receptors (TLRs) in the production of inflammatory mediators. TREM-1 signaling depends on the adapter protein DAP12, which results in the activation of NFkB, the expression of inflammatory genes, and the release of antimicrobial peptides, such as Beta-defensin 2. We evaluated the activation of the TREM-1 signaling pathways in Cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis and linage human keratinocytes exposed to these parasites since the host immune response against Leishmania plays a critical role in promoting parasite killing but also participates in inflammation and tissue damage. We analyzed publicly available transcriptome data from the lesions of CL patients. In the CL biopsies, we found increased expression of the molecules involved in the TREM-1 pathway. We then validated these findings with RT-qPCR and immunohistochemistry in new...
Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patie... more Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis treated at a referral center in the state of Bahia, Brazil. Methods: A cross-sectional study, with prospective data collection, carried out at the Cystic Fibrosis Referral Center of Bahia of the Octavio Mangabeira Specialized Hospital. We evaluated 74 patients diagnosed with cystic fibrosis, older than
Cutaneous leishmaniasis (CL), caused by Leishmania braziliensis, is the most important presentati... more Cutaneous leishmaniasis (CL), caused by Leishmania braziliensis, is the most important presentation of tegumentary leishmaniasis (TL) in Latin American. While the role of dogs as reservoirs of Leishmania infantum, and the clinic features of canine visceral leishmanisis are well described, little is known about the importance of dogs in the transmission of L. braziliensis to humans. In the present study, we determine the frequency of L. braziliensis infection in dogs with cutaneous and mucosal ulcers in an endemic area of CL. We also describe the clinical manifestations and histopathologic features, and determine if the parasites isolated from dogs are genetically similar to those found in humans. This is a cross sectional study in which 61 dogs living in an endemic area of CL and presenting ulcerated lesions were evaluated. Detection of L. braziliensis DNA by polymerase chain reaction (PCR) in skin biopsies, serology and leishmania skin test (LST) with soluble L. braziliensis antigen were performed. The clinical and histopathologic features were described, and we compared the genotypic characteristics of isolates obtained from dogs and humans. The sensitivity of the three tests together to detect exposure was 89% and the concordance between the tests was high. The skin lesions were most frequent in the ears, followed by scrotal sac. The PCR was positive in 41 (67%) of animals, and the lesions in the snout, followed by the scrotal sac and ears were the sites where parasite DNA was most detected. There were genotype similarities between L.braziliensis isolates from dogs and humans.
Despite highly variable efficacy, BCG (Bacillus Calmette-Guérin) is the only vaccine available to... more Despite highly variable efficacy, BCG (Bacillus Calmette-Guérin) is the only vaccine available to prevent the tuberculosis (TB). Genomic heterogeneity between attenuated BCG strains and virulent Mycobacterium tuberculosis might help to explain this vaccine's impaired capacity to induce long-term protection. Here, we investigate the lipid-related genes absent in attenuated BCG strains in order to correlate changes in both lipid metabolism and cell-wall lipid content to vaccine impairment. Whole genome sequences of M. tuberculosis H37Rv and the six most used BCG strains worldwide were aligned and the absent regions functionally categorized. Genomes of the BCG strains showed a total of 14 non-homologous lipid-related genes, including those belonging to mce3 operon, as well as the gene echaA1, which encodes an enoyl-CoA hydratase, and the genes encoding phospholipases PlcA, PlcB and PlcC. Taken together, the depletion of these M. tuberculosis H37Rv genomic regions were associated with marked alterations in lipid-related genes of BCG strains. Such alterations may indicate a dormant-like state and can be determining factors to the vaccine's inability to induce long-term protection. These lipids can be further evaluated as an adjuvant to boost the current BCG-based vaccine.
Psoriasis is a chronic, inflammatory disease affecting the skin and joints. The pathogenesis of t... more Psoriasis is a chronic, inflammatory disease affecting the skin and joints. The pathogenesis of this disease is associated with genetic, environmental and immunological factors, especially unbalanced T cell activation and improper keratinocyte differentiation. Psoriatic lesion infiltrate is composed of monocytes and T cells, and most studies have focused on the participation of T cells in the pathogenesis of this disease. Here we investigated the contribution of mononuclear phagocytes in the immunopathology observed in psoriatic patients. Significant increases in the levels of TNF, IL-1β, CXCL9, as well as the soluble forms of CD14 and CD163, were observed within the lesions of psoriatic patients compared to skin biopsies obtained from healthy individuals. Moreover, we found an association between the levels of CCL2, a monocyte attractant chemokine, and disease severity. In conclusion, our findings suggest a potential role for mononuclear phagocytes in the pathogenesis of psoriasis.
IFN-γ and TNF play critical roles in the control of Mycobacterium tuberculosis infection. Despite... more IFN-γ and TNF play critical roles in the control of Mycobacterium tuberculosis infection. Despite leading to an exaggerated production of inflammatory cytokines, HTLV-1 infection increases the risk of developing tuberculosis (TB). However, the immune mechanisms accounting for this phenomenon are still unclear. The aim of this study was to evaluate immunological aspects of the HTLV-1/M. tuberculosis co-infection. In this cross-sectional study, the levels of TNF, IL-1β, and IL-17 were determined by ELISA in the supernatants of either unstimulated or tuberculin purified protein derivative (PPD) stimulated peripheral blood mononuclear cells. Cells from HTLV-1 infected individuals produced lower levels of TNF following PPD stimulation compared to unstimulated cells. IL-1β and IL-17 production by cells from HTLV-1/M. tuberculosis co-infected individuals was lower than in cells from patients with TB. Impairment in TNF, IL-1β, and IL-17 production upon stimulation with mycobacterial antigen...
Leprosy is a chronic infectious disease caused by the obligate intracellular bacillus Mycobacteri... more Leprosy is a chronic infectious disease caused by the obligate intracellular bacillus Mycobacterium leprae. Because leprosy diagnosis is complex and requires professional expertise, new tools and methodologies are needed to detect cases in early stages and prevent transmission. The M. leprae genome contains mce1A, which encodes a putative mammalian cell entry protein (Mce1A). We hypothesised that the presence of Mce1A on the cell surface could be detected by the host's immune system. The aim of this study was to evaluate antibody responses against the Mce1A protein in leprosy patients, household contacts of patients, and the general population to present an addition tool for leprosy diagnosis. A cross-sectional study involving 89 volunteers [55 leprosy cases, 12 household contacts (HHC) and 22 endemic controls (EC)] was conducted at Couto Maia Hospital, in Salvador, Bahia (BA), Brazil. The median anti-Mce1A IgA was significantly higher in multibacillary (MB) and paucibacillary (...
The Journal of investigative dermatology, Jan 12, 2017
Cutaneous leishmaniasis due to Leishmania braziliensis infection is an inflammatory disease which... more Cutaneous leishmaniasis due to Leishmania braziliensis infection is an inflammatory disease which skin ulcer development is associated with mononuclear cells infiltrate and high levels of inflammatory cytokines production. Recently, NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and IL-1β production has been associated with increased pathology in murine cutaneous leishmaniasis. We hypothesized that cutaneous leishmaniasis patients have increased expression of NLRP3 leading to high levels of IL-1β production. In this work we show high production of IL-1β in biopsies and Leishmania antigen-stimulated peripheral blood mononuclear cells (PBMC) from patients infected with L. braziliensis, and reduced IL-1β levels after cure. IL-1β production positively correlated with the area of necrosis in lesions and duration of the lesions. The main source of IL-1β was intermediate monocytes (CD14++CD16+). Furthermore, our murine experiments show that IL-1β produc...
AIDS research and human retroviruses, Jan 26, 2017
The human T cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of HTLV-1-associated m... more The human T cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infected individuals have increased susceptibility to Mycobacterium tuberculosis infection but the influence of tuberculosis (TB) on the course of HTLV-1 infection is unknown. The aim of this study was to evaluate the influence of TB on immunological, virologic, and neurologic features of HTLV-1 infection. This is a retrospective analysis of individuals enrolled in a cohort study from an HTLV-1 clinic who were evaluated for past or latent tuberculosis (LTB) and classified clinically as HTLV-1 carriers, probable HAM/TSP and definite HAM/TSP. Spontaneous cytokine production (interferon-gamma [IFN-γ], tumor necrosis factor [TNF], and interleukin[IL]-10), serum chemokines (CXCL9 and CXCL10) and HTLV-1 proviral load were evaluated. Of 172 participants, 64 did not have histories of TB (TB- group), 81 had LTB and 27 had TB in the past (TB...
The American journal of tropical medicine and hygiene, Mar 23, 2017
Cutaneous leishmaniasis (CL), characterized by an ulcerated lesion, is the most common clinical f... more Cutaneous leishmaniasis (CL), characterized by an ulcerated lesion, is the most common clinical form of human leishmaniasis. Before the ulcer develops, patients infected with Leishmania (Viannia) braziliensis develop a small papule at the site of the sandfly bite, referred to as early cutaneous leishmaniasis (E-CL). Two to four weeks later the typical ulcer develops, which is considered here as late CL (L-CL). Although there is a great deal known about T-cell responses in patients with L-CL, there is little information about the in situ inflammatory response in E-CL. Histological sections of skin biopsies from 15 E-CL and 28 L-CL patients were stained by hematoxilin and eosin to measure the area infiltrated by cells, as well as tissue necrosis. Leishmania braziliensis amastigotes, CD4(+), CD8(+), CD20(+), and CD68(+) cells were identified and quantified by immunohistochemistry. The number of amastigotes in E-CL was higher than in L-CL, and the inflammation area was larger in classic...
A hipótese da higiene teoriza que diversos aspectos relacionados ao modo de vida moderna contribu... more A hipótese da higiene teoriza que diversos aspectos relacionados ao modo de vida moderna contribuem para o aumento nos últimos anos da incidência das doenças alérgicas. Segundo essa hipótese, a ausência de infecções que induzem uma resposta imune Th1 levaria ao desenvolvimento da resposta imune Th2 associada com as doenças alérgicas. No nosso meio, a tuberculose apresenta destaque e a BCG (Bacilo Calmette-Guérin) é uma vacina utilizada logo após o nascimento sendo eficaz para prevenir contra as formas graves da tuberculose e induzindo a ativação da resposta imune Th1. Estudos em animais experimentais demonstram a modulação da resposta imune Th2 com o uso da BCG. Dessa forma diversos trabalhos em diferentes populações humanas têm sido realizados avaliando a possível modulação das doenças alérgicas induzida pela vacinação com BCG com resultados variáveis. Alguns desses estudos avaliam apenas os parâmetros de natureza clínica associados com a expressão das doenças alérgicas enquanto em outros se compara a resposta tuberculínica cutânea ou a cicatriz da BCG entre indivíduos vacinados ou não com a BCG. Uma abordagem importante para esclarecer melhor essa controvérsia da influência da vacina BCG sobre a atopia seria através do estudo do efeito da revacinação BCG sobre a resposta imune em adultos atópicos. Palavras-chave: BCG, asma, alergia, tuberculose, resposta imune. The hygiene hypothesis states that some aspects related to the modern way of life contribute to the increase of allergic disease incidence in the last years. According to this hypothesis, the absence of infections that lead towards a Th1 immune response would induce the development of a Th2 immune response associated with allergic diseases. In our environment, the tuberculosis infection shows relevance and BCG (Bacille Calmette-Guérin) is a vaccine used soon after birth being efficacious against the severe forms of tuberculosis and inducing a Th1 immune response activation. Studies in animal experimental models have shown the down-modulation of Th2 immune response after BCG. Therefore, a lot of studies in different human population have been done to evaluate the possible modulation of allergic diseases induced by BCG vaccination with conflicting results. Some of these studies evaluate only the clinical aspects associated with the expression of allergic diseases whereas others compare the skin tuberculin response or the BCG scar between BCG vaccinated or non-vaccinated individuals. An important approach to solve the current controversy over BCG vaccination and allergy would be through studying the effects of BCC revaccination over the immune response in atopic adults.
The International Journal of Tuberculosis and Lung Disease the Official Journal of the International Union Against Tuberculosis and Lung Disease, Jun 1, 2009
Although treatment of latent tuberculosis infection (LTBI) is an essential component of tuberculo... more Although treatment of latent tuberculosis infection (LTBI) is an essential component of tuberculosis (TB) control in countries such as the United States, it is not widely practiced in most TB-endemic countries. O B J E C T I V E : To examine the practice of and adherence to LTBI treatment in a high-risk population in Brazil. D E S I G N : We followed household contacts (HHCs) of patients hospitalized with pulmonary TB in Salvador, Brazil, for 6 months after they initiated LTBI treatment with isoniazid (INH). HHCs were asked to return to the hospital once a month for 6 months for follow-up visits and INH refi lls. R E S U LT S : Of 101 HHCs who initiated LTBI treatment, 54 (53.5%) completed the 6-month regimen. The risk of treatment non-completion was signifi cantly higher in HHCs who reported side effects to INH (RR 2.69, 95%CI 1.3-5.8, P = 0.01), and in those who had to take two buses for a one-way trip to the hospital (RR 1.8, 95%CI 1.01-3.3, P = 0.04). Of the 101 HHCs, 29 (28.7%) did not return for any follow-up visits; these HHCs were signifi cantly more likely to have a 2-bus commute to the hospital compared to HHCs who completed treatment (OR 20.69, 95%CI 2.1-208.4, P = 0.01). C O N C L U S I O N : Nearly 50% of HHCs at high risk for developing TB completed a 6-month course of LTBI treatment. Completion of LTBI treatment was most affected by medication intolerance and commuting difficulties for follow-up visits.
Hemoglobinopathies are the most common genetic disorders in the world and include sickle cell ane... more Hemoglobinopathies are the most common genetic disorders in the world and include sickle cell anemia (SCA), which is a public health problem in Brazil. Nevertheless, the disease is highly unknown among health professionals, and delayed diagnosis constitutes an important cause of concern for caretakers of SCA patients. The purpose of this study was to compare the clinical and laboratory history of SCA patients whose diagnosis was established during the first year of life to those of other SCA patients who had delayed SCA diagnosis. Demographic, clinical, and laboratory data were all reviewed from 99 steady-state SCA patients who were followed in a public hematology and hemotherapy clinic in Salvador, Brazil. The patients were aged > or = 12 years and attended the outpatient unit at least once from November 2008 to June 2009. The data were analyzed in 2010. For all patients, the mean age (+/- SD) at diagnosis was 12.7(+/- 12.1) years, ranging from 0 to 47 years. Mean age was higher in patients whose SCA diagnosis was established after age 5 (32.9 +/- 11.9 years, P = .005). Increased unconjugated bilirubin, stroke and splenic sequestration were more prevalent in patients who were diagnosed in the first year of life (P = .043, .024 and .026 respectively). The data suggest that stroke, splenic sequestration and unconjugated bilirubin level may be influenced by age at SCA diagnosis.
Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patie... more Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis treated at a referral center in the state of Bahia, Brazil. Methods: A cross-sectional study, with prospective data collection, carried out at the Cystic Fibrosis Referral Center of Bahia of the Octávio Mangabeira Specialized Hospital. We evaluated 74 patients diagnosed with cystic fibrosis, older than six years of age, treated between December 9, 2003 and March 7, 2005. We analyzed the following variables: gender, age, forced vital capacity, forced expiratory volume in one second, pharmacodynamic response, chest X-ray findings, facial sinus X-ray findings, wheezing, cultures for Aspergillus spp., total immunoglobulin E (IgE), specific IgE for Aspergillus fumigatus and immediate skin test reactivity to A. fumigatus antigen. Results: Of the 74 patients, 2 were diagnosed with ABPA. We found total IgE levels > 1,000 IU/mL in 17 (23%), positive immediate skin reactivity to A. fumigatus antigen in 19 (25.7%) and wheezing in 60 (81.1%). Conclusions: The prevalence of ABPA was 2.7%. The high levels of total IgE, high incidence of wheezing and high rate of immediate skin test reactivity to A. fumigatus antigen suggest that these patients should be carefully monitored due to their propensity to develop ABPA.
The American journal of tropical medicine and hygiene, Jan 19, 2015
Skin ulcer development in cutaneous leishmaniasis due to Leishmania braziliensis infection is ass... more Skin ulcer development in cutaneous leishmaniasis due to Leishmania braziliensis infection is associated with a mononuclear cell infiltrate and high levels of tumor necrosis factor (TNF). Herein, we show that despite the absence of Leishmania-driven TNF, a cutaneous leishmaniasis patient with acquired immunodeficiency syndrome developed a skin ulcer. The presence of mononuclear phagocytes and high levels of TNF, chemokine (C-C motif) ligand 2 (CCL2), and metalloproteinase-9 in tissue are identified as potential contributors to immunopathology observed in L. braziliensis-infected patients.
The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases
The formula proposed by Rich in 1951 explained the formation in a tuberculous lesion in a period ... more The formula proposed by Rich in 1951 explained the formation in a tuberculous lesion in a period that was unknown cellular functions, cytokines and other immunological aspects involved in granuloma formation by tuberculosis; its components are assembled conceptually to explain the pathogenic mechanisms involved in the granulomatous lesion in tuberculosis. In this manuscript, we report an update of Rich's formula based on the new and old concepts about pathogenic mechanisms involved in the granulomatous lesion in tuberculosis. Current knowledge allows us to conclude that the balance between the characteristics of the bacillus and host protective response is necessary to indicate the outcome of pathogenesis, infection or active disease and the necrosis degree of the tuberculosis lesion.
Objectives. We investigated IFN-γ levels before and after a six month course of isoniazid among i... more Objectives. We investigated IFN-γ levels before and after a six month course of isoniazid among individuals with latent tuberculosis infection (LTBI) in a high-transmission setting. Design. A total of 26 household contacts of pulmonary tuberculosis patients who were positive for LTBI by tuberculin skin test completed six months of treatment and submitted a blood sample for a follow-up examination. The IFN-γ response to Mycobacterium tuberculosis-specific antigens was measured, and the results before and after the completion of LTBI treatment were compared. Results. Of the 26 study participants, 25 (96%) showed an IFN-γ level higher than their baseline level before treatment (P ≤ 0.001). Only one individual had a decreased IFN-γ level after treatment but remained positive for LTBI. Conclusion. In a high-transmission setting, the IFN-γ level has increased after LTBI treatment. Further studies must be undertaken to understand if this elevation is transient.
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Papers by Sergio Arruda