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1.  Characterization of regulatory T cell (Treg) function in patients infected with Leishmania braziliensis 
Human immunology  2013;74(12):10.1016/j.humimm.2013.08.269.
Th1 immune responses are crucial for eliminating Leishmania parasites. However, despite strong Th1 responses, cutaneous leishmaniasis (CL) patients infected with L. braziliensis develop the disease, while milder Th1 responses are found in sub-clinical (SC) infections. Therefore, CL patients may experience impaired regulatory T cell (Treg) function, causing excessive Th1 responses and tissue damage. To address this hypothesis, we characterized the function of circulating Tregs in L. braziliensis infected CL patients and compared them to Tregs from uninfected controls (UC) and SC subjects. The frequency of circulating Tregs was similar in CL patients, UC and SC subjects. Moreover, CL patients Tregs suppressed lymphocyte proliferation and PBMC pro-inflammatory cytokine production more efficiently than UC Tregs, and also produced higher levels of IL-10 than UC and SC Tregs. Furthermore, PBMC and mononuclear cells from lesions of CL patients responded normally to Treg-induced suppression. Therefore, the lesion development in CL patients infected with L. braziliensis is not associated with impairment in Treg function or failure of cells to respond to immunomodulation. Rather, the increased Treg activation in CL patients may impair parasite elimination, resulting in establishment of chronic infection. Thus, immunological strategies that interfere with this response may improve leishmaniasis treatment.
doi:10.1016/j.humimm.2013.08.269
PMCID: PMC3846617  PMID: 23993989
Regulatory T cells; Leishmania braziliensis; cutaneous leishmaniasis
2.  Matrix Metalloproteinase 9 Production by Monocytes is Enhanced by TNF and Participates in the Pathology of Human Cutaneous Leishmaniasis 
Introduction
Cutaneous leishmaniasis (CL) due to L.braziliensis infection is characterized by a strong inflammatory response with high levels of TNF and ulcer development. Less attention has been given to the role of mononuclear phagocytes to this process. Monocytes constitute a heterogeneous population subdivided into classical, intermediate and non-classical, and are known to migrate to inflammatory sites and secrete inflammatory mediators. TNF participates in the induction of matrix metalloproteinases (MMPs). MMP-9 is an enzyme that degrades basal membrane and its activity is controlled by the tissue inhibitor of metalloproteinase.
Methods
Mononuclear cells were obtained from ex-vivo labeling sub-populations of monocytes and MMP-9, and the frequency was determined by flow cytometry. Culture was performed during 72 hours, stimulating the cells with SLA, levels of MMP-9 and TIMP-1 in the supernatants were determined by ELISA.
Results
We observed that cells from CL lesions secrete high amounts of MMP-9 when compared to healthy subjects. Although MMP-9 was produced by monocytes, non-classical ones were the main source of this enzyme. We also observed that TNF produced in high level during CL contributes to MMP-9 production.
Conclusions
These observations emphasize the role of monocytes, TNF and MMP-9 in the pathogenesis of L. braziliensis infection.
Author Summary
To examine the participation of MMP-9 in the pathogenesis of L. braziliensis infection, we realized a cross-sectional study with CL patients in an early phase of the disease or with a classical ulcer, and healthy controls. We evaluated the frequency of MMP-9 in monocyte subsets and its mechanism of production. Our results showed that monocytes were the major cells producing MMP-9. The MMP-9 production by CL patients was presented in higher levels when compared with healthy subjects and early cutaneous leishmaniasis (ECL) patients, and the levels of MMP-9 inhibitor, TIMP-1, were lower in CL patients when compared to healthy subjects. The production of MMP-9 was enhanced by TNF, a cytokine associated with tissue damage in CL patients. Thus, therapeutic modulation of MMP-9 may be a useful approach for improving disease outcome in L. braziliensis patients.
doi:10.1371/journal.pntd.0003282
PMCID: PMC4230914  PMID: 25393535
3.  CD8+ T cells in situ in different clinical forms of human cutaneous leishmaniasis 
Introduction
Leishmania braziliensis infection induces a large spectrum of lesions that clinically manifest as nodules or papules that progress to ulcers. Although it is already known that T helper cells predominate in the lesions, cytotoxic T cells have also been reported to be present, and their role in leishmaniasis immunopathogenesis is not well known. This study investigated the amounts of CD8+ and granzyme B+ cells in different clinical forms of human cutaneous leishmaniasis (CL).
Methods
Forty tissue fragments from early (E-CL) and late CL (L-CL) lesions and from disseminated leishmaniasis (DL) - papules and ulcers - were characterized. The inflamed area per fragment was calculated, and the CD8 and granzyme B expression levels in the infiltrates were quantified by counting positive cells in 15 fields. The localization of CD8 and granzyme B was graded subjectively.
Results
Inflammation was higher in L-CL and DL ulcers. CD8 expression was increased in late ulcerated lesions compared to recent lesions. The increase in CD8+ cells also correlated with the duration of the lesion. Papules had a higher frequency of granzyme B+ cells than E-CL lesions, although the frequency was similar to those for late and DL ulcers. CD8+ cells were mostly found in the papillary dermis.
Conclusions
CD8+ T and granzyme B+ cells are present in the inflammatory infiltrates of CL and DL and may participate in the immunopathogenesis of Leishmania infection.
doi:10.1590/0037-8682-0174-2013
PMCID: PMC4105155  PMID: 24474014
Leishmaniasis; Cytotoxicity; Inflammation; Cutaneous; CD8; Human
4.  Comparative analysis of the tissue inflammatory response in human cutaneous and disseminated leishmaniasis 
Memórias do Instituto Oswaldo Cruz  2014;109(2):202-209.
Cutaneous leishmaniasis (CL) is the most frequent clinical form of tegumentary leishmaniasis and is characterised by a single or a few ulcerated skin lesions that may disseminate into multiple ulcers and papules, which characterise disseminated leishmaniasis (DL). In this study, cells were quantified using immunohistochemistry and haematoxylin and eosin staining (CD4+, CD68+, CD20+, plasma cells and neutrophils) and histopathology was used to determine the level of inflammation in biopsies from patients with early CL, late CL and DL (ulcers and papules). The histopathology showed differences in the epidermis between the papules and ulcers from DL. An analysis of the cells present in the tissues showed similarities between the ulcers from localised CL (LCL) and DL. The papules had fewer CD4+ T cells than the DL ulcers. Although both CD4+ cells and macrophages contribute to inflammation in early CL, macrophages are the primary cell type associated with inflammation intensity in late ulcers. The higher frequency of CD20+ cells and plasma cells in lesions demonstrates the importance of B cells in the pathogenesis of leishmaniasis. The number of neutrophils was the same in all of the analysed groups. A comparison between the ulcers from LCL and DL and the early ulcers and papules shows that few differences between these two clinical forms can be distinguished by observing only the tissue.
doi:10.1590/0074-0276130312
PMCID: PMC4015249  PMID: 24676653
leishmaniasis; disseminated leishmaniasis; histopathological aspects; inflammation; inflammatory cells
5.  Association between an Emerging Disseminated form of Leishmaniasis and Leishmania (Viannia) braziliensis Strain Polymorphisms 
Journal of Clinical Microbiology  2012;50(12):4028-4034.
Leishmania (Viannia) braziliensis causes three main types of American tegumentary leishmaniasis (ATL), localized cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and disseminated leishmaniasis (DL). All forms are observed among individuals of Corte de Pedra, Brazil. We previously used random amplified markers to identify a multiclonal population among L. (V.) braziliensis isolates from ATL patients, defining parasite clades associated with different clinical syndromes. Herein we compared sequences of random amplified markers to identify genotypes of L. (V.) braziliensis recovered from lesions of CL, ML, and DL patients. Six polymorphic genomic loci were sequenced from 35 parasite isolates. Single-nucleotide polymorphisms (SNPs) and insertions-deletions (indels) at each locus allowed us to segregate the L. (V.) braziliensis population according to haplotypes. Several SNPs, indels, and haplotypes were significantly associated with an increased risk of DL. Molecular genotyping may provide markers to identify L. (V.) braziliensis strains likely to cause this emerging, hard-to-treat form of ATL.
doi:10.1128/JCM.02064-12
PMCID: PMC3503016  PMID: 23035200
6.  Monitoring Leptospira Strain Collections: The Need for Quality Control 
The purpose of this study was to perform a 16S sequence-based quality control of two Leptospira strain collections. 16S rRNA gene sequencing was used to verify two Leptospira reference collections provided by the World Health Organization and maintained at a reference laboratory for leptospirosis in Brazil. Among the 89 serovars evaluated, four conflicting strains were identified in one of the collections. Although 16S rRNA gene sequencing cannot identify Leptospira beyond the species level, it is suitable for the identification of contamination and quality control of leptospiral reference collections. This study highlights the importance of the availability of high-quality 16S rRNA sequences in public databases. In addition, it emphasizes the need for periodical verifications and quality control of Leptospira reference collections.
doi:10.4269/ajtmh.2010.09-0558
PMCID: PMC2803514  PMID: 20065000
7.  Leptospira noguchii and Human and Animal Leptospirosis, Southern Brazil 
Emerging Infectious Diseases  2009;15(4):621-623.
doi:10.3201/eid1504.071669
PMCID: PMC2671420  PMID: 19331754
Zoonoses; Leptospira noguchii; leptospirosis; isolation; taxonomy; letter
8.  Impact of Environment and Social Gradient on Leptospira Infection in Urban Slums 
Background
Leptospirosis has become an urban health problem as slum settlements have expanded worldwide. Efforts to identify interventions for urban leptospirosis have been hampered by the lack of population-based information on Leptospira transmission determinants. The aim of the study was to estimate the prevalence of Leptospira infection and identify risk factors for infection in the urban slum setting.
Methods and Findings
We performed a community-based survey of 3,171 slum residents from Salvador, Brazil. Leptospira agglutinating antibodies were measured as a marker for prior infection. Poisson regression models evaluated the association between the presence of Leptospira antibodies and environmental attributes obtained from Geographical Information System surveys and indicators of socioeconomic status and exposures for individuals. Overall prevalence of Leptospira antibodies was 15.4% (95% confidence interval [CI], 14.0–16.8). Households of subjects with Leptospira antibodies clustered in squatter areas at the bottom of valleys. The risk of acquiring Leptospira antibodies was associated with household environmental factors such as residence in flood-risk regions with open sewers (prevalence ratio [PR] 1.42, 95% CI 1.14–1.75) and proximity to accumulated refuse (1.43, 1.04–1.88), sighting rats (1.32, 1.10–1.58), and the presence of chickens (1.26, 1.05–1.51). Furthermore, low income and black race (1.25, 1.03–1.50) were independent risk factors. An increase of US$1 per day in per capita household income was associated with an 11% (95% CI 5%–18%) decrease in infection risk.
Conclusions
Deficiencies in the sanitation infrastructure where slum inhabitants reside were found to be environmental sources of Leptospira transmission. Even after controlling for environmental factors, differences in socioeconomic status contributed to the risk of Leptospira infection, indicating that effective prevention of leptospirosis may need to address the social factors that produce unequal health outcomes among slum residents, in addition to improving sanitation.
Author Summary
Leptospirosis, a life-threatening zoonotic disease, has become an important urban slum health problem. Epidemics of leptospirosis now occur in cities throughout the developing world, as the growth of slum settlements has produced conditions for rat-borne transmission of this disease. In this prevalence survey of more than 3,000 residents from a favela slum community in Brazil, Geographical Information System (GIS) and modeling approaches identified specific deficiencies in the sanitation infrastructure of slum environments—open sewers, refuse, and inadequate floodwater drainage—that serve as sources for Leptospira transmission. In addition to the environmental attributes of the slum environment, low socioeconomic status was found to independently contribute to the risk of infection. These findings indicate that effective prevention of leptospirosis will need to address the social factors that produce unequal health outcomes among slum residents, in addition to improving sanitation.
doi:10.1371/journal.pntd.0000228
PMCID: PMC2292260  PMID: 18431445
9.  Isolation of Leptospira noguchii from sheep 
Veterinary microbiology  2006;121(1-2):144-149.
The main goal of this study was to obtain new isolates of Leptospira spp. from sheep. A total of ten kidney samples and 44 blood samples were collected from sheep slaughtered in Pelotas, Southern Brazil. One isolate was obtained which was identified by 16S rRNA gene sequencing and serogrouping to be Leptospira noguchii serogroup Autumnalis. Microscopic agglutination test (MAT) evaluation revealed that 4.5% of the sheep sera reacted against the Autumnalis serogroup. This is the first report of isolation of L. noguchii from sheep. Together these findings indicate that L. noguchii infections may be a potentially important veterinary problem in this domestic animal species.
doi:10.1016/j.vetmic.2006.11.010
PMCID: PMC1868676  PMID: 17222993
leptospirosis; Leptospira noguchii; isolation; serogrouping; sheep; Brazil
10.  High serum nitric oxide levels in patients with severe leptospirosis 
Acta tropica  2007;100(3):256-260.
Leptospirosis is a globally distributed zoonosis of major public health importance and is associated with severe disease manifestations such as acute renal failure and pulmonary haemorrhage syndrome. However, the extent to which the pathogenesis of leptospirosis mimics sepsis caused by Gram-negative bacteria remains unknown. The aim of this study was to evaluate serum levels of nitric oxide (NO) in patients diagnosed with severe leptospirosis. Sera from 35 confirmed cases of severe leptospirosis and 13 healthy subjects were analysed. Patients with severe leptospirosis had significantly higher NO levels compared to healthy individuals (30.82 ± 10.90 μM versus 3.86 ± 1.34 μM, P<0.001), indicating that this immune mediator plays a role in the underlying systemic inflammatory response.
doi:10.1016/j.actatropica.2006.11.006
PMCID: PMC1805659  PMID: 17196920
Leptospirosis; Nitric Oxide; Acute renal failure; Pulmonary haemorrhage
11.  Evaluation of Four Whole-Cell Leptospira-Based Serological Tests for Diagnosis of Urban Leptospirosis▿  
Four serologic assays for leptospirosis had sensitivities of 72 to 88% and specificities of 88 to 100% in the setting of highly endemic urban transmission, indicating that assays using enzyme-linked immunosorbency and rapid formats may be used as alternatives to the microscopic agglutination test for diagnosing urban leptospirosis. Testing a second sample will be required in cases with an initial negative result, since sensitivity was low (46 to 68%) during the first week of illness.
doi:10.1128/CVI.00217-07
PMCID: PMC2043306  PMID: 17652521
12.  Leptospira Immunoglobulin-Like Proteins as a Serodiagnostic Marker for Acute Leptospirosis▿  
Journal of Clinical Microbiology  2007;45(5):1528-1534.
There is an urgent need for improved diagnosis of leptospirosis, an emerging infectious disease which imparts a large disease burden in developing countries. We evaluated the use of Leptospira immunoglobulin (Ig)-like (Lig) proteins as a serodiagnostic marker for leptospirosis. Lig proteins have bacterial immunoglobulin-like (Big) tandem repeat domains, a moiety found in virulence factors in other pathogens. Sera from patients identified during urban outbreaks in Brazil reacted strongly with immunoblots of a recombinant fragment comprised of the second to sixth Big domains of LigB from L. interrogans serovar Copenhageni, the principal agent for transmission in this setting. Furthermore, the sera recognized an analogous LigB fragment derived from L. kirschneri serovar Grippotyphosa, a pathogenic serovar which is not endemic to the study area. The immunoblot assay detected anti-LigB IgM antibodies in sera from 92% (95% confidence interval, 85 to 96%) of patients during acute-phase leptospirosis. The assay had a sensitivity of 81% for sera from patients with less than 7 days of illness. Anti-LigB antibodies were found in sera from 57% of the patients who did not have detectable anti-whole-Leptospira responses as detected by IgM enzyme-linked immunosorbent assay and microagglutination test. The specificities of the assay were 93 to 100% and 90 to 97% among sera from healthy individuals and patients with diseases that have clinical presentations that overlap with those of leptospirosis, respectively. These findings indicate that the antibody response to this putative virulence determinant is a sensitive and specific marker for acute infection. The use of this marker may aid the prompt and timely diagnosis required to reduce the high mortality associated with severe forms of the disease.
doi:10.1128/JCM.02344-06
PMCID: PMC1865864  PMID: 17360842

Results 1-12 (12)