Egídio Torrado

University of Minho

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António G. Castro

University of Minho

Andrea M. Cooper

University of Leicester

Ana Margarida Barbosa

Federal Institute of São Paulo

Jorge Pedrosa

University of Minho

Cristina Cunha

University of Minho

Agostinho Carvalho

University of Minho

Fernando Rodrigues

University of Minho

Ricardo Silvestre

University of Minho

Alexandra G. Fraga

University of Minho

Margarida Saraiva

Instituto Português de Oncologia Francisco Gentil

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University of Minho

108

Universidade do Porto

Inserm

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto

Université Paris Cité

Universidade de São Paulo

Trudeau Institute

Instituto de Biologia Molecular e Celular

Institut des Maladies Génétiques Imagine

Centre National de la Recherche Scientifique

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Immune-evasion Strategies of Mycobacteria and Their Implications for the Protective Immune Response

Caister Academic Press eBooks (2017)

Alexandra G. Fraga Ana Margarida Barbosa Catarina M. Ferreira João Fevereiro Jorge Pedrosa

Infectious diseases continue to be a major threat to human health with predictions that these will account for one of five deaths globally over the coming decades.The worrying rise in antibiotic resistance in bacterial pathogens only serves to exacerbate this situation.Many pathogenic bacteria have evolved an array of sophisticated mechanisms to evade the host's immune response: some even exploit host functions to avoid detection by immune cells.Understanding the mechanisms of this subversion is critical for the understanding of bacterial pathogenesis and could be used for the development of novel antibacterial strategies.In this volume expert authors critically review the most important current research in this exciting field.Topics include: the seven most important bacterial secretion systems; within-host envelope remodelling; subversion of macrophages; pathogen manipulation of host autophagy; mechanisms involved in sensing and restriction of bacterial replication; mechanisms of evasion by Salmonella; evasion strategies of mycobacteria; and role of Cyclic di-GMP in virulence and evasion of plant immune systems.This text is essential reading for everyone involved in bacterial pathogenesis research and an invaluable reference work for those working in fields as diverse as medicine, biotechnology, agriculture, food and industry.A recommended acquisition for all microbiology laboratories.

Evasion (ethics)

10.21775/9781910190692.07

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Citations (1)

Ploidy Determination in the Pathogenic Fungus Sporothrix spp.

Frontiers in Microbiology (2019)

Beatriz H. Ferreira Jorge Humberto Ramírez-Prado Gabriela W. P. Neves Egídio Torrado Paula Sampaio

The pathogenic clade of the

Sporothrix schenckii

Sporothrix

Pathogenic fungus

10.3389/fmicb.2019.00284

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Citations (8)

Protection against systemic candidiasis in mice immunized with secreted aspartic proteinase 2

Immunology (2004)

Manuel Vilanova Luzia Teixeira Íris Caramalho Egídio Torrado Andreia Marques

Summary Secreted aspartic proteinases (Sap) have been described as virulence factors implicated in the mechanisms of host colonization by the yeast Candida albicans in different types of candidiasis. Intraperitoneal inoculation of C. albicans into BALB/c mice rapidly leads to systemic candidiasis, with significant colonization of the kidneys measurable in the following week. In this study we assessed the potential of vaccination with C. albicans secreted aspartic proteinase 2 (Sap2) in preventing systemic candidiasis in BALB/c mice. Intradermal injection of highly purified native Sap2 protein incorporated in alum adjuvant provided efficient immune protection, as indicated by a 20‐fold decrease in the colonization of kidneys. The protective effect of Sap2 immunization with alum adjuvant was also observed in mice infected with a lethal inoculum of C. albicans . Immunization with the native Sap2 alone, as well as with a denatured recombinant form of the protein, also conferred protection, albeit to a lesser level. In all cases, protection correlated with an increase in serum antibodies to Sap2. Moreover, passive transfer of anti‐Sap2 immunoglobulin G (IgG) significantly decreased the yeast burden in kidneys of C. albicans ‐infected mice. This result shows that immune protection against systemic candidiasis in mice immunized with Sap2 is antibody‐mediated. Taken together, these analyses demonstrate that Sap2 can be successfully used as a vaccination target in systemic candidiasis and reveals the potential immunomodulatory role of Sap2 on C. albicans infection.

Systemic candidiasis

10.1111/j.1365-2567.2004.01819.x

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Citations (70)

Cutting Edge: IFN-γ Regulates the Induction and Expansion of IL-17-Producing CD4 T Cells during Mycobacterial Infection

The Journal of Immunology (2006)

Andrea Cruz Shabaana A. Khader Egídio Torrado Alexandra G. Fraga John E. Pearl

Abstract T cell responses are important to the control of infection but are deleterious if not regulated. IFN-γ-deficient mice infected with mycobacteria exhibit enhanced accumulation of activated effector T cells and neutrophils within granulomatous lesions. These cells do not control bacterial growth and compromise the integrity of the infected tissue. We show that IFN-γ-deficient mice have increased numbers of IL-17-producing T cells following infection with Mycobacterium bovis bacille Calmette Guérin. Furthermore, exogenous IFN-γ increases IL-12 and decreases IL-23 production by bacille Calmette Guérin-infected bone marrow-derived dendritic cells and reduces the frequency of IL-17-producing T cells induced by these bone marrow-derived dendritic cells. These data support the hypothesis that, during mycobacterial infection, both IFN-γ- and IL-17-producing T cells are induced, but that IFN-γ serves to limit the IL-17-producing T cell population. This counterregulation pathway may be an important factor in limiting mycobacterially associated immune-mediated pathology.

10.4049/jimmunol.177.3.1416

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Citations (284)

Protecting the most vulnerable: tuberculosis in immunocompromised individuals

European Respiratory Society eBooks (2023)

Egídio Torrado Reinout vanCrevel Ana Raquel Afonso Diana Amorim Raquel Duarte

10.1183/2312508x.10025422

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The Absence of HIF-1α Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis

Cell Reports (2020)

Inês Mesquita Carolina Ferreira Diana Moreira George Eduardo Gabriel Kluck Ana Margarida Barbosa

Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in infected HIF-1α−/− macrophages. L. donovani-infected HIF-1α-deficient mice develop hypertriglyceridemia and lipid accumulation in splenic and hepatic myeloid cells. Most importantly, our data demonstrate that manipulating FASN or SREBP-1c using pharmacological inhibitors significantly reduced parasite burden. As such, genetic deficiency of HIF-1α is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells.

Lipogenesis

mTORC2

10.1016/j.celrep.2020.02.098

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Citations (39)

Cellular Immunity Confers Transient Protection in Experimental Buruli Ulcer following BCG or Mycolactone-Negative Mycobacterium ulcerans Vaccination

PLoS ONE (2012)

Alexandra G. Fraga Teresa G. Martins Egídio Torrado Kris Huygen Françoise Portaels

Background Buruli ulcer (BU) is an emerging infectious disease caused by Mycobacterium ulcerans that can result in extensive necrotizing cutaneous lesions due to the cytotoxic exotoxin mycolactone. There is no specific vaccine against BU but reports show some degree of cross-reactive protection conferred by M. bovis BCG immunization. Alternatively, an M. ulcerans-specific immunization could be a better preventive strategy. Methodology/Principal Findings In this study, we used the mouse model to characterize the histological and cytokine profiles triggered by vaccination with either BCG or mycolactone-negative M. ulcerans, followed by footpad infection with virulent M. ulcerans. We observed that BCG vaccination significantly delayed the onset of M. ulcerans growth and footpad swelling through the induction of an earlier and sustained IFN-γ T cell response in the draining lymph node (DLN). BCG vaccination also resulted in cell-mediated immunity (CMI) in M. ulcerans-infected footpads, given the predominance of a chronic mononuclear infiltrate positive for iNOS, as well as increased and sustained levels of IFN-γ and TNF. No significant IL-4, IL-17 or IL-10 responses were detected in the footpad or the DLN, in either infected or vaccinated mice. Despite this protective Th1 response, BCG vaccination did not avoid the later progression of M. ulcerans infection, regardless of challenge dose. Immunization with mycolactone-deficient M. ulcerans also significantly delayed the progression of footpad infection, swelling and ulceration, but ultimately M. ulcerans pathogenic mechanisms prevailed. Conclusions/Significance The delay in the emergence of pathology observed in vaccinated mice emphasizes the relevance of protective Th1 recall responses against M. ulcerans. In future studies it will be important to determine how the transient CMI induced by vaccination is compromised.

Mycobacterium ulcerans

Buruli ulcer

BCG vaccine

10.1371/journal.pone.0033406

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Citations (45)

Mycobacterium ulcerans Triggers T-Cell Immunity followed by Local and Regional but Not Systemic Immunosuppression

Infection and Immunity (2010)

Alexandra G. Fraga Andrea Cruz Teresa G. Martins Egídio Torrado Margarida Saraiva

Buruli ulcer is a neglected infectious disease caused by Mycobacterium ulcerans and is characterized by necrotic cutaneous lesions induced by the exotoxin mycolactone. Despite evidence of Th1-mediated protective immunity, M. ulcerans infection has been associated with systemic immunosuppression. We show that early during mouse infection with either mycolactone-positive or negative strains, pathogen-specific gamma interferon (IFN-γ)-producing T cells developed in the draining lymph node (DLN). CD4(+) cells migrated to the infection foci, but progressive infection with virulent M. ulcerans led to the local depletion of recruited cells. Moreover, dissemination of virulent M. ulcerans to the DLN was accompanied by extensive DLN apoptotic cytopathology, leading to depletion of CD4(+) T cells and abrogation of IFN-γ expression. Advanced footpad infection with virulent M. ulcerans did not induce increased susceptibility to systemic coinfection by Listeria monocytogenes. These results show that infection with M. ulcerans efficiently triggers a mycobacterium-specific T-cell response in the DLN and that progression of infection with highly virulent M. ulcerans leads to a local and regional suppression of that immune response, but without induction of systemic immunosuppression. These results suggest that prophylactic and/or therapeutic interventions to prevent dissemination of M. ulcerans to DLN during the early phase of infection would contribute for the maintenance of protective immunity and disease control.

Mycobacterium ulcerans

Buruli ulcer

Exotoxin

Immunosuppression

10.1128/iai.00820-10

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Citations (46)

IFN-γ–Dependent Activation of Macrophages during Experimental Infections by Mycobacterium ulcerans Is Impaired by the Toxin Mycolactone

The Journal of Immunology (2009)

Egídio Torrado Alexandra G. Fraga Elsa Logarinho Teresa G. Martins Jenny Andrea Carmona

Buruli ulcer, caused by Mycobacterium ulcerans infections, is a necrotizing skin disease whose pathogenesis is associated with the exotoxin mycolactone. Despite the relevance of this emergent disease, little is known on the immune response against the pathogen. Following the recent demonstration of an intramacrophage growth phase for M. ulcerans, we investigated the biological relevance of IFN-gamma and the antimycobacterial mechanisms activated by this cytokine in M. ulcerans-infected macrophages. Three M. ulcerans strains were tested: 5114 (mutant mycolactone-negative, avirulent strain); 94-1327 (intermediate virulence); and 98-912 (high virulence). We show in this study that IFN-gamma is expressed in mouse-infected tissues and that IFN-gamma-deficient mice display increased susceptibility to infection with strains 5114 and, to a lesser extent, 94-1327, but not with the highly virulent strain. Accordingly, IFN-gamma-activated cultured macrophages controlled the proliferation of the avirulent and the intermediate virulent strains. Addition of mycolactone purified from strain 98-912 to cultures of IFN-gamma-activated macrophages infected with the mycolactone-negative strain led to a dose-dependent inhibition of the IFN-gamma-induced protective mechanisms, involving phagosome maturation/acidification and increased NO production, therefore resulting in increased bacterial burdens. Our findings suggest that the protection mediated by IFN-gamma in M. ulcerans-infected macrophages is impaired by the local buildup of mycolactone.

Mycobacterium ulcerans

Buruli ulcer

Exotoxin

10.4049/jimmunol.0902717

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Citations (55)

Hypoxia inducible-factor 1 alpha regulates neutrophil recruitment during fungal-elicited granulomatous inflammation

Frontiers in Cellular and Infection Microbiology (2022)

Sara da Silva-Ferreira Cláudio Duarte‐Oliveira Daniela Antunes Catarina Barbosa-Matos Ana Mendes‐Frias

Chronic pulmonary aspergillosis (CPA) is a devastating disease with increasing prevalence worldwide. The characteristic granulomatous-like inflammation poses as the major setback to effective antifungal therapies by limiting drug access to fungi. These inflammatory lung structures are reported to be severely hypoxic; nevertheless, the underlying mechanisms whereby these processes contribute to fungal persistence remain largely unknown. Hypoxia-inducible factor 1 alpha (HIF-1α), besides being the major cellular response regulator to hypoxia, is a known central immune modulator. Here, we used a model of Aspergillus fumigatus airway infection in myeloid-restricted HIF-1α knock-out ( mHif1α -/- ) mice to replicate the complex structures resembling fungal granulomas and evaluate the contribution of HIF-1α to antifungal immunity and disease development. We found that fungal-elicited granulomas in mHif1α -/- mice had significantly smaller areas, along with extensive hyphal growth and increased lung fungal burden. This phenotype was associated with defective neutrophil recruitment and an increased neutrophil death, therefore highlighting a central role for HIF-1α-mediated regulation of neutrophil function in the pathogenesis of chronic fungal infection. These results hold the promise of an improved capacity to manage the progression of chronic fungal disease and open new avenues for additional therapeutic targets and niches of intervention.

Hypoxia

Granulomatous Inflammation

Hypoxia-Inducible Factors

10.3389/fcimb.2022.1005839

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Citations (4)