Immunobiology and Pathogenesis

Helena Soares -  2016-01-27 -3730

Helena Soares

Principal Investigator

Graduated in Pharmaceutical Sciences from University of Coimbra, Portugal.
PhD in Biomedicine from the Rockefeller University, NYC, USA and Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal, under the supervision of Ralph Steinman
Postdoctoral fellow and Research Associate at Pasteur Institute, Paris, France.

CV

 

Location:

CEDOC
Campus Sant'Ana
Pólo de Investigação, NMS, UNL
Rua do Instituto Bacteriológico, nº 5
Lab 1.2
1150-082 Lisboa, Portugal

Phone: (+351) 218 803 101 (Ext.27003)
Lab ext: 27020
E-mail: helena.soares(at)nms.unl.pt

Main interests

T cells play crucial roles in immune response against pathogens and tumors. However, T cells are also a major cause of chronic inflammation driving autoimmunity and HIV-1 infection. Our lab aims to illuminate the role of (mis)communication between T cells and the tissue microenvironments in the development of human chronic inflammatory diseases. The best way to provide insights to human disease that can be readily translatable into revolutionary new therapies is to study directly the pathological processes in patients. Using tissue samples from patients we are pursuing how biological variables such as gender/sex, infectious agents, autoimmune diseases, and tissue microenvironment impinge on the signaling and metabolic circuitry of T cells driving the chronic inflammation and pathology.

To cover the multiple facets of human disease we have established an interdisciplinary approach combining: clinical, bioinformatics, cellular and molecular immunology and cutting-edge microscopy. A better knowledge of the complex interactions between genetic, immunological and environmental factors will lead to the ultimate goal: to develop new approaches that will allow for patient stratification and to identify novel therapeutic targets that will enable the development of precision therapies.

Fig1_IAP-1

 
 

Research Areas

1-Elucidate the tissue specific mechanisms that convey and/or counter-regulate chronic inflammation

Plasticity endows T cells to be influenced by their microenvironment and respond to it accordingly. A specific microenvironment is defined by a variety of factors, including biological and chemical composition, cell-cell interactions, but also metabolic and mechanical cues. Tissue injury as well as inflammatory tissue alterations lead to changes in the niche influencing the plasticity and biology of residing/incoming T cells.

1A- Reprogramming inflammatory T cells to treat autoimmune diseases

CD4 T cells are key drivers of rheumatoid arthritis (RA), the most common inflammatory rheumatic disease. Current biological treatments, including inhibition of T cell co-stimulation, are successful at managing RA in a subset of patients, but 40 % of patients do not respond to therapy. There is an unmet need for therapies that precisely target the mechanisms underpinning CD4 T cell dysregulation rather than overall T cell activation or the end products, inflammatory cytokines. In rheumatoid arthritis, elucidating how the joint microenvironment imprints dysregulated T cell inflammation, drives and possibly diversifies their pathological functions could broaden the potential therapeutic targets, extending beyond the successful blockade of end-stage inflammatory mediators.

Our research breaches immunology and clinical studies. We start with clinical data and tissue samples from patients and probe for the cellular and molecular mechanisms involved. This research line focuses on defining the basis and consequences of pathogenic T cell populations in the development of Rheumatoid Arthritis. It combines high-throughput studies to identify genes/drug targets with molecular and cellular characterization of pathogenic T cell populations through multiparameter flow cytometry and advanced microscopy. Additionally, tissue explants will be used to elucidate the role of tissue microenvironment in driving joint chronic inflammation.

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1B- Homeostatic regulation of T cell plasticity by the tissue microenvironment

Using blood T cells from healthy donors and exposing them to particular tissue microenvironment conditioning, we are unveiling the cellular and molecular mechanisms by which tissue microenvironment counter-regulates T cell inflammatory profile conducive to tissue homeostasis/repair.

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2- Tackling HIV-1 follicular reservoirs: from HIV-1 genetic diversity to sex-biased immune responses

The compounded contribution of host intrinsic factors, immunological niches and viral genetic diversity to HIV-1 pathogenesis remain largely unknown. First, sex has been a neglected host intrinsic variable, yet women display faster HIV disease progression. Second, the immunological niche offered by follicular T (Tfh) cells allows for HIV-1 ongoing replication even in successfully treated patients. Finally, most of current knowledge on HIV-1 pathogenicity is based on the study of the fairly infrequent subtype B. The mechanisms underlying HIV-female bias, the establishment of Tfh replicating reservoirs and how HIV-genetic diversity impinge on pathogenicity remain largely undefined. We are addressing HIV-1 infection as a continuum of host intrinsic biological factors, immunological niches and HIV-1 genetic diversity.

2A- Eradicating HIV-1 follicular sanctuaries through immunotherapy

HIV-1 is primarily an infection of lymphoid tissues. Anti-retroviral therapy (ART) has rendered HIV-1 infection a manageable illness for those with access to treatment, still it does not clear reservoirs where the virus persists. Follicular helper T (Tfh) cells were recently identified as the major source of ongoing HIV-1 replication even in ART-treated patients. To dissect cellular and molecular characteristics of the follicular reservoir we are using human follicular T cells isolated from human tonsils through fluorescence-activated cell sorting (FACS) and infect them ex vivo with HIV-1. We are pursuing the identification, at the molecular level, the activation and metabolic pathways hijacked by HIV-1 through a combination of flow cytometry, metabolic assays and confocal analysis.

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2B- Sex-biased T cell immunity and HIV-1 pathogenicity

Women mount stronger immune responses and experience more severe HIV-1 pathogenesis. The precise mechanism mediating the sexual dimorphism in HIV-1 pathogenesis is not known, partly because sex has not been considered a biological variable. Using human blood and tonsillar samples, we aim at identifying the molecular determinants underpinning the interplay between sex hormones and HIV-1 infection in order to identify potential pathways for intervention, and to rationally control for biological differences relevant to therapeutic efficacy outcomes.

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2C- Impact of HIV-1 genetic diversity in immunodeficiency

HIV-1 genetic diversity explains 29% of the variation in disease severity, while host factors explain 8.4% (9). Even though it only accounts for ~10% of worldwide HIV-1 infections, the subtype B constitutes the almost exclusive source of HIV-1 laboratory studies. However, distinct HIV-1 subtypes have different biological properties including disease progression rates and cellular tropism. The impact of HIV genetic diversity can only be optimally undertaken in countries with high HIV genetic diversity through first-rate clinical registry.

In Angola, we are sequencing HIV-1 mutations found in newborn and mother samples and associating them to drug resistance. This study goal is to be able to adjust the ART regimen of these newborns and their mothers to their HIV-1 sequences and will improve the quality of life of Angolan children.

Fig6A_IAP-1

In our Portuguese cohort (in collaboration with Nuno Osório at Universidade do Minho), we are incorporating HIV phylogenetic and computational prediction of molecular evolution and immunogenicity analysis with immunovirological approaches to dissect the impact of HIV-genetic variability on HIV-pathogenesis and tropism for Tfh reservoirs.

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Projects

-PTDC/MEC-REU/29520/2017
“Reprogramming inflammatory-follicular T cells (Tfhi): from the clinic to precision immunotherapies”
PI: Helena Soares
Co-PI: Jaime C. Branco

- Gilead Génese: May 2018-April 2020
"Impact of HIV-1 Genetic Diversity on Immunodeficiency"
Total: 35500€
Co-PIs Nuno Osório from ICVS, Braga

- NOVASaúde Grant: July 2017-July 2018
“Development of Novel AZT Derivatives Based on Triazoles”.
Total: 12000€
Co-PIs Ana Petronilho from ITQB-NOVA

- Pfizer sponsored Sociedade Portuguesa de Reumatologia Award: June 2017-May 2018
“Bridging Innate and Adaptive Immunity through JAK signalling”
Total: 5000€
Co-PI: Fernando Pimentel-Santos

- Gilead Génese: April 2017-March 2019
“HIV-1 Replication in Follicular Sanctuaries”.
Total: 31200€

- Investigador FCT 2014-2019

- ANRS (French AIDS Research Foundation) Grant: 2013-2015

Selected Publications

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Collaborations

Jaime Branco - Rheumatological Diseases Unit CEDOC|FCM, Lisbon, Portugal

Fernando Pimentel-Santos - Rheumatological Diseases Unit CEDOC|FCM, Lisbon, Portugal

Ana Filipa Mourão - Hospital Egas Moniz, CHLO, Lisbon, Portugal

Cristina Caroça - CUF, Lisbon, Portugal

Ricardo Henriques - Quantitative Imaging and NanoBioPhysics Group, UCL, London, UK

Paula Videira - Laboratory of Glycoimmunology, Faculdade de Ciências e Tecnologia, Caparica, Portugal

Robert Weil - Laboratory of Signalling and Pathogenesis, Institut Pasteur, Paris, France

Team photos

foto grupo 2017

We welcome motivated technicians, students (undergraduates, master and PhD) and post-docs to join our lab. For enquiries on available positions contact Helena Soares (helena.soares(at)nms.unl.pt). Please add a letter detailing the reasons you are applying, your CV, and contact information of 3 references.