Ana Espada de Sousa Lab

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Group leader

Ana Espada de Sousa

Group Leader

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Human Immunodeficiency & Immune Reconstitution

We investigate immune regulation and human T-cell homeostasis with the goal of identifying new strategies for immunological reconstitution and targets for immune-based therapies.
Our core focus is on the development and homeostasis of CD4 T cells, the main orchestrators of the immune system.
An important part of our Lab research effort is centred on HIV/AIDS immunopathogenesis, mainly through the study of HIV-2 infection, a naturally attenuated form of HIV disease, and on Inborn Errors of Immunity leading to Human Immunodeficiency.
We prioritize the “bench-to-bedside-to-bench” cycle. Therefore, our Lab brings together physician/clinical researchers from different medical areas, and basic researchers.

Funders

Our research is mainly focused in four areas of human immunology:

T cell development in the human thymus

Lineage-committed Regulatory T cells (Tregs) in the thymus are essential for immune homeostasis and self-tolerance. We use a multi-omics approach to investigate their differentiation trajectories and functional heterogeneity including both CD4 and CD8 Tregs.

Human naïve T cell maintenance and homeostasis

Human naïve CD4 T cells acquire properties before and after leaving the thymus that impact on their homeostatic and differentiation capacity, and, consequently, on their ability to ensure immune competence throughout life. We have generated transcriptomic (RNA-seq) and epigenomic (ATAC-seq) high-throughput data from thymocytes, naive, and memory human CD4 T cells, sorted as Tregs and their conventional counterparts. Using linear regression modelling, we aim to identify the gene regulatory networks governing the expression profile defining the naive CD4 T-cell compartment within the conventional and regulatory lineages. To address the contribute of the thymus to the heterogeneity of the naïve compartment, we profiled at single-cell level the naïve compartment of adults submitted to thymus removal early in infancy in comparison with age-matched controls and have been exploring the pathways to cell resilience in the absence of thymic renewal.

HIV/AIDS immunopathogenesis through the study of a unique naturally occurring attenuated model of disease, the HIV-2 infection

HIV-2 establishes a better equilibrium with the host than HIV-1, leading to a much slower rate of disease progression and lower levels of circulating virus despite persistent viral reservoirs and evidence of ongoing HIV-2 replication in the lymphoid tissues. The comparative study of these two infections allowed us to clarify central issues in the human protection against lentiviral zoonosis and on AIDS immunopathogenesis. We take advantage of the fact that Portugal is the only non-African country with a significant HIV-2 prevalence, to decipher the protective responses induced by HIV-2 in the gut and lymph nodes. Ultimately, we aim to identify new targets for immune-based therapies to control persistent infections and inflammatory states.

Immunodeficiency due to inborn errors of immunity (IEI)

Additionally, our unit integrates a Primary Immunodeficiency Reference Centre that performs diagnosis, specialized follow-up and research in primary immunodeficiencies, rare diseases considered natural experiments from which we learn a great deal about the human immune system.

2021/2025: Fundação para a Ciência e Tecnologia, Portuguese Ministry of Science and Technology PTDC/MED-IMU/0938/2020 Targeting naïve CD4 T cells to avoid human immunodeficiency

B. Moleirinho, M. Paulo-Pedro, N. C. Martins, E. Jelagat, E. Conti, T. R. Velho, M. Abecasis, R. Anjos, A. R. M. Almeida, A. E. Sousa (2025). A backbone-based flow cytometry approach to decipher regulatory T cell trajectories in the human thymus. Frontiers in Immunology 16: 1553535. doi: 10.3389/fimmu.2025.1553535.

M. Paulo-Pedro, B. Moleirinho, D. F. Santos, A. M. C. Gomes, M. Rei, A. R. M. Almeida, J. G. Marques, S. L. Silva, A. E. Sousa (2025). Adulthood outcomes of thymic transplantation in a case of congenital athymia due to FOXN1mutation. Journal of Allergy and Clinical Immunology. doi: 10.1016/j.jaci.2025.02.006.

A. A. S. F. Raposo, P. Rosmaninho, S. L. Silva, S. Paço, M. E. Brazão, A. Godinho-Santos, Y. Tokunaga-Mizoro, H. Nunes-Cabaço, A. Serra-Caetano, A. R. M. Almeida, A. E. Sousa (2024). Decoding mutational hotspots in human disease through the gene modules governing thymic regulatory T cells. Frontiers in Immunology 15: 1458581. doi: 10.3389/fimmu.2024.1458581.

H. Nunes-Cabaço, A. Ramalho-Dos-Santos, A. R. Pires, L. R. Martins, J. T. Barata, A. E. Sousa (2022). Human CD4 T cells from thymus and cord blood are convertible into CD8 T cells by IL-4. Frontiers in Immunology 13: 834033. doi: 10.3389/fimmu.2022.834033.

Z. Grossman, N. J. Singh, F. R. Simonetti, M. M. Lederman, D. C. Douek, S. G. Deeks, T. Kawabe, G. Bocharov, M. Meier-Schellersheim, H. Alon, N. Chomont, Z. Grossman, A. E. Sousa, M. Margolis, F. Maldarelli (2020). ‘Rinse and replace’: boosting T cell turnover to reduce HIV-1 reservoirs. Trends in Immunology. doi: 10.1016/j.it.2020.04.003.

S. M. Fernandes, A. R. Pires, P. Matoso, C. Ferreira, H. Nunes-Cabaço, L. Correia, E. Valadas, J. Poças, P. Pacheco, H. Veiga-Fernandes, R. B. Foxall, A. E. Sousa (2018). HIV-2 infection is associated with preserved GALT homeostasis and epithelial integrity despite ongoing mucosal viral replication. Mucosal Immunology 11(1): 236–248.

A. J. Amaral, J. Andrade, R. B. Foxall, P. Matoso, A. M. Matos, R. S. Soares, C. Rocha, C. G. Ramos, R. Tendeiro, A. Serra-Caetano, J. A. Guerra-Assunção, M. Santa-Marta, J. Gonçalves, M. Gama-Carvalho, A. E. Sousa (2017). miRNA profiling of human naïve CD4 T cells links miR-34c-5p to cell activation and HIV replication. The EMBO Journal 36(3): 346–360.

I. Caramalho, V. Nunes-Silva, A. R. Pires, C. Mota, A. I. Pinto, H. Nunes-Cabaço, R. B. Foxall, A. E. Sousa (2015). Human regulatory T-cell development is dictated by interleukin-2 and -15 expressed in a non-overlapping pattern in the thymus. Journal of Autoimmunity 56: 98–110.

R. I. Azevedo, M. V. Soares, J. T. Barata, R. Tendeiro, A. Serra-Caetano, R. M. Victorino, A. E. Sousa (2009). IL-7 sustains CD31 expression in human naïve CD4+ T cells and preferentially expands the CD31+ subset in a PI3K-dependent manner. Blood 113: 2999–3007.

A. E. Sousa, J. Carneiro, M. Meier-Schellersheim, Z. Grossman, R. M. Victorino (2002). CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. Journal of Immunology 169: 3400–3406.

Z. Grossman, M. Meier-Schellersheim, A. E. Sousa, R. M. Victorino, W. E. Paul (2002). CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nature Medicine 8: 319–323.

A complete list of publications can be found here.

2019: Prémio de Investigação em Autoimunidade NEDAI, SPMI

2015: Prémio NEDAI de Investigação Básica em Autoimunidade, SPMI

2012: Prémio NEDAI de Investigação Básica em AutoImunidade, SPMI

2008: Prémio Pfizer de Investigação Clínica, SCML

2005: Prémio de Investigação Bristol-Myers Squibb em Infecção por VIH, APECS

2004: AMI – Saúde / Doenças Infecciosas e Parasitárias (Menção Honrosa), AMI

2004: VIH – Glaxo-Smith Kline, SPMI

2003: Prémio LabMed Saúde

2002: Prémio Dr. José Luís Champalimaud – Investigação aplicada, DGS

2002: Prémio Dr. José Luís Champalimaud – Investigação Básica (Menção Honrosa), DGS

1998: Prémio Pfizer (Menção Honrosa), SCML