Ana Espada de Sousa Lab

Human Immunodeficiency & Immune Reconstitution

Health relies on a competent immune system. Our aim is to understand the pathogenesis of immunodeficiency and find new strategies for immune reconstitution. We revealed mechanisms involved in human T cell homeostasis and immune regulation through the study of unique clinical settings, such as 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.

The comparative study of these two infections allowed us to clarify central issues in AIDS immunopathogenesis, taking advantage of the fact that Portugal is the only non-African country with a significant HIV-2 prevalence. Additionally, our unit integrates a reference centre that performs diagnosis, specialized follow-up and research in primary immunodeficiencies, rare diseases considered natural experiments from which we can learn a great deal about the human immune system. The ultimate goal is that our research on T-cell development in the human thymus and lymphoid tissue preservation, particularly in the context of persistent immune activation, translates into innovative immune-based therapies.

Research Team

Research Areas

• Human T-cell biology
• Human T-cell development
• HIV/AIDS Immunopathogenesis
• HIV-2 infection
• Primary Immunodeficiencies
• Immunological Reconstitution

Ongoing Research Projects

2019/2021 Contributo dos monócitos/macrófagos para a patogénese distinta da infeção por HIV-2 em comparação com HIV-1: correlações clínicas e perspetivas terapêuticas. Funding Agency: Gilead Sciences. Coordinator: Amelia Chiara Trombetta.

2018/2021 HIV2CURE: Células T foliculares no cerne da infecção HIV (LISBOA-01-0145-FEDER-030474). Funding Agency: Fundação para a Ciência e a Tecnologia and PT2020. Coordinator: Ana Espada de Sousa.

2018/2021 Estudos quantitativos de latência no VIH. Funding Agency: Fundação para a Ciência e a Tecnologia. Coordinator: Ruy Ribeiro.

2018/2021 Explorando o papel de microRNAs na função de células T e defesa anti-HIV. Funding Agency: Fundação para a Ciência e a Tecnologia. Coordinator: Margarida Gama-Carvalho.

Awards

2019 Prémio Investigação em Autoimunidade NEDAI 2019 (SPMI). “Expansion of FOXP3+ regulatory CD4 T-cells upon exposure to hymenoptera venom during the beekeeping season”.

2016 Prémio GAPIC David-Ferreira. From immune phenotype to clinical manifestations in CVID.

2015 First Prize Award NEDAI 2015 | 2015 NEDAI Award in Research in Autoimmunity, NEDAI/Portuguese Society of Internal Medicine.

2012 NEDAI | MSD Award in Basic Research in Autoimmunity, NEDAI/Portuguese Society of Internal Medicine.

2008 Pfizer Award in Clinical Research, Lisbon Society of Medical Science.

2005 Bristol-Myers Squibb Research Award in Infection by virus of Human Immunodeficiency, Portuguese Association for AIDS Clinical Research (APECS).

2004 VIH Researches/ Glaxo-Smith Kline, Portuguese Society of Internal Medicine (SPMI).

2002 Dr. José Luís Champalimaud Award, Applied Research National, Commission of Fight Against AIDS.

Selected Publications

Godinho-Santos A, Foxall RB, Antão AV, Tavares B, Ferreira T, Serra-Caetano A, Matoso P, Sousa AE. (2019) Follicular Helper T Cells Are Major Human Immunodeficiency Virus-2 Reservoirs and Support Productive Infection. The Journal of Infectious Diseases, jiz431, doi: 10.1093/infdis/jiz431.

Silva SL, Fonseca M, Pereira M, Silva SP, Barbosa R, Serra-Caetano A, Blanco E, Rosmaninho P, Perez-Andres M, Sousa AB, Raposo AA, Gama-Carvalho M, Victorino RM, Sousa AE. (2019) Monozygotic twins concordant for common variable immunodeficiency: strikingly similar clinical and immune profile associated with polygenic burden. Front. Immunol. doi: 10.3389/fimmu.2019.02503

Blanco E, Pérez-Andrés M, Arriba-Méndez S, Serrano C, Criado I, Del Pino-Molina L, Silva S, Madruga I, Bakardjieva M, Martins C, Serra-Caetano A, Romero A, Contreras-Sanfeliciano T, Bonroy C, Sala F, Martín A, Bastida JM, Lorente F, Prieto C, Dávila I, Marcos M, Kalina T, Vlkova M, Chovancova Z, Cordeiro AI, Philippé J, Haerynck F, López-Granados E, Sousa AE, van der Burg M, van Dongen JJM, Orfao A; EuroFlow PID group. (2019) Defects in memory B-cell and plasma cell subsets expressing different immunoglobulin-subclasses in patients with CVID and immunoglobulin subclass deficiencies. J Allergy Clin Immunol. Feb 28. pii: S0091-6749(19)30280-5. doi: 10.1016/j.jaci.2019.02.017. [Epub ahead of print]

van Dongen JJM, van der Burg M, Kalina T, Perez-Andres M, Mejstrikova E, Vlkova M, Lopez-Granados E, Wentink M, Kienzler AK, Philippé J, Sousa AE, van Zelm MC, Blanco E, Orfao A. (2019) EuroFlow-Based Flowcytometric Diagnostic Screening and Classification of Primary Immunodeficiencies of the Lymphoid System. Front Immunol. Jun 13;10:1271. doi: 10.3389/fimmu.2019.01271. eCollection 2019.

Santos MCP, Serra-Caetano A, Pedro E, Melo A, Caramalho I, Barbosa MP, Victorino RMM, Sousa AE. (2019) Expansion of FOXP3+ regulatory CD4 T-cells upon exposure to hymenoptera venom during the beekeeping season. Allergy 68(4):673-685doi: 10.1111/all.13713.

Dorhoi A, Glaría E, Garcia-Tellez T, Nieuwenhuizen NE, Zelinskyy G, Favier B, Singh A, Ehrchen J, Gujer C, Münz C, Saraiva M, Sohrabi Y, Sousa AE, Delputte P, Müller-Trutwin M, Valledor AF. (2019) MDSCs in infectious diseases: regulation, roles, and readjustment. Cancer Immunol Immunother. 68(4):673-685. doi: 10.1007/s00262-018-2277-y.

van der Burg M, Kalina T, Perez-Andres M, Vlkova M, Lopez-Granados E, Blanco E, Bonroy C, Sousa AE, Kienzler AK, Wentink M, Mejstríková E, Šinkorova V, Stuchly J, van Zelm MC, Orfao A, van Dongen JJM. (2019) The EuroFlow PID Orientation Tube for Flow Cytometric Diagnostic Screening of Primary Immunodeficiencies of the Lymphoid System. Front Immunol. Mar 4;10:246. doi: 10.3389/fimmu.2019.00246. eCollection 2019.

Blanco E, Pérez-Andrés M, Arriba-Méndez S, Contreras-Sanfeliciano T, Criado I, Pelak O, Serra-Caetano A, Romero A, Puig N, Remesal A, Torres Canizales J, López-Granados E, Kalina T, Sousa AE, Van Zelm M, Van der Burg M, van Dongen JJM, Orfao A; EuroFlow PID group. (2018) Age-associated distribution of normal B-cell and plasma cell subsets in peripheral blood. J Allergy Clin Immunol. Jun;141(6):2208-2219.e16. doi: 10.1016/j.jaci.2018.02.017.

Fernandes SM, Pires AR, Matoso P, Ferreira C, Nunes-Cabaço H, Correia L, Valadas E, Poças J, Pacheco P, Veiga-Fernandes H, Foxall RB, Sousa AE. (2018) HIV-2 infection is associated with preserved GALT homeostasis and epithelial integrity despite ongoing mucosal viral replication. Mucosal Immunol. Jan;11(1):236-248. doi: 10.1038/mi.2017.44. Epub 2017 May 17.

Fonseca VR, Agua-Doce A, Maceiras AR, Pierson W, Ribeiro F, Romão VC, Pires AR, da Silva SL, Fonseca JE, Sousa AE, Linterman MA, Graca L (2017) Human blood Tfr cells are indicators of ongoing humoral activity not fully licensed with suppressive function. Sci Immunol. Aug 11;2(14). pii: eaan1487. doi: 10.1126/sciimmunol.aan1487.

Silva SL, Albuquerque AS, Matoso P, Charmeteau-de-Muylder B, Cheynier R, Ligeiro D, Abecasis M, Anjos R, Barata JT, Victorino RM, Sousa AE (2017). IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity. Front Immunol. 2017 Jan 19;8:20. doi: 10.3389/fimmu.2017.00020. eCollection 2017

Amaral AJ, Andrade J, Foxall RB, Matoso P, Matos AM, Soares RS, Rocha C, Ramos CG, Tendeiro R, Serra-Caetano A, Guerra-Assunção JA, Santa-Marta M, Gonçalves J, Gama-Carvalho M, Sousa AE (2017). miRNA profiling of human naive CD4 T cells links miR-34c-5p to cell activation and HIV replication. EMBO J. 2017 Feb 1;36(3):346-360. doi: 10.15252/embj.201694335. Epub 2016 Dec 19.

Susana L Silva, Ana E Sousa (2016). Establishment and maintenance of the human naïve CD4+ T-cell compartment. Frontiers in Pediatrics. doi: 10.3389/fped.2016.00119.

Silva SL, Albuquerque AS, Serra-Caetano A, Foxall RB, Pires AR, Matoso P, Fernandes SM, Ferreira J, Cheynier R, Victorino RM, Caramalho I, Barata JT, Sousa AE. (2016) Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7. Oncotarget. 15;7(11):12163-75.

Nunes-Cabaço H, Matoso P, Foxall RB, Tendeiro R, Pires AR, Carvalho T, Pinheiro AI, Soares RS, Sousa AE. (2015) Thymic HIV-2 infection uncovers posttranscriptional control of viral replication in human thymocytes. J Virol. 89, 2201-8.

Caramalho I, Nunes-Silva V, Pires AR, Mota C, Pinto AI, Nunes-Cabaço H, Foxall RB, Sousa AE. (2015) Human regulatory T-cell development is dictated by Interleukin-2 and -15 expressed in a non-overlapping pattern in the thymus. J Autoimmun. 56:98-110.

Caramalho I, Nunes-Cabaço H, Foxall RB, Sousa AE. (2015) Regulatory T-cell development in the human thymus. Front Immunol. 6:395 eCollection.

Caramalho I, Melo A, Pedro E, Barbosa MM, Victorino RM, Pereira Santos MC, Sousa AE. (2015) Bee venom enhances the differentiation of human regulatory T cells, Allergy. 70, 1340-5.

Mota C, Nunes-Silva V, Pires AR, Matoso P, Victorino RM, Sousa AE, Caramalho I. (2014) Delta-like 1-mediated Notch signaling enhances the in vitro conversion of human memory CD4 T cells into FOXP3-expressing regulatory T cells. J Immunol. 193, 5854-62.

Fernandes SM, Pires AR, Ferreira C, Foxall RB, Rino J, Santos C, Correia L, Poças J, Veiga-Fernandes H, Sousa AE. (2014) Enteric Mucosa Integrity in the Presence of a Preserved Innate Interleukin 22 Compartment in HIV Type 1-Treated Individuals. J Infect Dis. 210:630-40.

Barbosa RR, Silva SL, Silva SP, Melo AC, Pereira-Santos MC, Barata JT, Hammarström L, Cascalho M, Sousa AE. (2014) Reduced BAFF-R and Increased TACI Expression in Common Variable Immunodeficiency. J Clin Immunol 34:573-83.

Cavaleiro R, Tendeiro R, Foxall RB, Soares RS, Baptista AP, Gomes P, Valadas E, Victorino RMM, Sousa AE. (2013) Monocyte and myeloid dendritic cell activation occurs throughout the course of HIV-2 infection, an attenuated form of HIV disease. J Infect Dis 207:1730-42.

Tendeiro R, Foxall RB, Baptista AP, Pinto F, Soares RS, Cavaleiro R, Valadas E, Gomes P, Victorino RM, Sousa AE. (2012) PD-1 and its ligand PD-L1 are progressively up-regulated on CD4 and CD8 T-cells in HIV-2 infection irrespective of the presence of viremia. AIDS 26:1065-1071.

Nunes-Cabaço H, Caramalho I, Sepúlveda N, Sousa AE. (2011) Differentiation of human thymic regulatory T-cells at the double positive stage. Eur J Immunol 41:3604-14.

Foxall RB, Albuquerque AS, Soares RS, Baptista AP, Cavaleiro R, Tendeiro R, Gomes P, Victorino RM, Sousa AE. (2011) Memory and naïve-like regulatory CD4+ T cells expand during HIV-2 infection in direct association with CD4+ T-cell depletion irrespectively of viremia. AIDS 25:1961-70.

Markert ML, Marques JG, Neven B, Devlin BH, McCarthy EA, Chinn IK, Albuquerque AS, Silva SL, Pignata C, de Saint Basile G, Victorino RM, Picard C, Debre M, Mahlaoui N, Fischer A, Sousa AE. (2011) First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases. Blood 117:688-96.

Soares RS, Tendeiro R, Foxall RB, Baptista AP, Cavaleiro R, Gomes P, Camacho R, Valadas E, Doroana M, Lucas M, Antunes F, Victorino RM, Sousa AE. (2011) Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patients. J Virol 85: 2429-38.

Barbosa RR, Silva SP, Silva SL, Melo AC, Pedro E, Barbosa MP, Pereira-Santos MC, Victorino RM, Sousa AE. (2011) Primary B-Cell Deficiencies Reveal a Link between Human IL-17-Producing CD4 T-Cell Homeostasis and B-Cell Differentiation. PLoS One 6:e22848.

Cavaleiro R, Baptista AP., Soares RS, Tendeiro R, Foxall RB, Gomes P, Victorino RMM, Sousa AE. (2009) Major depletion of plasmacytoid dendritic cells in HIV-2 infection, an attenuated form of HIV disease. PloS Pathog 5:e1000667.

Azevedo RI, Soares MV, Barata JT, Tendeiro R, Serra-Caetano A, Victorino RM, Sousa AE. (2009) IL-7 sustains CD31 expression in human naive CD4+ T cells and preferentially expands the CD31+ subset in a PI3K-dependent manner. Blood 113:2999-3007.

Foxall RB, Cortesão CS, Albuquerque AS, Soares RS, Victorino RM, Sousa AE. (2008) Gag-specific CD4+ T-cell frequency is inversely correlated with proviral load and directly correlated with immune activation in infection with human immunodeficiency virus type 2 (HIV-2) but not HIV-1. J Virol 82:9795-9.

Pereira-Santos M.C., Baptista A.P., Melo A., Alves R.R., Soares R.S., Pedro E., Pereira-Barbosa M., Victorino R.M.M., Sousa A.E.. (2008) Expansion of circulating FoxP3+CD25bright CD4+ T cells during specific venom immunotherapy. Clin Exp Allergy 38:291-297.

Sousa, A. E., J. Carneiro, M. Meier-Schellersheim, Z. Grossman, and 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. J Immunol 169:3400-06.

Grossman, Z., M. Meier-Schellersheim, A. E. Sousa, R. M. Victorino, and W. E. Paul. (2002) CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nature Medicine 8:319-21.

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