A protective role for ataxia-telangiectasia mutated in hemolytic conditions

• Autor(a) principal: Martins, Susana Gomes Rodrigues
• Data de Publicação: 2019
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/90764
• topic: Ataxia-telangiectasia mutated (ATM); heme; DNA damage; hematopoietic compartment; malaria and disease tolerance; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Ataxia-telangiectasia mutated (ATM) is a kinase that plays key roles in DNA repair signaling pathways and oxidative stress response, among others. ATM mutations lead to ataxia-telangiectasia (A-T), a disease characterized for example by ataxia, immunodeficiencies and redox potential dysregulation. Malaria is characterized by excessive hemolysis with hemoglobin and heme being accumulated in plasma, causing tissue damage. Unpublished data from the host laboratory showed that: i) mice without Atm are more susceptible to malaria than controls, revealing a new disease where the presence of Atm is essential; ii) control mice infected with malaria show increased activation of DNA repair pathways in the spleen, a hematopoietic organ. Considering these data, the main objective of the present study is to address the contribution of Atm in the hematopoietic compartment in the protection against malaria. Data obtained during the present study showed that control mice treated with heme, released from cells in the context of malaria, show increased activation of DNA repair pathways in the spleen, supporting a possible protective function of Atm in the hematopoietic compartment in respect to malaria. To test this hypothesis, mice with Atm deletion exclusively in this compartment, Vavicre/wtAtmΔ/Δ, were generated and characterized. These mice are fertile and have normal weight, in contrast to Atm ko mice. Malaria-infected Vavicre/wtAtmΔ/Δ mice were found to be more susceptible than control mice, but had similar levels of parasites, suggesting that Atm plays a role that is not associated with resistance against the malaria parasite, but protects against potential damage caused by it, a mechanism designated disease tolerance. This study represents an important step in understanding the role of Atm in the context of malaria and may also have implications for other hemolytic diseases.