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Master's Dissertation
DOI
https://doi.org/10.11606/D.42.2022.tde-15022023-153957
Document
Author
Full name
Yan de Souza Angelo
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2022
Supervisor
Committee
Peron, Jean Pierre Schatzmann (President)
Kowaltowski, Alícia Juliana
Modena, José Luiz Proença
Sato, Maria Notomi
Title in Portuguese
Impactos da infecção por ZIKV e SARS-CoV-2 no funcionamento mitocondrial de astrócitos primários
Keywords in Portuguese
Astrocitos
Mitocondria
SARS-CoV-2
ZIKV
Abstract in Portuguese
A humanidade, infelizmente, sempre se viu assolada por pandemias. A peste negra, gripe espanhola, tuberculose, poliomielite e, recentemente, as pandemias de Zika virus e de SARS-CoV-2. Se ha algo com as quais aprendemos, e que a manutencao do conhecimento cientifico e crucial para a mitigacao e controle dos danos por elas causados. Neste trabalho, focamos nas ultimas duas pandemias, sendo que a de SARS-CoV-2 ainda se apresenta em curso. No Brasil, durante os anos de 2015 -2016, houve um grande aumento no numero de bebes nascidos com microcefalia, posteriormente caracterizada como Sindrome Congenita do Zika (SCZ), assim como de adultos com Sindrome de Guillain-Barre. Ja o SARS-CoV-2, um virus que emergiu no final de 2019, e causador da COVID-19, se espalhou rapidamente por todo globo, causando ate o momento mais de 500 milhoes de mortes e um devastador impacto economicos e social. Muito ainda se desconhece sobre seus mecanismos patogenicos e sua interacao frente ao organismo hospedeiro, principalmente no que tange seu tropismo e capacidade de afetar o CNS. Os astrocitos, uma das mais abundantes populacoes celulares do sistema nervoso central(CNS), executam uma enorme miriade de funcoes, principalmente na manutencao e suporte metabolico neuronal, mas tambem na resposta imune local. Como grande parte de suas funcoes tem base metabolica, e essencial que suas mitocondrias estejam integras e em pleno funcionamento. De forma interessante, nos ultimos anos as mitocondrias vem sendo reconhecidas nao somente como organelas metabolicas, mas tambem como pecas criticas em diferentes processos celulares, incluindo a resposta imune inata. Desta maneira, considerando a habilidade de diversos virus em sequestrar vias metabolicas para facilitar sua replicacao, a compreensao de como a infeccao pelo ZIKV e SARS-CoV-2 impactam nas funcoes mitocondriais astrocitarias, pode dar luz a novas abordagens terapeuticas, alem de elucidar mecanismos celulares e moleculares. Com isso, neste trabalho, investigamos varios aspectos do perfil mitocondrial frente a infeccao pelo ZIKV em astrocitos primarios humanos e murinos. De maneira analoga, utilizando o modelo de Hamster Sirio, investigamos tambem se SARS-CoV-2 poderia infectar astrocitos e causar alteracoes significativas quanto ao metabolismo celular alem de induzir processos inflamatorios no SNC in vitro e in vivo. Como esperado, observamos que a infeccao por esses virus foi capaz de alterar significativamente funcoes mitocondriais, impactando de forma relevante no funcionamento dos astrocitos. Ainda, demonstramos a dependência do substrato glutamina para replicacao e subsequente inducao de efeitos deleterios em astrocitos primarios durante a infeccao pelo SARS-CoV-2, evidenciando possíveis mecanismos e consequencias da sequela pos COVID-19.
Title in English
Impacts of ZIKV and SARS-CoV-2 infection on mitochondrial functioning of primary astrocytes
Keywords in English
Astrocytes
Mitochondria
SARS-CoV-2
ZIKV
Abstract in English
Humanity, unfortunately, has always been plagued by pandemics. The Black Death,Spanish Flu, Tuberculosis, Polio, and recently, the Zika virus and SARS-CoV-2 pandemics. If there is one thing we have learned from, it is that maintaining scientific knowledge is crucial in mitigating and controlling the damage they cause. In this work, we focus on the last two pandemics, including the still ongoing SARS-CoV-2 one. In Brazil, during the years 2015 -2016, there was a large increase in the number of newborns with microcephaly, later characterized as Congenital Zika Syndrome (CZS), as well as adults with Guillain-Barre Syndrome. SARS-CoV-2, a virus that emerged in late 2019 and causes COVID-19, has spread rapidly across the globe, causing more than 500 million deaths to date and devastating economics and social impacts. Much is still unknown about its pathogenic mechanisms and its interaction with the host organism, especially regarding its tropism and ability to affect the SNC. Astrocytes, one of the most abundant cell populations in the central nervous system (SNC), perform a myriad of functions, mainly regarding neuronal maintenance and metabolic support, but also in the local immune response. Since most of your functions have a metabolic basis, it is essential that your mitochondria are healthy and fully functioning. Interestingly, in recent years mitochondria have been recognized not only as solely metabolic organelles, but also as critical players in different cellular processes, including the innate immune response. In this way, considering the ability of several viruses to hijack metabolic pathways to facilitate their replication, the understanding of how ZIKV and SARS-CoV-2 infection impact astrocytic mitochondrial functions may shed light on new therapeutic approaches, in addition to elucidating mechanisms. cellular and molecular. Therefore, in this work, we investigated several aspects of the mitochondrial activity against ZIKV infection in human and murine primary astrocytes. Similarly, using the Syrian Hamster model, we also investigated whether SARS-CoV-2 could infect astrocytes and cause significant changes in cellular metabolism, in addition to inducing inflammatory processes in the SNC in vitro and in vivo. As expected, we observed that infection by these viruses was able to significantly alter mitochondrial functions, significantly impacting the functioning of astrocytes. Furthermore, we demonstrate the dependence of the glutamine substrate for replication and subsequent induction of deleterious effects in primary astrocytes during SARS-CoV-2 infection, highlighting possible mechanisms and consequences of post-COVID-19 sequelae.
 
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Publishing Date
2023-02-16
 
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