• JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
 
  Bookmark and Share
 
 
Master's Dissertation
DOI
Document
Author
Full name
Anna Julia Pietrobon
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Sato, Maria Notomi (President)
Hinds, Luciana Barros de Arruda
Martins, Joilson de Oliveira
Silveira, Eduardo Lani Volpe da
Title in Portuguese
Imunomodulação da resposta antiviral de macrófagos de recém-natos por adjuvantes de interferon tipo I
Keywords in Portuguese
Adjuvantes de IFN-I
HIV
Macrófagos
Recém-natos
Abstract in Portuguese
Recém-natos (RNs) são mais susceptíveis a infecções devido à relativa imaturidade das respostas imunes inata e adaptativa. Nesse cenário, a modulação imunológica tem sido investigada como uma estratégia para aumentar a proteção contra infecções. Os macrófagos atuam tanto na imunidade inata quanto adaptativa, sendo potenciais alvos para estimular a resposta imune neonatal. Na infecção pelo HIV, os macrófagos atuam como reservatórios virais contribuindo com a replicação viral por longos períodos de tempo. Agonistas de receptores do tipo Toll podem controlar a replicação do HIV-1 em macrófagos de adultos in vitro, mas o impacto de tais moléculas em macrófagos de RNs ainda não foi verificado. Assim, o objetivo desse trabalho foi avaliar o efeito imunomodulador e antiviral de adjuvantes indutores de interferon tipo I em macrófagos de neonatos e adultos. Para isso, macrófagos foram gerados a partir de monócitos isolados de sangue de cordão umbilical e sangue periférico de adultos. Foi observado que os macrófagos de RNs possuem um perfil anti-inflamatório e de produção de IL-10. Os achados mostram ainda que os macrófagos neonatais são semelhantes aos macrófagos de adultos quanto à expressão gênica de componentes da imunidade inata. No entanto, as células neonatais mostram maior replicação viral quando infectadas com HIV-1 in vitro. Também verificou-se que o tratamento com os agonistas de TLR7/TLR8 (CL097), STING (cGAMP) e TLR3/RIG-I/MDA-5 (Poly-I:C) induz a expressão de IFN-β e do fator antiviral MxA em macrófagos de RNs e adultos, mas CL097 é mais eficaz em promover a expressão de sensores citosólicos, em especial RIG-I e cGAS, além de inibir a expressão de TREX-1. Esse agonista também promove a indução de citocinas inflamatórias e ß-quimiocinas, bem como, da citocina reguladora IL-10. Os resultados indicam ainda que CL097 inibe a replicação do HIV-1 em macrófagos de RNs e adultos, e esse efeito não parece ser dependente da ativação de NF-χB. Portanto, o agonista CL097 mostra um potencial terapêutico relevante como adjuvante da resposta neonatal, sendo capaz de induzir fatores antivirais que inibem a replicação do HIV-1.
Title in English
Immunomodulation of the antiviral response of macrophages of newborns by type I interferon adjuvants
Keywords in English
HIV
IFN-I Adjuvants
Macrophages
Newborns
Abstract in English
Newborns (NBs) are more susceptible to infections due to the relative immaturity of innate and adaptive immune responses. In this scenario, immunological modulation has been investigated as a strategy to increase protection against infections. Macrophages play a role on both innate and adaptive immunity, being potential targets for stimulating the neonatal immune response. In HIV infection, macrophages act as viral reservoirs contributing to viral replication for long periods of time. Toll-like receptor agonists can control HIV-1 replication in adult macrophages in vitro but the impact of such molecules on macrophages of NBs has not yet been verified. Therefore, the aim of this study was to evaluate the immunomodulatory and antiviral effects of type I interferon adjuvants on macrophages of neonates and adults. For this, macrophages were generated from monocytes isolated from umbilical cord blood and peripheral blood from adults. It was observed that the macrophages of NBs have an anti-inflammatory profile with IL-10 production. The findings also show that neonatal macrophages are similar to adult macrophages regarding the gene expression of innate immunity components. However, neonatal cells show increased viral replication when infected with HIV-1 in vitro. It has also been found that the treatment with TLR7/TLR8 (CL097), STING (cGAMP) and TLR3/RIG-I/MDA-5 (Poly-I:C) agonists induces the expression of IFN-ß and the antiviral factor MxA in macrophages of NBs and adults, however CL097 is more effective in promoting the expression of cytosolic sensors, especially RIG-I and cGAS, in addition to inhibit the expression of TREX-1. This agonist also promotes the induction of inflammatory cytokines and ß-chemokines, as well as the regulatory cytokine IL-10. The results further indicate that CL097 inhibits HIV-1 replication in macrophages of NBs and adults, and this effect does not seem to be dependent on NF-χB activation. Therefore, CL097 shows a relevant therapeutic potential as adjuvant of the neonatal response, being able to induce antiviral factors that inhibit HIV-1 replication.
 
WARNING - Viewing this document is conditioned on your acceptance of the following terms of use:
This document is only for private use for research and teaching activities. Reproduction for commercial use is forbidden. This rights cover the whole data about this document as well as its contents. Any uses or copies of this document in whole or in part must include the author's name.
There are withheld file due to requirements (data publishing, patents or rights).
Release Date
2021-04-28
Publishing Date
2019-05-06
 
WARNING: Learn what derived works are clicking here.
All rights of the thesis/dissertation are from the authors
CeTI-SC/STI
Digital Library of Theses and Dissertations of USP. Copyright © 2001-2020. All rights reserved.