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Experimental maternal viral infections and responses of offsprings to the challenge: repercussions on protection and susceptibility

Abstract

Little is known about the importance of the maternal virome in modulating the immune system of the fetus or newborn. The studies are focused on intrauterine, perinatal or postnatal vertical transmission of infectious viruses, on the pathogenesis of congenital infections and on therapeutic interventions to be carried out during the infection of a pregnant or lactating woman. However, it is known that there is an intense sharing of soluble and bioactive molecules, cells and other components between the pregnant woman and the fetus via the transplacental route and between the mother and the newborn through breastfeeding. Therefore, based on the absence of studies that evaluate the consequences of this exchange of components and on the preliminary results of our team, the present project aims to investigate the mechanisms that may be involved in the protection and susceptibility of gestated and/or breastfed offspring in female BALB/c mice infected by arboviruses and respiratory viruses. First, we will evaluate the occurrence of microchimerism through breastfeeding, which is the transfer of cells from females infected by the Chikungunya virus (CHIKV) and Influenza A (IAV) and the establishment of these cells in the tissues of the offspring. The course of these cells in the mammary glands and in the tissues of neonates will be investigated by intravital microscopy and flow cytometry. It will be investigated whether these cells carry important immunological information, capable of influencing the protection and susceptibility of offspring for long periods after birth. In addition to cells, milk is rich in particles delimited by lipid bilayers called extracellular vesicles (EVs). EVs transport proteins, messenger RNAs (mRNAs), microRNAs (miRNAs) and other bioactive components, which are delivered to the cytoplasm of cells in the infant's gastrointestinal tract after fusion of EVs with cell membranes. We will therefore analyze the proteome and transcriptome of EVs purified from milk of CHIKV and IAV infected females in comparison with the content found in EVs from uninfected females. The transcriptome and proteome of EVs will be determined by next generation sequencing (NGS) and mass spectrometry, respectively. The most promising targets found in these analyzes will be selected for experimental and functional validations. We will also investigate the presence of viral antigens in milk fractions and the structures associated with them through co-immunoprecipitation with antibodies directed to structural and non-structural proteins of CHIKV and IAV in order to assess whether these antigens are linked to any component of the milk that facilitates its absorption in the infant's gastrointestinal tract and exposure to pathogens. Finally, experimental models will be developed with other arboviruses and respiratory viruses of epidemiological importance in human health, such as the Zika virus (ZIKV), the novel coronavirus responsible for severe acute respiratory syndrome (SARS-CoV-2) and the human syncytial virus (HRSV), in order to assess whether the phenomena observed for CHIKV and IAV also occur with viruses from other families. (AU)

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