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Effets de la régulation des « Toll like receptors » dans la réponse immunitaire néonatale aux infections à Gram négatif en zone d’endémie palustre

Abstract : Neonatal sepsis is one of the major causes of newborn mortality in the world and particularly in sub-Saharan Africa. In this part of the world where malaria infections are common among pregnant women, in utero exposure to P. falciparum antigens is known to impair the immune functions of the foetus and is responsible for a greater susceptibility of the newborn to malaria and non-malarial infections. Our previous data and those of other teams suggest that gestational malaria may play an important role in the pathogenesis of Gram-negative bacterial infections through in utero modulation of Toll Like receptors (TLR) signalling pathways. Our hypothesis is that in utero exposure to P. falciparum antigens modulates the transcriptional signature of the primary mRNA transcripts of the TLR4/MD-2 endotoxin recognition complex of the newborn, modifying the host response to bacterial infections. In the first part of our work, we evaluated the performance of transcriptional (CX3CR1, CD74) and protein (PCT, IL-6, IL-10, IP-10) biomarkers for the diagnosis and prognosis of neonatal sepsis in neonates born in malaria endemic areas. Our results show that procalcitonin in cord blood is not a sufficiently accurate biomarker for the diagnosis and prognosis of neonatal sepsis. Low CD74 expression is predictive of mortality in infants developing neonatal sepsis and the CD74/IP-10 ratio may be more accurate for the diagnosis of neonatal sepsis than all biomarkers and clinical combinations studied. The second part of our work focused on the consequences of in utero exposure to plasmodial antigens on the regulation of TLR4 (V1, V3, and V4) and MD-2 (L-long and SH-Short) primary transcript isoform expression in the development of immunological responses in the newborn. Our results do not show an effect of gestational malaria on the modulation of the expression of the MD-2/TLR4 recognition complex and its response to endotoxins, but rather an effect of prenatal exposure to infectious risk factors on the expression of the MD-2/TLR4 complex with an overexpression of the short isoform MD-2SH involved in the inhibition of the endotoxin response.
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Submitted on : Thursday, September 16, 2021 - 5:20:10 PM
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  • HAL Id : tel-03346963, version 1
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Sem Ezinmegnon. Effets de la régulation des « Toll like receptors » dans la réponse immunitaire néonatale aux infections à Gram négatif en zone d’endémie palustre. Immunité innée. Université Paris-Saclay, 2021. Français. ⟨NNT : 2021UPASQ017⟩. ⟨tel-03346963⟩

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