Browsing by Author "Chenge, Samuel"

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    PublicationOpen Access
    Infectious and environmental placental insults: from underlying biological pathways to diagnostics and treatments
    (Pathogens and Disease, 2023-09-19) Chenge, Samuel; Ngure, Harrison; Kanoi, Bernard N.; Sferruzzi-Perr, Amanda N.; Kobia, Francis M.
    Because the placenta is bathed in maternal blood, it is exposed to infectious agents and chemicals that may be present in the mother’s circulation. Such exposures, which do not necessarily equate with transmission to the fetus, may primarily cause placental injury, thereby impairing placental function. Recent research has improved our understanding of the mechanisms by which some infectious agents are transmitted to the fetus, as well as the mechanisms underlying their impact on fetal outcomes. However, less is known about the impact of placental infection on placental structure and function, or the mechanisms underlying infection-driven placental pathogenesis. Moreover, recent studies indicate that noninfectious environmental agents accumulate in the placenta, but their impacts on placental function and fetal outcomes are unknown. Critically, diagnosing placental insults during pregnancy is very difficult and currently, this is possible only through postpartum placental examination. Here, with emphasis on humans, we discuss what is known about the impact of infectious and chemical agents on placental physiology and function, particularly in the absence of maternal–fetal transmission, and highlight knowledge gaps with potential implications for diagnosis and intervention against placental pathologies.
  • Thumbnail Image
    PublicationOpen Access
    Infectious and environmental placental insults: from underlying biological pathways to diagnostics and treatments
    (Pathogens and Disease, 2023-09-19) Chenge, Samuel; Ngure, Harrison; Kanoi, Bernard N.; Sferruzzi-Perri, Amanda N.; Kobia, Francis M.
    Because the placenta is bathed in maternal blood, it is exposed to infectious agents and chemicals that may be present in the mother’s circulation. Such exposures, which do not necessarily equate with transmission to the fetus, may primarily cause placental injury, thereby impairing placental function. Recent research has improved our understanding of the mechanisms by which some infectious agents are transmitted to the fetus, as well as the mechanisms underlying their impact on fetal outcomes. However, less is known about the impact of placental infection on placental structure and function, or the mechanisms underlying infection-driven placental pathogenesis. Moreover, recent studies indicate that noninfectious environmental agents accumulate in the placenta, but their impacts on placental function and fetal outcomes are unknown. Critically, diagnosing placental insults during pregnancy is very difficult and currently, this is possible only through postpartum placental examination. Here, with emphasis on humans, we discuss what is known about the impact of infectious and chemical agents on placental physiology and function, particularly in the absence of maternal–fetal transmission, and highlight knowledge gaps with potential implications for diagnosis and intervention against placental pathologies.
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    PublicationOpen Access
    PA-773 Placental foetal-maternal innate immune responses to placental malaria
    (BMJ Global Health, 2023-11-10) Kobia, Francis; Chenge, Samuel; Ngure, Harrison; Gitaka, Jesse
    Background During malaria in pregnancy (MiP), Plasmodium falciparum-infected erythrocytes sequester in the placenta, causing placental malaria (PM) and poor pregnancy outcomes, including low birthweight, preterm birth, and stillbirth. Mouse data indicate that innate immune response to PM on the placenta’s maternal side adversely affects the foetus and in response, the placenta’s foetal side mounts an innate counterresponse that improves foetal outcomes. However, this has not been observed in human PM. Methods We used histological and molecular analyses to characterize the PM status of bio banked placentas and corresponding maternal sera. Molecular tools were used to characterize innate immune responses to human PM in the foetal and maternal sides of the placenta. Results Histology and molecular assays showed that 50% of women who had no history of MiP and had received malaria chemoprophylaxis, had PM. Among women with MiP history, the PM rate was 70%. RT-qPCR revealed that foetal sides of PM-negative samples had lower levels of Toll-like receptor (TLR)- 4 and 9 when compared with maternal sides of the same placentas. However, in PM-positive placentas, their levels were higher in foetal sides than maternal sides of the same placentas. Moreover, TLR4 was significantly upregulated in maternal sides of PM-positive placentas versus maternal sides of PM-negative placentas. Intriguingly, TLR4 was significantly upregulated in foetal sides of PM-positive placentas versus foetal sides of PM-free placentas. Immunohistochemical analysis revealed that when compared with PM-negative tissue, PM-positive samples expressed markedly higher levels of 8-hydroxy-2’-deoxyguanosine, a marker of oxidative DNA damage. RT-qPCR showed that this was accompanied by the upregulation of p21, a marker of DNA damage repair. Conclusion Our data indicate that human PM drives differential innate immune response in foetal vs maternal sides of the placenta, and triggers placental oxidative DNA damage. These observations may have implications for the diagnosis and management of PM. https://doi.org/10.1136/bmjgh-2023-EDC.297
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    PublicationOpen Access
    Placental malaria is associated with a TLR–Endothelin-3–oxidative damage response in 1 human placenta tissues
    (medRxiv and bioRxiv, 2024-04-20) Chenge, Samuel; Mbalitsi, Melvin; Ngure, Harrison; Obimbo, Moses; Singoei, Mercy; Kangogo, Mourine; Kanoi1, Bernard N; Gitaka, Jesse; Kobia, Francis M.
    Placental malaria, which is mainly caused by the sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, is an important driver of poor pregnancy outcomes, including fetal growth restriction, preterm birth, and stillbirth. However, the mechanisms underlying its adverse outcomes are unclear. Mouse models have previously shown that placental malaria (PM) triggers a proinflammatory response in the placenta, which is accompanied by a fetal Toll-like receptor (TLR)4-mediated innate immune response associated with improved fetal outcomes. Here, we used hematoxylin and eosin staining to identify PM-positive and negative samples in our biobank of placentas donated by women living in a malaria-endemic region of Kenya and assessed the impact of PM on the expression of TLRs, Endothelins, and oxidative damage. RT-qPCR analysis revealed that PM was associated with an upregulation of TLR4, TLR7, and Endothelin-3. Moreover, immunohistochemistry showed that PM was associated with elevated expression levels of the oxidative DNA damage marker, 8-hydroxy-2’-deoxyguanosine, while RT-qPCR revealed that this was accompanied by an upregulation of p21, an inhibitor of cell cycle progression and marker of cellular response to DNA damage. These findings allude to a novel mechanism of PM pathogenesis driven by a TLR–Endothelin-3–oxidative DNA damage signaling axis.