Investigating the biomarker potential of exosomes in preeclampsia.
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Date
2019
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Abstract
Preeclampsia is a hypertensive disorder of pregnancy and one of the leading causes of maternal and perinatal morbidity, affecting up to 7 -10% of pregnancies globally which results in 50 000-76 000 maternal deaths per year worldwide. Preeclampsia remains an enigmatic phenomenon due to its unknown etiology. This is attributed to its multifactorial nature, which complicates clinical diagnosis and management, hence the need for a definitive biomarker. Several candidate biomarkers of preeclampsia have been identified but none have the potential to diagnose preeclampsia in early pregnancy. Exosomes have recently emerged as promising biomarkers of the disease and the present study, therefore, focuses on determining the context
of the use of exosomes as biomarkers of preeclampsia. In our approach, we developed a theoretical framework for the evaluation of exosomes as potential biomarkers of preeclampsia in terms of the specified criteria defined by the Food & Drug Administration (US) (FDA) Biomarker Workgroup. This subsequently led to the evaluation of the context of use of
exosomes as biomarkers of preeclampsia by determining the role of exosomal microRNA in the pathophysiology of preeclampsia using direct digital detection, computational algorithms and biological databases. We identified distinct exosomal miRNAs signatures involved in the aberrant pathophysiology of preeclampsia which serve as promising biomarkers. Furthermore,
in terms of the FDA criteria, it is important to incorporate the intent-to-diagnose preeclampsia in combination with comorbidities associated with the increased susceptibility/risk of preeclampsia. It is clinically evident that HIV-positive pregnant women on (Highly Active Antiretroviral Therapy) HAART are at a greater risk of developing preeclampsia due to an unknown immune-related pathology caused by HAART. We, therefore, determined the potential diagnostic application of exosomal cytokines in preeclamptic and HIV-positive preeclamptic women on HAART. In doing so we have identified altered exosomal cytokine
levels in both preeclampsia and HIV-positive pregnant women, which suggests an aberrant mechanism of exosomal cytokine encapsulation, which modulates immune responses in both disease states. Importantly, we show that exosomal Tumor necrosis factor alpha (TNF-α) may have clinical validity in diagnosing preeclampsia and preeclampsia in HIV-infected pregnant
women.
Abstract (isiZulu)
I-preeclampsia iyinkinga ephezulu yokukhulelwa kanye neyodwa yezimbangela ezibangela ukugula komama nokubeletha, okuphazamisa ama-7 -10% wezokukhulelwa emhlabeni wonke okuholela ekufeni kwabantu abangu-50 000-76 000 emhlabeni wonke. I-preeclampsia iyisici esiyinkimbinkimbi ngenxa ye-etiology engaziwayo. Lokhu kubangelwa uhlobo olunezinhlobonhlobo zezinto ezihlukahlukene, okubandakanya ukuxilongwa nokuphathwa kwemitholampilo, ngakho-ke isidingo se-biomarker ecacile. Kunezimboni eziningana zepreeclampsia ezikhethwe yi-candidate kodwa azikho ongakwazi ukuhlolisisa i-preeclampsia
ekukhulelwe kokuqala. Ama-Exosome asanda kuvela njengezicikumezi ezithembisayo zesifo futhi isifundo samanje, sigxile ekunqumeni umongo wokusetshenziswa kwama-exosomes njengama-biomarkers we-preeclampsia. Endleleni yethu, sathuthukisa uhlaka lwezinhlelo zokuhlola ama-exosomes njengama-biomarkers angaba yi-preeclampsia ngokwemigomo
ebekiwe echazwe yi-Food & Drug Administration (US) (FDA) Biomarker Workgroup. Lokhu kwaholela ekuhlolweni kokusetshenziswa kwama-exosomes njengama-biomarkers of preeclampsia ngokunquma indima ye-exosomal microRNA ekuziphatheni kwe-preeclampsia esebenzisa ngokuqondile ukutholakala kwedatha, ukuhlelwa kwezinto zokusebenzisa izibalo
kanye nolwazi lwezinto eziphilayo. Sithole amasignesha ama-miRNA ahlukile asebenzayo kuperosis of preeclampsia esebenza njengama-biomarkers athembisayo. Ngaphezu kwalokho, ngokwemigomo ye-FDA kubalulekile ukufaka i-preeclampsia ye-inten-to-diagnostic ngokubambisana nama-comorbidities ehambisana nokwehluleka / ukulimala kwepreeclampsia.
Kuyabonakala emitholampilo ukuthi abesifazane abane-HIV abakhulelwe (i-Highly Active Antiretroviral Therapy) i-HAART ingengozini enkulu yokuthuthukisa ipreeclampsia ngenxa yokugula okungaziwa komzimba okubangelwa i-HAART. Ngakho-ke,
sinquma ukuthi kungenzeka yini ukuhlolwa kwesifo se-cytokines exosomal ku-preeclamptic nakwabesifazane abane-HIV ngaphambili kwe-HAART. Ngokwenza kanjalo sesiye sabona amazinga e-cytokine ashintshiwe eguquguqukayo kokubili preeclampsia nabesifazane abakhulelwe abane-HIV, okusikisela indlela engavamile yokukhipha i-exosomal cytokine
encapsulation, eyenza ukuthi izimpendulo zamasosha omzimba zisetshenziswe. Okubaluleke kakhulu, sibonisa ukuthi i-tumor necrosis factor alpha (TNF-α) ingaba nokusebenza komtholampilo ekuhloleni i-preeclampsia kanye ne-preeclampsia kwabesifazane abakhulelwe abane-HIV.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.