Plasmodium falciparum Malaria Elicits Inflammatory Responses that Dysregulate Placental Amino Acid Transport

Boeuf, Philippe; Aitken, Elizabeth H.; Chandrasiri, Upeksha P.; Chua, Caroline Lin Lin; McInerney, Bernard V.; McQuade, Leon R.; Duffy, Michael; Molyneux, Malcolm E.; Brown, Graham V.; Glazier, Jocelyn D.; Rogerson, Stephen J.

doi:10.1371/journal.ppat.1003153

Cited by 70 publications

(80 citation statements)

References 67 publications

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“…Sequestering parasites release bioactive molecules that stimulate both maternal cells [4] and fetal syncytiotrophoblast [5, 6] to produce proinflammatory cytokines and chemokines, which in turn recruit, activate and retain inflammatory cells in the maternal intervillous space [4, 6-12]. Indeed, accumulation of maternal monocyte/macrophages, and increased levels of inflammatory cytokines, especially tumor necrosis factor (TNF), are common in human PM [4, 7, 12-14], and directly or indirectly, via impaired materno-fetal exchange of nutrients and gases and/or high metabolic demand of infiltrated leukocytes [15], contribute to poor birth outcomes [16]. These important contributions notwithstanding, the precise molecular and cellular mechanisms that lead to placental failure and fetal compromise must still be identified.…”

Section: Introductionmentioning

confidence: 99%

Differential roles of inflammation and apoptosis in initiation of mid-gestational abortion in malaria-infected C57BL/6 and A/J mice

et al. 2015

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Introduction Plasmodium chabaudi AS-infection in pregnant A/J and C57BL/6J mice results in mid-gestational pregnancy loss. Although associated with increased systemic and placental pro-inflammatory responses and coagulopathy, the molecular mechanisms that underlie poor pregnancy outcomes in these mice are not yet fully understood. This study investigates the relationships between inflammation, apoptosis and malaria-induced pregnancy loss. Methods Infection with Plasmodium chabaudi AS in early murine pregnancy and term human placental tissues from an endemic setting were assessed by histology, immunohistochemistry, TUNEL staining, real-time PCR, flow cytometry, western blot, and ELISA. Results Quantitative PCR reveals accumulation of lymphocytes and monocytes and upregulation of chemokines that attract these cell types in malaria-exposed mid-gestational A/J conceptuses. Monocyte accumulation is confirmed by flow cytometry and placental immunohistochemistry. Concurrent with initiation of malaria-induced abortion, markers of apoptosis are evident in the junctional zone, but not the labyrinth, of A/J placentae. In contrast, mid-gestation conceptuses in infected C57BL/6J lack evidence for monocyte accumulation, exhibiting low or no in situ placental staining despite trophoblast immunoreactivity for the monokine, CCL2. Additionally, placental apoptosis is not consistently observed, and when evident, appears after malaria-induced abortion typically initiates. Similarly, trophoblast apoptosis in term human placental malaria is not observed. Of those studied, a sole common feature of malaria-induced abortion in A/J and C57BL/6J mice is elevation of plasma tumor necrosis factor. Discussion Consistent with our previous observations, tumor necrosis factor is likely to be a central driver of malaria-induced pregnancy loss in both strains, but likely operates through mechanisms distinct from placental apoptosis in C57BL/6J mice.

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Section: Introductionmentioning

confidence: 99%

Differential roles of inflammation and apoptosis in initiation of mid-gestational abortion in malaria-infected C57BL/6 and A/J mice

et al. 2015

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“…Beyond malaria infection, local inflammation-triggered fetal growth restriction was found in a cohort of Malawian women and their infants26. Furthermore the association between local inflammation and micronutrient transport was confirmed in an in vitro model of placental malaria with local inflammation.…”

Section: Discussionmentioning

confidence: 76%

“…Furthermore the association between local inflammation and micronutrient transport was confirmed in an in vitro model of placental malaria with local inflammation. Specifically maternal monocyte products impaired the activity of amino acid transporters on placental cells, leading to fetal growth restriction26. We have recently reported that free heme and heme-mediated signaling pathways play important roles in the pathogenesis of severe P. falciparum malaria (children/adults)27; and that elevated levels of IL-10 in maternal peripheral blood can serve as a biomarker associated with asymptomatic malaria in pregnant women28.…”

Section: Discussionmentioning

confidence: 99%

Heme-mediated apoptosis and fusion damage in BeWo trophoblast cells

Liu

Salifu

Stiles

2016

Sci Rep

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Placental malaria (PM) is a complication associated with malaria infection during pregnancy that often leads to abortion, premature delivery, intrauterine growth restriction and low birth weight. Increased levels of circulating free heme, a by-product of Plasmodium-damaged erythrocytes, is a major contributor to inflammation, tissue damage and loss of blood brain barrier integrity associated with fatal experimental cerebral malaria. However, the role of heme in PM remains unknown. Proliferation and apoptosis of trophoblasts and fusion of the mononucleated state to the syncytial state are of major importance to a successful pregnancy. In the present study, we examined the effects of heme on the viability and fusion of a trophoblast-derived cell line (BeWo). Results indicate that heme induces apoptosis in BeWo cells by activation of the STAT3/caspase-3/PARP signaling pathway. In the presence of forskolin, which triggers trophoblast fusion, heme inhibits BeWo cell fusion through activation of STAT3. Understanding the effects of free plasma heme in pregnant women either due to malaria, sickle cell disease or other hemolytic diseases, will enable identification of high-risk women and may lead to discovery of new drug targets against associated adverse pregnancy outcome.

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“…y por ende no desarrolla una inmunidad efectiva en comparación con las multigestantes 24 , además, la concentración de hormonas sexuales y el cortisol, tienden a disminuir a medida que aumenta la paridad 10,19,18 Fisiopatología de malaria placentaria Los eritrocitos infectados por Plasmodium spp., expresan un antígeno variante en su membrana, denominado -Plasmodium falciparum erythrocyte membrane protein 1-(PfEMP1) 25 , que facilita la adhesión de las células infectadas a receptores de condroitín sulfato A (CSA), presentes en la placenta 26 ; esta unión facilita el ingreso y secuestro del patógeno en el espacio intervelloso 27 , allí se desencadena una respuesta inmune pro-inflamatoria, mediada inicialmente por la liberación de TNF-α por parte de las células natural killer uterinas (NKu), que tiene un efecto químioatrayente sobre monocitos y macrófagos para amplificar la respuesta inmunitaria TH1 , en un intento por defender el contexto placentario contra la infección 19 .…”

Section: Malaria Y Paridadunclassified

Diagnóstico y manejo de la restricción del crecimiento intrauterino en fetos de gestantes provenientes de zonas endémicas para la malaria

Calderón

Zea²

2018

Rev. chil. obstet. ginecol.

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Diagnóstico y manejo de la restricción del crecimiento intrauterino en fetos de gestantes provenientes de zonas endémicas para la malaria. RESUMENIntroducción: La malaria es una enfermedad infecciosa tropical de gran impacto epidemiológico a nivel mundial; las poblaciones con mayor susceptibilidad de padecerla son los niños menores de 5 años y las gestantes, en quienes, se pude no solo comprometer la salud de la madre sino también la del producto y su desarrollo, pudiendo ocurrir diferentes desenlaces adversos entre ellos la restricción del crecimiento intrauterino (RCIU), incrementando sustancialmente las tasas de mortalidad materna y perinatal. Es importante establecer un diagnóstico preciso y oportuno de la RCIU en fetos de gestantes que padecen de malaria, con el fin de llevar a cabo un enfoque de seguimiento y de manejo que puedan disminuir las complicaciones asociadas a la enfermedad. Métodos: Se realizó una búsqueda bibliográfica en la base de datos de Cochrane y PubMed, libros de la especialidad y consensos de sociedades científicas, relativos a los términos de: malaria during pregnancy, intrauterine growth restriction y malaria and fetal growth restriction. Se seleccionaron finalmente 42 artículos para análisis completo y crítico, que justificara la elaboración de esta revisión. Conclusión: esta revisión aporta elementos para establecer un alto grado de sospecha diagnóstica de malaria durante el embarazo en zonas endémicas para la malaria; además revela la necesidad de implementar protocolos de manejo especifico ante la RCIU según sea la etiología; ya que estas medidas impactaran positivamente en los resultados adversos de la enfermedad, sin olvidar que lo primordial es proteger plenamente a las mujeres contra la malaria desde el comienzo del embarazo hasta el parto. PALABRAS CLAVE:Malaria durante el embarazo, malaria gestacional, malaria placentaria, restricción del crecimiento intrauterino. INTRODUCCIÓNLa malaria es una enfermedad infecciosa tropical, causada por un protozoo intracelular del género Plasmodium spp. y transmitida al ser humano por un mosquito hembra del género Anofeles 1 , se estima alrededor de 212 millones de casos anuales alrededor del mundo y aproximadamente 429 mil muertes por esta causa 2 .Esta enfermedades endémica en gran parte del mundo subdesarrollado y en especial en regiones localizadas por debajo de los 1600 metros sobre el nivel del mar; entre las áreas más afectadas en orden de frecuencia, se encuentran, África subsahariana, Asia, Oceanía y América del sur 3 .En la actualidad se conocen 5 especies de Plasmodium que afectan al ser humano estas son: P. falciparum, P. vivax, P. ovale, P. malariae y P.knowlesi 4 , siendo P. falciparum la especie de mayor importancia en cuestión de morbi-mortalidad y aunque se encuentra en todos los continentes, es más prevalente en África subsahariana, seguido del P.

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Plasmodium falciparum Malaria Elicits Inflammatory Responses that Dysregulate Placental Amino Acid Transport

Cited by 70 publications

References 67 publications

Differential roles of inflammation and apoptosis in initiation of mid-gestational abortion in malaria-infected C57BL/6 and A/J mice

Differential roles of inflammation and apoptosis in initiation of mid-gestational abortion in malaria-infected C57BL/6 and A/J mice

Heme-mediated apoptosis and fusion damage in BeWo trophoblast cells

Diagnóstico y manejo de la restricción del crecimiento intrauterino en fetos de gestantes provenientes de zonas endémicas para la malaria

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