Papers by Sabrina Epiphanio
Cell Death & Disease
Malaria is an enormous burden on global health that caused 409,000 deaths in 2019. Severe malaria... more Malaria is an enormous burden on global health that caused 409,000 deaths in 2019. Severe malaria can manifest in the lungs, an illness known as acute respiratory distress syndrome (ARDS). Not much is known about the development of malaria-associated ARDS (MA-ARDS), especially regarding cell death in the lungs. We had previously established a murine model that mimics various human ARDS aspects, such as pulmonary edema, hemorrhages, pleural effusion, and hypoxemia, using DBA/2 mice infected with Plasmodium berghei ANKA. Here, we explored the mechanisms and the involvement of apoptosis in this syndrome. We found that apoptosis contributes to the pathogenesis of MA-ARDS, primarily as facilitators of the alveolar-capillary barrier breakdown. The protection of pulmonary endothelium by inhibiting caspase activation could be a promising therapeutic strategy to prevent the pathogenicity of MA-ARDS. Therefore, intervention in the programmed death cell mechanism could help patients not to dev...
Antimicrobial Agents and Chemotherapy, 2021
Cerebral malaria (CM) is a severe immune vasculopathy which presents a high mortality rate (15 to... more Cerebral malaria (CM) is a severe immune vasculopathy which presents a high mortality rate (15 to 20%), despite the availability of artemisinin-based therapy. More effective immunomodulatory and/or antiparasitic therapies are urgently needed.
PLOS ONE, 2020
Malaria-associated acute respiratory distress syndrome (ARDS) is an inflammatory disease causing ... more Malaria-associated acute respiratory distress syndrome (ARDS) is an inflammatory disease causing alveolar-pulmonary barrier lesion and increased vascular permeability characterized by severe hypoxemia. Computed tomography (CT), among other imaging techniques, allows the morphological and quantitative identification of lung lesions during ARDS. This study aims to identify the onset of malaria-associated ARDS development in an experimental model by imaging diagnosis. Our results demonstrated that ARDS-developing mice presented decreased gaseous exchange and pulmonary insufficiency, as shown by the SPECT/CT technique. The pulmonary aeration disturbance in ARDS-developing mice on the 5 th day post infection was characterized by aerated tissues decrease and nonaerated tissue accumulation, demonstrating increased vascular permeability and pleural effusion. The SPECT/CT technique allowed the early diagnosis in the experimental model, as well as the identification of the pulmonary aeration. Notwithstanding, despite the fact that this study contributes to better understand lung lesions during malaria-associated ARDS, further imaging studies are needed.
Scientific Reports, 2019
Malaria causes hepatic inflammation and damage, which contribute to disease severity. The proinfl... more Malaria causes hepatic inflammation and damage, which contribute to disease severity. The proinflammatory cytokine interleukin (IL)-1α is released by non-hematopoietic or hematopoietic cells during liver injury. This study established the role of IL-1α in the liver pathology caused by blood-stage P. chabaudi malaria. During acute infection, hepatic inflammation and necrosis were accompanied by NLRP3 inflammasome-independent IL-1α production. Systemically, IL-1α deficiency attenuated weight loss and hypothermia but had minor effects on parasitemia control. In the liver, the absence of IL-1α reduced the number of TUNEL + cells and necrotic lesions. This finding was associated with a lower inflammatory response, including TNF-α production. The main source of IL-1α in the liver of infected mice was inflammatory cells, particularly neutrophils. The implication of IL-1α in liver inflammation and necrosis caused by P. chabaudi infection, as well as in weight loss and hypothermia, opens up new perspectives for improving malaria outcomes by inhibiting IL-1 signaling.
Science Advances, 2020
IL-1 axis activation during placental malaria induces poor pregnancy outcomes that are obliterate... more IL-1 axis activation during placental malaria induces poor pregnancy outcomes that are obliterated after treatment with Anakinra.
PLOS ONE, 2019
Plasmodium (P.) falciparum malaria during pregnancy has been frequently associated with severe co... more Plasmodium (P.) falciparum malaria during pregnancy has been frequently associated with severe consequences such as maternal anemia, abortion, premature birth, and reduced birth weight. Placental damage promotes disruption of the local homeostasis; though, the mechanisms underlying these events are still to be elucidated. Autophagy is a fundamental homeostatic mechanism in the natural course of pregnancy by which cells self-recycle in order to survive in stressful environments. Placentas from non-infected and P. falciparuminfected women during pregnancy were selected from a previous prospective cohort study conducted in the Brazilian Amazon (Acre, Brazil). Newborns from infected women experienced reduced birth weight (P = 0.0098) and placental immunopathology markers such as monocyte infiltrate (P < 0.0001) and IL-10 production (P = 0.0122). The placentas were evaluated for autophagy-related molecules. As a result, we observed reduced mRNA levels of ULK1 (P = 0.0255), BECN1 (P = 0.0019), and MAP1LC3B (P = 0.0086) genes in placentas from P. falciparum-infected, which was more striking in those diagnosed with placental malaria. Despite the protein levels of these genes followed the same pattern, the observed reduction was not statistically significant in placentas from P. falciparum-infected women. Nevertheless, our data suggest that chronic placental immunopathology due to P. falciparum infection leads to autophagy dysregulation, which might impair local homeostasis during malaria in pregnancy that may result in poor pregnancy outcomes.
Journal of Immunology Research, 2019
The severity of Plasmodium falciparum malaria is associated with parasite cytoadherence, but ther... more The severity of Plasmodium falciparum malaria is associated with parasite cytoadherence, but there is limited knowledge about the effect of parasite cytoadherence in malaria-associated acute respiratory distress syndrome (ARDS). Our objective was to evaluate the cytoadherence of infected red blood cells (iRBCs) in a murine model of ARDS and to appraise a potential function of endothelial protein C receptor (EPCR) in ARDS pathogenesis. DBA/2 mice infected with P. berghei ANKA were classified as ARDS- or hyperparasitemia- (HP-) developing mice according to respiratory parameters and parasitemia. Lungs, blood, and bronchoalveolar lavage were collected for gene expression or protein analyses. Primary cultures of microvascular lung endothelial cells from DBA/2 mice were analyzed for iRBC interactions. Lungs from ARDS-developing mice showed evidence of iRBC accumulation along with an increase in EPCR and TNF concentrations. Furthermore, TNF increased iRBC adherence in vitro. Dexamethasone...
JAMA Network Open, 2019
IMPORTANCE Malaria during pregnancy is associated with adverse events for the fetus and newborn, ... more IMPORTANCE Malaria during pregnancy is associated with adverse events for the fetus and newborn, but the association of malaria during pregnancy with the head circumference of the newborn is unclear. OBJECTIVE To investigate the association of malaria during pregnancy with fetal head growth. DESIGN, SETTING, AND PARTICIPANTS Two cohort studies were conducted at the general maternity hospital of Cruzeiro do Sul (Acre, Brazil) in the Amazonian region. One cohort study prospectively enrolled noninfected and malaria-infected pregnant women who were followed up
ABSTRACTBackgroundMalaria during pregnancy is one of the major causes of mortality in tropical re... more ABSTRACTBackgroundMalaria during pregnancy is one of the major causes of mortality in tropical regions, causing maternal anemia, intrauterine growth retardation, preterm birth, and low birth weight (LBW). The integration of the information systems is crucial to assess the dimension of gestational malaria in a wide and useful way, to improve decision making and maternal-child health.Methods and FindingsAn observational population-based study acquired information retrospectively from all live births that occurred between 2006 and 2014 in Cruzeiro do Sul (Acre, Brazil). Social and clinical data of the mother and newborn was extracted from the Information System of Live Births. Malaria episodes information was obtained from the Brazilian Epidemiological Surveillance Information System Malaria. A deterministic record linkage was performed to assess malaria impact on pregnancy. The studied population presented a malaria incidence of 8.9%, of which 63.9% infected byPlasmodium (P.) vivax.Re...
Frontiers in Microbiology, 2019
Annually, many pregnancies occur in areas of Plasmodium spp. transmission, particularly in underd... more Annually, many pregnancies occur in areas of Plasmodium spp. transmission, particularly in underdeveloped countries with widespread poverty. Estimations have suggested that several million women are at risk of developing malaria during pregnancy. In particular cases, systemic infection caused by Plasmodium spp. may extend to the placenta, dysregulating local homeostasis and promoting the onset of placental malaria; these processes are often associated with increased maternal and fetal mortality, intrauterine growth restriction, preterm delivery, and reduced birth weight. The endeavor to understand and characterize the mechanisms underlying disease onset and placental pathology face several ethical and logistical obstacles due to explicit difficulties in assessing human gestation and biological material. Consequently, the advent of murine experimental models for the study of malaria during pregnancy has substantially contributed to our understanding of this complex pathology. Herein, we summarize research conducted during recent decades using murine models of malaria during pregnancy and highlight the most relevant findings, as well as discuss similarities to humans and the translational capacity of achieved results.
The severity of Plasmodium falciparum malaria is associated with parasite cytoadherence, but ther... more The severity of Plasmodium falciparum malaria is associated with parasite cytoadherence, but there is limited knowledge about the effect of parasite cytoadherence in malaria-associated acute respiratory distress syndrome (ARDS). Our objective was to evaluate the cytoadherence of infected red blood cells (iRBCs) in a murine model of ARDS and to appraise a potential function of endothelial protein C receptor (EPCR) in ARDS pathogenesis. DBA/2 mice infected with P. berghei ANKA were classified as ARDS- or hyperparasitemia (HP)-developing mice according to respiratory parameters and parasitemia. Lungs, blood and bronchoalveolar lavage were collected for gene expression or protein analyses. Primary cultures of microvascular lung endothelial cells from DBA/2 mice were analyzed for iRBC interactions. Lungs from ARDS-developing mice showed evidence of iRBC accumulation along with an increase in EPCR and TNF concentrations. Furthermore, TNF increased iRBC adherence in vitro. Dexamethasone-tr...
PLoS neglected tropical diseases, Aug 1, 2018
Cardiomyopathy is the most serious consequence of Chagas disease, a neglected human disorder caus... more Cardiomyopathy is the most serious consequence of Chagas disease, a neglected human disorder caused by Trypanosoma cruzi infection. Because T. cruzi parasites invade cardiomyocytes, we sought to investigate whether these cells recognize the parasite in vivo by receptors signaling through the MyD88 adaptor, which mediates the activation pathway of most Toll-like receptors (TLRs) and IL-1/IL-18 receptors, and influence the development of acute cardiac pathology. First, we showed that HL-1 cardiac muscle cell line expresses MyD88 gene and protein at resting state and after T. cruzi infection. To evaluate the role in vivo of MyD88 expression in cardiomyocytes, we generated Mer+MyD88flox+/+ mice in which tamoxifen treatment is expected to eliminate the MyD88 gene exclusively in cardiomyocytes. This Cre-loxP model was validated by both PCR and western blot analysis; tamoxifen treatment of Mer+MyD88flox+/+ mice resulted in decreased MyD88 gene and protein expression in the heart, but not i...
PloS one, 2018
Malaria in pregnancy (MiP) is one of the major causes of mortality and morbidity in tropical regi... more Malaria in pregnancy (MiP) is one of the major causes of mortality and morbidity in tropical regions, causing maternal anemia, intrauterine growth retardation, preterm birth, and low birth weight (LBW). The integration of the information systems on pregnancy and malaria could prove to be a useful method of improved decision making for better maternal-child health. A population-based observational study acquired information retrospectively from all live births that occurred between 2006 and 2014 in Cruzeiro do Sul (Acre, Brazil). Social and clinical data of the mother and newborn was extracted from the Information System of Live Births. Malaria episodes information was obtained from the Brazilian Epidemiological Surveillance Information System Malaria. A deterministic record linkage was performed to assess malaria impact on pregnancy. The studied population presented a malaria incidence of 8.9% (1283 pregnant women infected), of which 63.9% infected by Plasmodium (P.) vivax. Reductio...
Frontiers in cellular and infection microbiology, 2018
Malaria is a serious disease and was responsible for 429,000 deaths in 2015. Acute lung injury/ac... more Malaria is a serious disease and was responsible for 429,000 deaths in 2015. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications of severe malaria; it is characterized by a high mortality rate and can even occur after antimalarial treatment when parasitemia is not detected. Rodent models of ALI/ARDS show similar clinical signs as in humans when the rodents are infected with murine . In these models, it was shown that the induction of the enzyme heme oxygenase 1 (HO-1) is protective against severe malaria complications, including cerebral malaria and ALI/ARDS. Increased lung endothelial permeability and upregulation of VEGF and other pro-inflammatory cytokines were found to be associated with malaria-associated ALI/ARDS (MA-ALI/ARDS), and both were reduced after HO-1 induction. Additionally, mice were protected against MA-ALI/ARDS after treatment with carbon monoxide- releasing molecules or with carbon monoxide, which is also rel...
Scientific reports, Jan 6, 2018
A correction to this article has been published and is linked from the HTML and PDF versions of t... more A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Veterinary research, Jan 19, 2018
Anaplasma marginale (A. marginale) has a remarkable impact on livestock production, and an effect... more Anaplasma marginale (A. marginale) has a remarkable impact on livestock production, and an effective vaccine is not currently available due to the inexistence of a small animal model. Recently, BALB/c mice were successfully infected with A. marginale, resulting in an acute and persistent anaplasmosis infection. Here, we designed a hybrid protein containing repeats of polypeptide 1a from major surface protein-1 complex (MSP1a) repeats and common epitopes of outer membrane proteins (OMPs) OMP7, OMP8 and OMP9 expressed in Escherichia coli. Our proof-of-concept assessed vaccinal effectiveness against a challenge with live bacteria. The MSP1a/OMP7/8/9 immunized BALB/C mice exhibited a strong reduction in rickettsemia and had no signs of anaplasmosis or hepatic lesions. In contrast, the non-immunized mice exhibited signs of anaplasmosis and a body weight loss associated with increases in monocyte and neutrophil counts. Furthermore, the non-immunized mice displayed atrophies with chronic i...
Scientific reports, Jan 17, 2017
Malaria-associate pregnancy has a significant impact on infant morbidity and mortality. The detri... more Malaria-associate pregnancy has a significant impact on infant morbidity and mortality. The detrimental effects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. Herein we sought to evaluate the effect of Toll-like receptors (TLRs) activation on placental malaria (PM) development by using the Plasmodium berghei NK65(GFP) infection model. We observed that activation of the innate immune system by parasites leads to PM due to local inflammation. We identified TLR4 activation as the main pathway involved in the inflammatory process in the placental tissue since the absence of functional TLR4 in mice leads to a decrease in the pro-inflammatory responses, which resulted in an improved pregnancy outcome. Additionally, a similar result was obtained when infected pregnant mice were treated with IAXO-101, a TLR4/CD14 blocker. Together, this study illustrates the importance of TLR4 signalling for the generation of the severe inf...
Malaria journal, Jun 15, 2017
Plasmodium vivax parasites are the predominant cause of malaria infections in the Brazilian Amazo... more Plasmodium vivax parasites are the predominant cause of malaria infections in the Brazilian Amazon. Infected individuals are treated with primaquine, which can induce haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals and may lead to severe and fatal complications. This X-linked disorder is distributed globally and is caused by allelic variants with a geographical distribution that closely reflects populations exposed historically to endemic malaria. In Brazil, few studies have reported the frequency of G6PD deficiency (G6PDd) present in malaria-endemic areas. This is particularly important, as G6PDd screening is not currently performed before primaquine treatment. The aim of this study was to determine the prevalence of G6PDd in the region of Alto do Juruá, in the Western Brazilian Amazon, an area characterized by a high prevalence of P. vivax infection. Five-hundred and sixteen male volunteers were screened for G6PDd using the fluorescence spot te...
PLoS pathogens, Dec 1, 2016
Malaria remains one of the greatest burdens to global health, causing nearly 500,000 deaths in 20... more Malaria remains one of the greatest burdens to global health, causing nearly 500,000 deaths in 2014. When manifesting in the lungs, severe malaria causes acute lung injury/acute respiratory distress syndrome (ALI/ARDS). We have previously shown that a proportion of DBA/2 mice infected with Plasmodium berghei ANKA (PbA) develop ALI/ARDS and that these mice recapitulate various aspects of the human syndrome, such as pulmonary edema, hemorrhaging, pleural effusion and hypoxemia. Herein, we investigated the role of neutrophils in the pathogenesis of malaria-associated ALI/ARDS. Mice developing ALI/ARDS showed greater neutrophil accumulation in the lungs compared with mice that did not develop pulmonary complications. In addition, mice with ALI/ARDS produced more neutrophil-attracting chemokines, myeloperoxidase and reactive oxygen species. We also observed that the parasites Plasmodium falciparum and PbA induced the formation of neutrophil extracellular traps (NETs) ex vivo, which were ...
Mediators of Inflammation, 2016
Malaria is a serious disease, caused by the parasite of the genusPlasmodium, which was responsibl... more Malaria is a serious disease, caused by the parasite of the genusPlasmodium, which was responsible for 440,000 deaths in 2015. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications in severe malaria. The murine model DBA/2 reproduces the clinical signs of ALI/ARDS in humans, when infected withPlasmodium bergheiANKA. High levels of HO-1 were reported in cases of severe malaria. Our data indicated that the HO-1 mRNA and protein expression are increased in mice that develop malaria-associated ALI/ARDS (MA-ALI/ARDS). Additionally, the hemin, a HO-1 inducing drug, prevented mice from developing MA-ALI/ARDS when administered prior to the development of MA-ALI/ARDS in this model. Also, hemin treatment showed an amelioration of respiratory parameters in mice, high VEGF levels in the sera, and a decrease in vascular permeability in the lung, which are signs of ALI/ARDS. Therefore, the induction of HO-1 before the development of MA-ALI/ARDS...
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Papers by Sabrina Epiphanio