Unraveling Cell Death Pathways during Malaria Infection: What Do We Know So Far?

Sena-dos-Santos, Camille; Braga-da-Silva, Cíntia; Marques, Denílson Bezerra; Pinheiro, Jhully Azevedo Dos Santos; Ribeiro-dos-Santos, Ândrea; Cavalcante, Giovanna C.

doi:10.3390/cells10020479

Cited by 92 publications

(20 citation statements)

References 253 publications

(243 reference statements)

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“…Il1β transcript abundance positively correlated with parasitemia in the E6.5 infection group and multivariate modeling showed that infection at E8.5 increased placental transcription of this factor. This observation is consistent with another model of malaria infection, in which reduction of IL-1β signaling improved pregnancy outcome [ 22 ]; thus, IL-1β appears to be a universal driver of poor birth outcomes in malaria, perhaps through inflammasome assembly and/or the initiation of pyroptosis [ 55 ].…”

Section: Discussionsupporting

confidence: 86%

A novel murine model of post-implantation malaria-induced preterm birth

2022

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Despite major advances made in malaria treatment and control over recent decades, the development of new models for studying disease pathogenesis remains a vital part of malaria research efforts. The study of malaria infection during pregnancy is particularly reliant on mouse models, as a means of circumventing many challenges and costs associated with pregnancy studies in endemic human populations. Here, we introduce a novel murine model that will further our understanding of how malaria infection affects pregnancy outcome. When C57BL/6J (B6) mice are infected with Plasmodium chabaudi chabaudi AS on either embryonic day (E) 6.5, 8.5, or 10.5, preterm birth occurs in all animals by E16.5, E17.5, or E18.5 respectively, with no evidence of intrauterine growth restriction. Despite having the same outcome, we found that the time to delivery, placental inflammatory and antioxidant transcript upregulation, and the relationships between parasitemia and transcript expression prior to preterm birth differed based on the embryonic day of infection. On the day before preterm delivery, E6.5 infected mice did not experience significant upregulation of the inflammatory or antioxidant gene transcripts examined; however, peripheral and placental parasitemia correlated positively with Il1β, Cox1, Cat, and Hmox1 placental transcript abundance. E8.5 infected mice had elevated transcripts for Ifnγ, Tnf, Il10, Cox1, Cox2, Sod1, Sod2, Cat, and Nrf2, while Sod3 was the only transcript that correlated with parasitemia. Finally, E10.5 infected mice had elevated transcripts for Ifnγ only, with a tendency for Tnf transcripts to correlate with peripheral parasitemia. Tumor necrosis factor deficient (TNF-/-) and TNF receptor 1 deficient (TNFR1-/-) mice infected on E8.5 experienced preterm birth at the same time as B6 controls. Further characterization of this model is necessary to discover the mechanism(s) and/or trigger(s) responsible for malaria-driven preterm birth caused by maternal infection during early pregnancy.

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Section: Discussionsupporting

confidence: 86%

A novel murine model of post-implantation malaria-induced preterm birth

2022

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“…Il1β transcript abundance positively correlated with parasitemia in the E6.5 infection group only but no changes in its expression were detected in the other infection models. This observation is noteworthy because in another model of infection during late pregnancy, reduction of IL-1β signaling improves pregnancy outcome [13]; thus, IL-1β may play a pathogenic role in our E6.5 infection model as well, perhaps through inflammasome assembly and/or the initiation of pyroptosis in gestational tissues, as has been demonstrated in other models of PM [45].…”

Section: Discussionsupporting

confidence: 59%

Novel murine models of post-implantation and midgestional malaria-induced preterm birth

Andrew

Cooper

Moore

2021

Preprint

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Despite major advances made in malaria treatment and control over recent decades, the development of new models for studying disease pathogenesis remains a vital part of malaria research efforts. The study of malaria infection during pregnancy is particularly reliant on mouse models, as a means of circumventing many challenges and costs associated with pregnancy studies in endemic human populations. Here, we introduce three novel murine models that will further our understanding of how post-implantation and midgestional malaria infection affects pregnancy outcomes. When C57BL/6J (B6) mice are infected with Plasmodium chabaudi chabaudi AS on either embryonic day (E) 6.5, 8.5, or 10.5, preterm birth occurs in all animals by E16.5, E17.5, or E18.5 respectively, with no evidence of intrauterine growth restriction. We found that the time to delivery, placental inflammatory and antioxidant transcript upregulation, and the relationships between parasitemia and transcript expression prior to preterm birth are different based on the embryonic day of infection. On the day before preterm delivery, E6.5 infected mice did not experience significant upregulation of the inflammatory or antioxidant gene transcripts examined; however, parasitemia correlated positively with Il1β , Cox1 , and Hmox1 placental transcript abundance. E8.5 infected mice had elevated transcripts for Ifn g , Tnf , Il10 , Cox1 , Cox2 , Sod1 , Sod2 , Cat , and Nrf2 , while Sod3 was the only transcript that correlated with parasitemia. Finally, E10.5 infected mice had elevated transcripts for Ifn g only, with a tendency for Tnf transcripts to correlate with parasitemia. Tumor necrosis factor deficient (TNF -/- ) and TNF receptor 1 deficient (TNFR1 -/- ) mice infected on E8.5 experienced preterm birth at the same time as B6 controls. Further characterization of these models is necessary to discover new and/or existing mechanism(s) or trigger(s) responsible for malaria-driven preterm birth that is determined by gestational age upon maternal infection, parasite-host dynamics, or both.

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“…Malaria is a parasitic disease caused by the protozoa pathogens of the Plasmodium genus, which accounts for 228 million infected people globally in 2018 ( 259 ). Transmission occurs primarily through the bite of an infected female Anopheles mosquitoes, which inoculate the highly infective sporozoite forms into the mammalian host ( 260 , 261 ).…”

Section: Pyroptosis Defends Against Intracellular Protozoan Parasitesmentioning

confidence: 99%

Gasdermins in Innate Host Defense Against Entamoeba histolytica and Other Protozoan Parasites

2022

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Gasdermins (GSDMs) are a group of proteins that are cleaved by inflammatory caspases to induce pore formation in the plasma membrane to cause membrane permeabilization and lytic cell death or pyroptosis. All GSDMs share a conserved structure, containing a cytotoxic N-terminal (NT) pore-forming domain and a C-terminal (CT) repressor domain. Entamoeba histolytica (Eh) in contact with macrophages, triggers outside-in signaling to activate inflammatory caspase-4/1 via the noncanonical and canonical pathway to promote cleavage of gasdermin D (GSDMD). Cleavage of GSDMD removes the auto-inhibition that masks the active pore-forming NT domain in the full-length protein by interactions with GSDM-CT. The cleaved NT-GSDMD monomers then oligomerize to form pores in the plasma membrane to facilitate the release of IL-1β and IL-18 with a measured amount of pyroptosis. Pyroptosis is an effective way to counteract intracellular parasites, which exploit replicative niche to avoid killing. To date, most GSDMs have been verified to perform pore-forming activity and GSDMD-induced pyroptosis is rapidly emerging as a mechanism of anti-microbial host defence. Here, we review our comprehensive and current knowledge on the expression, activation, biological functions, and regulation of GSDMD cleavage with emphases on physiological scenario and related dysfunctions of each GSDM member as executioner of cell death, cytokine secretion and inflammation against Eh and other protozoan parasitic infections.

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Unraveling Cell Death Pathways during Malaria Infection: What Do We Know So Far?

Cited by 92 publications

References 253 publications

A novel murine model of post-implantation malaria-induced preterm birth

A novel murine model of post-implantation malaria-induced preterm birth

Novel murine models of post-implantation and midgestional malaria-induced preterm birth

Gasdermins in Innate Host Defense Against Entamoeba histolytica and Other Protozoan Parasites

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