Immunological observations and transcriptomic analysis of trimester‐specific full‐term placentas from three Zika virus‐infected women

Lum, Fok‐Moon; Narang, Vipin; Hue, Susan Swee-Shan; Chen, Jie; McGovern, Naomi; Rajarethinam, Ravisankar; Tan, Jeslin J. L.; Amrun, Siti Naqiah; Chan, Yi‐Hao; Lee, Cheryl Yi‐Pin; Chua, Tze-Kwang; Yee, Wearn-Xin; Yeo, Nicholas Kim‐Wah; Tan, T. Y. T.; Liu, Xuan; Haldenby, Sam; Leo, Yee‐Sin; Ginhoux, Florent; Chan, Jerry Ky; Hiscox, Julian A.; Chong, Chia-Yin; Ng, Lisa F. P.

doi:10.1002/cti2.1082

Cited by 23 publications

(25 citation statements)

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“…Fibrin deposits in the placenta can observed in cases of spontaneous abortion, premature birth and fetal death, which suggests a direct affect on the development of the fetus and pregnancy ( 40 ). The expression of VEGFR has already been related to other pathologies in the placenta and RANTES/CCL5 has been previously observed in ZIKV placental infection ( 15 , 31 , 41 , 42 ). Their changes can lead to edema and a failure in the distribution of nutrients as well as hormones necessary to maintain tissue homeostasis.…”

Section: Discussionmentioning

confidence: 76%

“…In addition, fluorescence microscopy captured colocalization of ZIKV NS1 in CD163 + activated macrophages that suggested these cells were sites of virus replication. Macrophages have been previously identified as principal targets for ZIKV infection and could provide a pathway for the vertical transmission of ZIKV through their activation that can lead to a prominent and diffuse hyperplasia ( 15 , 21 , 29 – 31 ). Infected CD163 + cells have already been suggested as one of the factors associated with virus delivery to the fetus that lead to ZIKV-induced fetal damage ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

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Zika Induces Human Placental Damage and Inflammation

et al. 2020

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In Brazil, an epidemic of Zika virus (ZIKV) infections was declared in 2015 that coincided with alarming reports of microcephaly in newborns associated with mother infection. Although the virus has placental tropism, changes in the tissue morphology and immunity of infected patients have not yet been elucidated. Here, we investigated the histopathological and ultrastructural changes along with the immunological profile and the BDNF expression in rare placental material. Tissues were obtained in the 2015–2016 Brazilian epidemic, of ten ZIKV-infected patients during pregnancy, five resulting in cases of fetal microcephaly and five non-microcephaly, compared to five non-infected control placentae. Viral antigens were only detected in samples from the ZIKV infected patients. Infected placentae presented histopathological severe damage, while the ultrastructural evaluation showed abnormal organelles, such as clusters of virus-like particles consistent with the ZIKV dimensions. Increased infiltration of CD68 + and TCD8 + cells, expression of MMPs, cytokines (IFN-γ and TNF-α) and other immunological mediators (RANTES/CCL5 and VEGFR-2) confirmed excessive inflammation and vascular permeability dysfunction. An evaluation of BDNF showed a decrease that could modulate neuronal damage in the developing fetus. The placental changes caused by ZIKV are not pathognomonic, however, the data provide evidence that this infection leads to severe placental injury.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Zika Induces Human Placental Damage and Inflammation

et al. 2020

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“…Gene expression analysis by defining mRNA profiles in clinical samples can be used to characterise the host response to infection. For example, this approach has been used to analyse blood samples to differentiate patients with acute Ebola virus disease who went on to survive or die 16 or to characterise Zika virus infection in the placenta during different trimesters 17 . Therefore, we used this approach to compare SARS-CoV-2 infection between the cynomolgus and rhesus macaques.…”

Section: Resultsmentioning

confidence: 99%

Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19

et al. 2021

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A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to assess the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques. Immune responses against SARS-CoV-2 are also similar in both species and equivalent to those reported in milder infections and convalescent human patients. This finding is reiterated by our transcriptional analysis of respiratory samples revealing the global response to infection. We describe a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the preferred study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of interventions against SARS-CoV-2. Importantly, accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.

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“…53 Furthermore, additional processes may also be involved in ZIKV pathogenesis, such as mitochondrial and oxidative phosphorylation gene dysregulation ( Table 1 ). This dysregulation has been previously observed during placental transcriptome profiling 29 and may be related to an overall cellular energy imbalance induced by ZIKV infection. 54 In summary, we conclude that ZIKV differs from other flaviviruses in downregulating IGF2 gene expression, although further studies are necessary to investigate the mechanisms involved.…”

Section: Discussionmentioning

confidence: 52%

“…In addition to this evidence, a unique study explored placental gene modulation in humans after ZIKV infection to reveal transcriptional differences in eIF2 signaling and mitochondrion and oxidative phosphorylation-related genes. 29 during the first trimester of pregnancy, and the possibility cannot be excluded that other affected pathways were not detected during the time that elapsed between the time of infection and the delivery, when the tissues were obtained. Furthermore, individual intrinsic genetic heterogeneity must be considered.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of IGF2 expression in third trimester placental tissues from Zika virus infected women in Brazil

Suzukawa

Zanluca

Jorge³

et al. 2020

Journal of Infection

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Objectives: Screening for genes differentially expressed in placental tissues, aiming to identify transcriptional signatures that may be involved in ZIKV congenital pathogenesis. Methods: Transcriptome data from placental tissues of pregnant women naturally infected with Zika virus during the third trimester were compared to those from women who tested negative for Zika infection. The findings were validated using both a cell culture model and an immunohistochemistry/morphological analysis of naturally infected placental tissues. Results: Transcriptome analysis revealed that Zika virus infection induces downregulation of insulin-like growth factor II (IGF2) gene, an essential factor for fetal development. The Caco-2 cell culture model that constitutively expresses IGF2 was used for the transcriptome validation. Asiatic and African Zika virus strains infection caused downregulated IGF2 gene expression in Caco-2 cells, whereas other flaviviruses, such as dengue serotype 1, West Nile and wild-type yellow fever viruses, had no effect on this gene expression. Immunohistochemical assays on decidual tissues corroborated our transcriptome analysis, showing that IGF2 is reduced in the decidua of Zika virus-infected women. Conclusions: Our results draw attention to IGF2 modulation in uterine tissues, and this finding is expected to support future studies on strategies to ameliorate the harmful effects of Zika virus infection during pregnancy.

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Immunological observations and transcriptomic analysis of trimester‐specific full‐term placentas from three Zika virus‐infected women

Cited by 23 publications

References 51 publications

Zika Induces Human Placental Damage and Inflammation

Zika Induces Human Placental Damage and Inflammation

Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19

Downregulation of IGF2 expression in third trimester placental tissues from Zika virus infected women in Brazil

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