Congenital Zika Syndrome and Extra-Central Nervous System Detection of Zika Virus in a Pre-term Newborn in Mexico

Valdespino-Vázquez, María Yolotzin; Sevilla-Reyes, Edgar; Lira, Rosalía; Yocupicio-Monroy, Martha; Pitén-Isidro, Elvira; Boukadida, Célia; Hernández-Pando, Rogelio; Soriano-Jimenez, Juan David; Herrera‐Salazar, Alma; Figueroa-Damián, Ricardo; Reyes‐Terán, Gustavo; Zamora-Escudero, Rodrigo; Cardona–Pérez, Jorge Arturo; Maldonado-Rodriguez, Angelica; Moreno-Verduzco, Elsa Romelia; Torres-Flores, Jesús

doi:10.1093/cid/ciy616

Cited by 16 publications

(19 citation statements)

References 44 publications

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“…In 5 out of the 6 thymuses analyzed, we detected the presence of viral protein colocalized with TEC, as ascertained by immunofluorescence using the 4G2 anti-flavivirus and anti-cytokeratin antibodies. Not only we detected the viral protein in Hassall's corpuscles, as briefly reported by Valdespino-Vázquez and co-workers 48 , but also in TEC outside the corpuscles and that are located in close contact with developing thymocytes.…”

Section: Discussionsupporting

confidence: 86%

Zika virus targets the human thymic epithelium

Messias

Loss-Morais

Carvalho

et al. 2020

Sci Rep

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Previous work showed that the thymus can be infected by RNA viruses as HIV and HTLV-1. We thus hypothesized that the thymus might also be infected by the Zika virus (ZIKV). Herein we provide compelling evidence that ZIKV targets human thymic epithelial cells (TEC) in vivo and in vitro. ZIKVinfection enhances keratinization of TEC, with a decrease in proliferation and increase in cell death. Moreover, ZIKV modulates a high amount of coding RNAs with upregulation of genes related to cell adhesion and migration, as well as non-coding genes including miRNAs, circRNAs and lncRNAs. Moreover, we observed enhanced attachment of lymphoblastic T-cells to infected TEC, as well as virus transfer to those cells. Lastly, alterations in thymuses from babies congenitally infected were seen, with the presence of viral envelope protein in TEC. Taken together, our data reveals that the thymus, particularly the thymic epithelium, is a target for the ZIKV with changes in the expression of molecules that are relevant for interactions with developing thymocytes. Zika virus (ZIKV) epidemics in 2015-2016 resulted in devastating effects, causing microcephaly, other related congenital defects at birth and neurodevelopmental delay after two years in children born from mothers infected by the virus during pregnancy 1-4. Additionally, ZIKV infection in adults correlated with a rise in the frequency of cases of Guillain-Barré syndrome 5,6. Although the knowledge on the cellular and molecular alterations caused by the ZIKV in the nervous tissue largely increased in the last few years 2,7,8 , the effects of this virus upon hematopoietic tissues are much less defined. In terms of secondary lymphoid organs, ZIKV RNA and protein have been described in lymph nodes of Rhesus monkeys in both paracortex and germinal centers 9,10. The virus was also found in macrophages, dendritic cells, and B-cells, in both spleen and axillary lymph nodes of this non-human primate. However, in the same study, the presence of ZIKV RNA in T-cells was observed only in axillary lymph nodes from one animal 10. Much less is known on the putative infection of primary lymphoid organs, and more particularly in the thymus. This central lymphoid organ is responsible for the generation of T lymphocytes under the control of the thymic microenvironment, a three-dimensional cellular network mainly composed by thymic epithelial cells-TEC 11. In this respect, it is interesting to note the thymus as a target organ for other RNA viruses, such as HIV 12 and HTLV-1 13,14. In fact, we showed that cultured human TEC can be infected by HTLV-1 and convey virus particles to lymphoblastic T cells 15,16. We thus hypothesized that the thymic epithelium might also be infected by the Zika virus. Herein we provide compelling evidence that ZIKV targets human TEC both in vivo and in vitro. Data are provided showing that ZIKV-infection enhances keratinization of TEC, with a decrease in proliferation and increase in cell death. Moreover, in vitro data revealed that the virus could modulate a high amount ...

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Section: Discussionsupporting

confidence: 86%

Zika virus targets the human thymic epithelium

Messias

Loss-Morais

Carvalho

et al. 2020

Sci Rep

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“…Traveller/non-traveller populations: In this update, we found further evidence that congenital abnormalities occurred in infants born to women travellers returning from ZIKV-affected areas and women remaining in those areas. In total, 25 publications report on 272 congenital abnormalities due to ZIKV infection in travellers 27, 29, 30, 32, 34, 36, 38, 42, 45, 56, 58, 61, 89, 94, 98, 109, 117, 122, 123, 137, 140, 151, 153, 166, 173 , with 109 publications reporting congenital abnormalities due to ZIKV in 2652 non travellers 24– 26, 28, 31, 33, 35, 37, 39– 41, 43, 44, 46– 48, 50, 51, 54, 57, 60, 62– 79, 81, 83– 85, 87, 88, 90– 93, 95– 97, 100, 101, 104– 106, 110– 113, 115, 116, 118, 119, 121, 124– 135, 142– 147, 149, 152, 154, 156– 164, 167, 168, 171, 172, 175– 180, 182, …”

Section: Resultsmentioning

confidence: 99%

Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: A living systematic review

et al. 2019

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Background: The Zika virus (ZIKV) caused a large outbreak in the Americas leading to the declaration of a Public Health Emergency of International Concern in February 2016. A causal relation between infection and adverse congenital outcomes such as microcephaly was declared by the World Health Organization (WHO) informed by a systematic review structured according to a framework of ten dimensions of causality, based on the work of Bradford Hill. Subsequently, the evidence has continued to accumulate, which we incorporate in regular updates of the original work, rendering it a living systematic review. Methods: We present an update of our living systematic review on the causal relation between ZIKV infection and adverse congenital outcomes and between ZIKV and GBS for four dimensions of causality: strength of association, dose-response, specificity, and consistency. We assess the evidence published between January 18, 2017 and July 1, 2019. Results: We found that the strength of association between ZIKV infection and adverse outcomes from case-control studies differs according to whether exposure to ZIKV is assessed in the mother (OR 3.8, 95% CI: 1.7-8.7, I2=19.8%) or the foetus/infant (OR 37.4, 95% CI: 11.0-127.1, I2=0%). In cohort studies, the risk of congenital abnormalities was 3.5 times higher after ZIKV infection (95% CI: 0.9-13.5, I2=0%). The strength of association between ZIKV infection and GBS was higher in studies that enrolled controls from hospital (OR: 55.8, 95% CI: 17.2-181.7, I2=0%) than in studies that enrolled controls at random from the same community or household (OR: 2.0, 95% CI: 0.8-5.4, I2=74.6%). In case-control studies, selection of controls from hospitals could have biased results. Conclusions: The conclusions that ZIKV infection causes adverse congenital outcomes and GBS are reinforced with the evidence published between January 18, 2017 and July 1, 2019.

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“…Recent gynecological reports demonstrate that the dramatic presentation of microcephaly in ZIKV-infected fetuses is not the most prominent clinical presentation, and is overshadowed by radiological findings of ventriculomegaly, cortical atrophy, calcifications (particularly located at the cortico-subcortical junction), and anomalies of the corpus callosum (Netto et al, 2017; Schaub et al, 2017a). Furthermore, emerging pediatric case reports of congenitally ZIKV-infected infants support that the spectrum of fetal brain and other anomalies is broader and more complex than microcephaly alone and includes subtle fetal brain injuries (Walker et al, 2018), ocular and auditory defects (Peloggia et al, 2018), as well as histopathological findings of viral dissemination and detection within extra-CNS tissues of post-mortem samples (Valdespino-Vazquez et al, 2018).…”

Section: Perspectivesmentioning

confidence: 99%

The Unfolded Protein Response: A Key Player in Zika Virus-Associated Congenital Microcephaly

Alfano

Gladwyn-Ng

Couderc

et al. 2019

Front. Cell. Neurosci.

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Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flaviviridae family, together with dengue, yellow fever, and West Nile viruses. In the wake of its emergence in the French Polynesia and in the Americas, ZIKV has been shown to cause congenital microcephaly. It is the first arbovirus which has been proven to be teratogenic and sexually transmissible. Confronted with this major public health challenge, the scientific and medical communities teamed up to precisely characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. This review focuses on the critical impact of the unfolded protein response (UPR) on ZIKV-associated congenital microcephaly. ZIKV infection of cortical neuron progenitors leads to high endoplasmic reticulum (ER) stress. This results in both the stalling of indirect neurogenesis, and UPR-dependent neuronal apoptotic death, and leads to cortical microcephaly. In line with these results, the administration of molecules inhibiting UPR prevents ZIKV-induced cortical microcephaly. The discovery of the link between ZIKV infection and UPR activation has a broader relevance, since this pathway plays a crucial role in many distinct cellular processes and its induction by ZIKV may account for several reported ZIKV-associated defects.

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Congenital Zika Syndrome and Extra-Central Nervous System Detection of Zika Virus in a Pre-term Newborn in Mexico

Abstract: Our findings demonstrate the ability of congenitally acquired ZIKV to produce disseminated infections and the viral tropism towards epithelial cells.

Cited by 16 publications

References 44 publications

Zika virus targets the human thymic epithelium

Zika virus targets the human thymic epithelium

Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: A living systematic review

The Unfolded Protein Response: A Key Player in Zika Virus-Associated Congenital Microcephaly

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