Zika Virus Induces Mitotic Catastrophe in Human Neural Progenitors by Triggering Unscheduled Mitotic Entry in the Presence of DNA Damage While Functionally Depleting Nuclear PNKP

Rychłowska, Małgorzata; Agyapong, Abigail; Weinfeld, Michael; Schang, Luis M.

doi:10.1128/jvi.00333-22

Cited by 8 publications

(5 citation statements)

References 133 publications

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“…Many pathogens can invade and infect placental cells [38]. Once infection of the maternal–placental–fetal triad is established, damage to the developing fetus can occur by infection of developing brain cells [39 ▪ ,40 ▪ ,41]; fetal exposure to inflammation and pro-inflammatory cytokines during maternal infection (i.e. maternal immune activation) [39 ▪ ,40 ▪ ,42,43 ▪ ,44,45 ▪ ], which affects fetal development and outcomes [39 ▪ ,40 ▪ ,44,46,47 ▪ ]; direct damage to the placenta in the context of infection [48 ▪ ,49,50], leading to poor function and malperfusion, affecting fetal development [40 ▪ ].…”

Section: Mechanisms Of Diseasementioning

confidence: 99%

Neurodevelopmental outcomes in congenital and perinatal infections

Fortin

Mulkey

2023

Current Opinion in Infectious Diseases

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Purpose of review Congenital infections are a major cause of childhood multidomain neurodevelopmental disabilities. They contribute to a range of structural brain abnormalities that can cause severe neurodevelopmental impairment, cerebral palsy, epilepsy, and neurosensory impairments. New congenital infections and global viral pandemics have emerged, with some affecting the developing brain and causing neurodevelopmental concerns. This review aims to provide current understanding of fetal infections and their impact on neurodevelopment. Recent findings There are a growing list of congenital infections causing neurodevelopmental issues, including cytomegalovirus, Zika virus, syphilis, rubella, lymphocytic choriomeningitis virus, and toxoplasmosis. Fetal exposure to maternal SARS-CoV-2 may also pose risk to the developing brain and impact neurodevelopmental outcomes, although studies have conflicting results. As Zika virus was a recently identified congenital infection, there are several new reports on child neurodevelopment in the Caribbean and Central and South America. For many congenital infections, children with in-utero exposure, even if asymptomatic at birth, may have neurodevelopmental concerns manifest over time. Summary Congenital infections should be considered in the differential diagnosis of a child with neurodevelopmental impairments. Detailed pregnancy history, exposure risk, and testing should guide diagnosis and multidisciplinary evaluation. Children with congenital infections should have long-term follow-up to assess for neurodevelopmental delays and other neurosensory impairments. Children with confirmed delays or high-risk should be referred for rehabilitation therapies.

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Section: Mechanisms Of Diseasementioning

confidence: 99%

Neurodevelopmental outcomes in congenital and perinatal infections

Fortin

Mulkey

2023

Current Opinion in Infectious Diseases

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“…In iPSC-derived human neural progenitor cells, ZIKV increased total protein levels of the tumor suppressor gene p53 and also induced its phosphorylation at Ser15, which resulted in genotoxic stress and apoptosis [138]. In neural progenitor cells, ZIKV hijacked a critical DNA damage repair enzyme, polynucleotide 5 -kinase 3 -phosphatase (PNKP), sequestering it in the cytoplasm during viral replication, rendering the cell unable to repair damaged DNA [139]. In another cell culture model of human neural progenitor cells, ZIKV halted replicating cells during S phase, inducing DNA damage.…”

Section: Zika Virusmentioning

confidence: 99%

Molecular and Cellular Mechanisms Underlying Neurologic Manifestations of Mosquito-Borne Flavivirus Infections

Blackhurst,

Funk

2023

Viruses

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Flaviviruses are a family of enveloped viruses with a positive-sense RNA genome, transmitted by arthropod vectors. These viruses are known for their broad cellular tropism leading to infection of multiple body systems, which can include the central nervous system. Neurologic effects of flavivirus infection can arise during both acute and post-acute infectious periods; however, the molecular and cellular mechanisms underlying post-acute sequelae are not fully understood. Here, we review recent studies that have examined molecular and cellular mechanisms that may contribute to neurologic sequelae following infection with the West Nile virus, Japanese encephalitis virus, Zika virus, dengue virus, and St. Louis encephalitis virus. Neuronal death, either from direct infection or due to the resultant inflammatory response, is a common mechanism by which flavivirus infection can lead to neurologic impairment. Other types of cellular damage, such as oxidative stress and DNA damage, appear to be more specific to certain viruses. This article aims to highlight mechanisms of cellular damage that are common across several flavivirus members and mechanisms that are more unique to specific members. Our goal is to inspire further research to improve understanding of this area in the hope of identifying treatment options for flavivirus-associated neurologic changes.

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“…Recently, a link between PNKP inhibition and ZIKV infection has been identified. Here, PNKP depletion led to DNA damage accumulation in NPCs after ZIKV infection, failure to activate the DNA damage checkpoints Chk1 and Chk2 and cytoplasmic accumulation of CycA/CDK1 complexes resulting in mitotic catastrophe ( Rychlowska et al, 2022 ).…”

Section: Environmental Exposures Leading To Dna Damage-associated Mic...mentioning

confidence: 99%

DNA damage and repair: underlying mechanisms leading to microcephaly

Ribeiro,

Altinisik,

Rajan

et al. 2023

Front. Cell Dev. Biol.

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DNA-damaging agents and endogenous DNA damage constantly harm genome integrity. Under genotoxic stress conditions, the DNA damage response (DDR) machinery is crucial in repairing lesions and preventing mutations in the basic structure of the DNA. Different repair pathways are implicated in the resolution of such lesions. For instance, the non-homologous DNA end joining and homologous recombination pathways are central cellular mechanisms by which eukaryotic cells maintain genome integrity. However, defects in these pathways are often associated with neurological disorders, indicating the pivotal role of DDR in normal brain development. Moreover, the brain is the most sensitive organ affected by DNA-damaging agents compared to other tissues during the prenatal period. The accumulation of lesions is believed to induce cell death, reduce proliferation and premature differentiation of neural stem and progenitor cells, and reduce brain size (microcephaly). Microcephaly is mainly caused by genetic mutations, especially genes encoding proteins involved in centrosomes and DNA repair pathways. However, it can also be induced by exposure to ionizing radiation and intrauterine infections such as the Zika virus. This review explains mammalian cortical development and the major DNA repair pathways that may lead to microcephaly when impaired. Next, we discuss the mechanisms and possible exposures leading to DNA damage and p53 hyperactivation culminating in microcephaly.

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Zika Virus Induces Mitotic Catastrophe in Human Neural Progenitors by Triggering Unscheduled Mitotic Entry in the Presence of DNA Damage While Functionally Depleting Nuclear PNKP

Cited by 8 publications

References 133 publications

Neurodevelopmental outcomes in congenital and perinatal infections

Neurodevelopmental outcomes in congenital and perinatal infections

Molecular and Cellular Mechanisms Underlying Neurologic Manifestations of Mosquito-Borne Flavivirus Infections

DNA damage and repair: underlying mechanisms leading to microcephaly

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