Long-Term Clinical, Audiological, Visual, Neurocognitive and Behavioral Outcome in Children With Symptomatic and Asymptomatic Congenital Cytomegalovirus Infection Treated With Valganciclovir

Colonna, Arianna Turriziani; Buonsenso, Danilo; Pata, Davide; Salerno, Gilda; Chieffo, Daniela Pia Rosaria; Romeo, Domenico M.; Faccia, Valerio; Conti, Guido; Molle, Fernando; Baldascino, Antonio; Waure, Chiara de; Acampora, Anna; Luciano, Rita Paola Maria; Santangelo, Rosaria; Valentini, Piero

doi:10.3389/fmed.2020.00268

Cited by 30 publications

(17 citation statements)

References 23 publications

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“…Thus, vICA protects from cell death and promotes viral replication in a broader range of cell types than previously recognized. Our observations on TNF remains relevant to HCMV infection and associated pathologies [17,83]. Implications of these data extend to the reported ability of HCMV-encoded vICA to stabilize MLKL [34].…”

Section: Discussionsupporting

confidence: 70%

“…Cytomegaloviruses (CMVs) are ubiquitous pathogens that infect mammals in a species-specific manner and rely on multiple cell death suppressors to prevent the elimination of infected cells. Human (H)CMV causes severe disease in the newborn following transplacental transmission, where this virus is a common cause of pathogen-associated birth defects [15][16][17], as well as in immunosuppressed patients, where retinitis, encephalitis, colitis, and pneumonitis predominate [18][19][20][21][22]. Viral replication and inflammatory signaling contribute in poorly understood ways to CMV disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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TNF Signaling Dictates Myeloid and Non-Myeloid Cell Crosstalk to Execute MCMV-Induced Extrinsic Apoptosis

Mandal

McCormick

Mocarski

2020

Viruses

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Cytomegaloviruses all encode the viral inhibitor of caspase-8-induced apoptosis (vICA). After binding to this initiator caspase, vICA blocks caspase-8 proteolytic activity and ability to activate caspase-3 and/or caspase-7. In this manner, vICA has long been known to prevent apoptosis triggered via tumor necrosis factor (TNF) family death receptor-dependent extrinsic signaling. Here, we employ fully wild-type murine cytomegalovirus (MCMV) and vICA-deficient MCMV (∆M36) to investigate the contribution of TNF signaling to apoptosis during infection of different cell types. ∆M36 shows the expected ability to kill mouse splenic hematopoietic cells, bone marrow-derived macrophages (BMDM), and dendritic cells (BMDC). Antibody blockade or genetic elimination of TNF protects myeloid cells from death, and caspase-8 activation accompanies cell death. Interferons, necroptosis, and pyroptotic gasdermin D (GSDMD) do not contribute to myeloid cell death. Human and murine fibroblasts or murine endothelial cells (SVEC4-10) normally insensitive to TNF become sensitized to ∆M36-induced apoptosis when treated with TNF or TNF-containing BMDM-conditioned medium. We demonstrate that myeloid cells are the natural source of TNF that triggers apoptosis in either myeloid (autocrine) or non-myeloid cells (paracrine) during ∆M36 infection of mice. Caspase-8 suppression by vICA emerges as key to subverting innate immune elimination of a wide variety of infected cell types.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

TNF Signaling Dictates Myeloid and Non-Myeloid Cell Crosstalk to Execute MCMV-Induced Extrinsic Apoptosis

Mandal

McCormick

Mocarski

2020

Viruses

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“…While the neonatal outcomes are currently reassuring, the long-term effects on newborns exposed in utero or early in the postnatal life is still unknown and poorly addressed. The natural history of congenital infections taught us that even asymptomatic newborns can develop significant long-term effects in terms of audiologic, visual, and neuropsychiatric problems [ 8 , 33 , 34 ]. The recent evidence that maternal SARS-CoV-2 infection induces a robust placental inflammation [ 14 ] further reinforces this hypothesis, and for these reasons we decided, in our center, to offer a long-term multidisciplinary follow-up to all infants exposed in utero or within the first hours of life.…”

Section: Discussionmentioning

confidence: 99%

“…During the last decade, we learnt that congenital cytomegalovirus infection, even when newborns are completely asymptomatic, is associated with a significant degree of sensorineural hearing loss and neuropsychiatric involvement [ 8 ]. Recent data from a long-term follow-up of children exposed in utero to a newly identified virus, the Zika virus, showed clinical sequelae, even in those children that were not vertically infected [ 9 ], further highlighting the importance of establishing a comprehensive follow-up of children exposed to viruses in utero.…”

Section: Introductionmentioning

confidence: 99%

Short- and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 in utero or during the perinatal period: preliminary findings

et al. 2022

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The long-term outcomes of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life are still unknown. We performed a single-center, prospective, observational study of newborns born from mothers with microbiologically confirmed SARS-CoV-2 infection in pregnancy or at time of delivery. Infants were offered a multidisciplinary follow-up consisting of nasopharyngeal Polymerase Chain Reaction test at birth and at 48–72 h of life, auxological growth and neurological development, serologic testing, and audiological and ophthalmological assessments. One-hundred ninety-eight mothers and 199 newborns were enrolled. Of the 199 newborns, 171 underwent nasopharyngeal swab, four (2.3%) and two (1.15%) children tested positive at birth and 48–72 h of life, respectively. None had SARS-CoV-2 related symptoms. Auxologic and neurologic development were normal in all children during follow-up. Nine out of 59 infants had SARS-CoV-2 IgG at 3 months of life, which was associated with a positive nasopharyngeal swab at birth ( P = 0.04). Twenty seven out of 143 (18.8%) newborns had pathologic transitory evoked otoacoustic emissions at birth, although 14/27 repeated after 1 month were normal. Audiological evaluation was completed with Auditory Brainstem Response between the third and sixth month of life in 34 children, showing in all normal hearing threshold. The ophthalmological evaluation found retinal vascular anomalies in 3/20 (15%) children, immature visual acuity in 5/20 (25%) children, and reduced distance attention in 6/20 cases (30%). Conclusions : Our study showed that the neonatal and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life are mostly positive, with the exception of ophthalmologic findings which, in a preliminary cohort, were abnormal in about 15% of cases. Further prospective, longitudinal studies are needed to better understand the clinical outcomes of children exposed to SARS-CoV-2 in utero and in the early postnatal life. What is Known: • In utero mother-to-child transmission of SARS-CoV-2 has been documented by several independent studies. • Neonatal COVID-19 is a systemic disease that can be severe, although rarely. What is New: • Newborns exposed in utero to SARS-CoV-2 have mostly a normal auxological, audiological, and neurological development during the first months of life. • Fundus fluorescein angiography revealed that up to 5% of newborns exposed in utero to SARS-CoV2 can show retinal and choroidal abnormalities, including peripheral hypofluorescence of the choroid and increased vascular tortuosity. Supplementary Info...

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“…HCMV is a significant pathogen with protean clinical manifestations where pathogenesis depends on viral replication as well as immune cell-driven inflammation [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. The contribution of PCD suppression to pathogenesis remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness

Mandal

Nagrani

Hernández

et al. 2021

Viruses

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Programmed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.5-encoded viral mitochondrial inhibitor of apoptosis (vMIA), a BAX suppressor that functions in concert with M41.1-encoded viral inhibitor of BAK oligomerization (vIBO), (ii) M36-encoded viral inhibitor of caspase-8 activation (vICA), and (iii) M45-encoded viral inhibitor of RIP/RHIM activation (vIRA). Following infection of bone marrow-derived macrophages, the virus initially deflected receptor-interacting protein kinase (RIPK)3-dependent necroptosis, the most potent of the three cell death pathways. This process remained independent of caspase-8, although suppression of this apoptotic protease enhances necroptosis in most cell types. Second, the virus deflected TNF-mediated extrinsic apoptosis, a pathway dependent on autocrine TNF production by macrophages that proceeds independently of mitochondrial death machinery or RIPK3. Third, cytomegalovirus deflected BCL-2 family protein-dependent mitochondrial cell death through combined TNF-dependent and -independent signaling even in the absence of RIPK1, RIPK3, and caspase-8. Furthermore, each of these cell death pathways dictated a distinct pattern of cytokine and chemokine activation. Therefore, cytomegalovirus employs sequential, non-redundant suppression strategies to specifically modulate the timing and execution of necroptosis, extrinsic apoptosis, and intrinsic apoptosis within infected cells to orchestrate virus control and infection-dependent inflammation. Virus-encoded death suppressors together hold control over an intricate network that upends host defense and supports pathogenesis in the intact mammalian host.

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Long-Term Clinical, Audiological, Visual, Neurocognitive and Behavioral Outcome in Children With Symptomatic and Asymptomatic Congenital Cytomegalovirus Infection Treated With Valganciclovir

Cited by 30 publications

References 23 publications

TNF Signaling Dictates Myeloid and Non-Myeloid Cell Crosstalk to Execute MCMV-Induced Extrinsic Apoptosis

TNF Signaling Dictates Myeloid and Non-Myeloid Cell Crosstalk to Execute MCMV-Induced Extrinsic Apoptosis

Short- and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 in utero or during the perinatal period: preliminary findings

Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness

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