Congenital Virus Infection Research Articles

Congenital and Perinatal Viral Infections: Consequences for the Mother and Fetus

Viruses are the most common congenital infections in humans and an important cause of foetal malformations, neonatal morbidity, and mortality. The effects of these infections, which are transmitted in utero (transplacentally), during childbirth or in the puerperium depend on the timing of the infections. These vary from miscarriages (usually with infections in very early pregnancy), congenital malformations (when the infections occur during organogenesis) and morbidity (with infections occurring late in pregnancy, during childbirth or after delivery). The most common of these viruses are cytomegalovirus, hepatitis, herpes simplex type-2, parvovirus B19, rubella, varicella zoster and zika viruses. There are currently very few efficacious antiviral agents licensed for use in pregnancy. For most of these infections, therefore, prevention is mainly by vaccination (where there is a vaccine). The administration of immunoglobulins to those exposed to the virus to offer passive immunity or appropriate measures to avoid being infected would be options to minimise the infections and their consequences. In this review, we discuss some of the congenital and perinatal infections and their consequences on both the mother and fetus and their management focusing mainly on prevention.

National survey on Congenital Cytomegalovirus Awareness and Screening Practices among Healthcare Professionals

ObjectivesCongenital cytomegalovirus (CMV) infection, resulting from maternal-fetal transmission of CMV, poses a substantial risk to maternal and child health. It is the most prevalent congenital viral infection, and the prevention and management of this condition rely heavily on the knowledge and awareness of healthcare professionals. MethodsThis cross-sectional survey was conducted between March 1, 2023, and August 31, 2023, across multiple tertiary centers in various Saudi Arabian cities. It assessed the understanding and awareness of congenital CMV infection among 400 healthcare professionals from diverse specialties. The study utilized a structured questionnaire to evaluate knowledge levels, obtain demographic data, and identify factors influencing awareness. ResultsThe study revealed significant disparities in knowledge levels, with around 84 % of participants categorized as having “low" knowledge. Obstetricians and gynecologists exhibited better knowledge. Factors like specialization, age, and professional experience significantly affected knowledge levels. Additionally, many healthcare professionals perceived a lack of information and awareness regarding CMV among their peers. ConclusionCongenital CMV infection is a major public health concern with potential severe consequences. The study identified knowledge disparities, particularly among non-specialist healthcare practitioners, emphasizing the need for targeted educational programs and focused awareness initiatives. Key factors, such as expertise, age, and experience, underscore the importance of addressing ongoing knowledge gaps, highlighting the need for continuous efforts to mitigate challenges associated with CMV infection.

Clinical Characteristics and Outcomes of Intrauterine Blood Transfusion (IUT) for Infectious Etiologies.

Congenital viral infection may result in fetal anemia and thrombocytopenia. While intrauterine blood transfusions (IUTs) are more commonly performed for Rh alloimmunization, reports using IUT for infection have varying success. Our primary objective was to characterize the outcomes of patients undergoing IUT for infectious etiologies at our center compared with Rh disease. This was a case series of patients undergoing IUT from 2012-2023. Infectious etiologies were identified by maternal serologies and confirmed by amniotic fluid polymerase chain reactions (PCR). Clinical outcomes were obtained from electronic medical records. During the study period, 70 patients underwent IUT, 34% (24/70) for Rh alloimmunization and 17% (12/70) for infection. Those with infectious etiologies were more likely to be diagnosed at earlier gestational ages (22 vs. 25weeks, p=0.04), with hydrops (75 vs. 33%, p=0.03), and thrombocytopenia (27±33×103 vs. 163±112×103, p<0.01). Perinatal death was significantly greater in cases of CMV (4/5, 80%) compared to parvovirus (1/7, 14%) or Rh alloimmunization (5/24, 21%) (p=0.02). Anemias and thrombocytopenias related to fetal infection may be indications for IUT. Compared with Rh alloimmunization, IUT in fetal infections was performed significantly earlier, and hydrops were more common at the time of IUT. In the case of CMV, greater rates of IUFD (80%) were observed. Patients should be counseled on the various outcomes by indication.

Maternal Cytomegalovirus (CMV) Serology: The Diagnostic Limitations of CMV IgM and IgG Avidity in Detecting Congenital CMV Infection.

Congenital cytomegalovirus (cCMV) is a common congenital viral infection. Testing for cCMV usually begins with assessing maternal CMV serology, specifically IgM and IgG antibodies. A negative maternal CMV IgM suggests a low risk of recent maternal CMV infection, thereby suggesting a low risk of cCMV in the fetus. Consequently, cCMV is often ruled out when maternal CMV IgM is negative. In our perinatal autopsy and placental pathology database, we identified 5 cases of cCMV despite negative maternal CMV IgM results in the second trimester. In all 5 cases, fetal abnormalities were first detected by ultrasound in the second trimester, prompting maternal CMV testing. Since second trimester maternal CMV IgM was negative in all cases, cCMV was considered unlikely, thus precluding further prenatal CMV testing in 4 of these cases. The diagnosis of cCMV was subsequently made through placental and/or autopsy examinations. Following this diagnosis, retrospective CMV serology and IgG avidity testing was performed on stored frozen first-trimester maternal blood samples in 3 cases. Among these, the first-trimester samples in 2 cases were IgG+, IgM+, and exhibited low IgG avidity, suggesting a primary maternal CMV infection around the time of conception. In the third case, both first and second-trimester maternal blood samples were IgG+, IgM-, and showed high IgG avidity, suggesting a non-primary maternal CMV infection (i.e., reactivation or reinfection of CMV). A negative maternal CMV IgM in the second trimester cannot exclude cCMV infection. While CMV IgG avidity testing and analysis of stored frozen first-trimester maternal blood samples provide valuable insights, they have limitations. CMV PCR performed on amniotic fluid is a useful prenatal diagnostic tool. For cases of unexplained fetal abnormalities or death, autopsy and placental examination are recommended.

Cutting Edge: Retinoic Acid Promotes Brain-homing of CD8+ T Cells during Congenital Cytomegalovirus Infection.

The most common congenital viral infection is CMV, which leads to numerous neurologic disabilities. Using a mouse model of congenital CMV, we previously determined that Ag-specific CD8+ T cells traffic to the brain in a CCR9-dependent manner. The mechanism by which these CD8+ T cells acquire a CCR9-dependent "brain-tropic" phenotype remains unclear. In this study, we identify the key factor that imprints brain homing specificity on CD8+ T cells, the source of production, and the location where CCR9 expression is induced. Specifically, we discovered that CCR9 is induced on CD8+ T cells by retinoic acid-producing CD8α+ dendritic cells in the cervical lymph node postinfection. We found that retinoic acid is important for CD8+ T cells to establish tissue residency in the brain. Collectively, our data expand the role of retinoic acid during infection and mechanistically demonstrate how CD8+ T cells are primed to protect the brain during congenital viral infection.

Investigation of Targeted Genes and Identification of Novel Variants with Next Generation Sequencing Method in Hearing Loss.

Hearing loss is a widespread condition throughout the world. It may affect patients from newborns to the elderly. There are too many reasons for hearing loss, including congenital hearing loss, virus infections, age-related situations, and traumatic situations, which may be related to the immune-mediated system. Fifty percent of hearing loss is related to genetic mutations and defects; genetic causes are highly heterogeneous, so the analysis of new variants are important for diagnosis. We aimed to describe the importance of detected gene variations by using targeted gene panels in the Next-Generation-Sequencing (NGS) platform. Eighty-one hearing loss targeted genes were investigated using Illumina NextSeq550 technology in 100 participants with hearing loss between 2017 and 2022 in our Genetic Diseases Evaluation Center. Targeted genes were performed on 100 patients with hearing loss diagnosis. The total number of detected variants was 77. Forty-seven cases have likely pathogenic/pathogenic variants. Thirty of them have uncertain clinical significance variants, and from the detected variants, 8 are novel. In this research, we highlighted that earlier detection of hearing loss using molecular genetic methods may help us understand the etiology and orient for a better prognosis. Results detected by using the NGS platform can assist and improve the diagnosis. In this study, the diagnostic rate with targeted genes was detected as 35.29%. It has an important role in clinical practice as the recommendation of cochlear implants. Clarifying the genotype and phenotype correlation helps us figure out the etiology of hearing loss and also the worth of genetic counseling in hereditary hearing loss.

Short- and long-term neurological outcomes of congenital cytomegalovirus infection.

Cytomegalovirus (CMV) is the most common congenital viral infection. Although most children with congenital CMV (approximately 85%-90%) are asymptomatic at birth, findings such as sensorineural hearing loss, microcephaly, and neurodevelopmental retardation can be observed during the follow-up. Among the brain magnetic resonance imaging (MRI) findings of CMV are white matter abnormalities, polymicrogyria, and periventricular calcification. Since a definitive diagnosis of congenital CMV cannot be made after the neonatal period, the identification of the associated phenotype is diagnostically important, but data are limited in patients who have been retrospectively diagnosed with congenital CMV infection. The aim of this study was to evaluate the short- and long-term neurological follow-up results of congenital CMV infections in a tertiary hospital. The neurological results of fifteen patients under the age of 18 years, who had a definitive diagnosis of congenital CMV infection and were followed up in a tertiary care hospital between 2011 and 2020, were retrospectively evaluated. Ten of the patients in our study group were male. The mean age at presentation for neurological evaluation was 2.02 ± 1.54 months, with a median follow-up time of 36.3 months (range: 9.3-129.4 months). Neurological disorders detected during the long-term follow-up included cerebral palsy (46.7%), cognitive impairment (46.7%), epilepsy (40%), and sensorineural hearing loss (26.7%). The most common abnormality observed on MRI scans was white matter involvement (53.3%). Early diagnosis and intervention are crucial in congenital CMV infection, as it commonly results in neurological involvement among the patients in our series. This preventable condition warrants further research regarding prenatal/neonatal screening.

Understanding the impact of congenital infections and perinatal viral exposures on the developing brain using white matter magnetic resonance imaging: a scoping review

BackgroundMagnetic Resonance Imaging (MRI)-based imaging techniques are useful for assessing white matter (WM) structural and microstructural integrity in the context of infection and inflammation. The purpose of this scoping review was to assess the range of work on the use of WM neuroimaging approaches to understand the impact of congenital and perinatal viral infections or exposures on the developing brain.MethodsThis scoping review was conducted according to the Arksey and O’ Malley framework. A literature search was performed in Web of Science, Scopus and PubMed for primary research articles published from database conception up to January 2022. Studies evaluating the use of MRI-based WM imaging techniques in congenital and perinatal viral infections or exposures were included. Results were grouped by age and infection.ResultsA total of 826 articles were identified for screening and 28 final articles were included. Congenital and perinatal infections represented in the included studies were cytomegalovirus (CMV) infection (n = 12), human immunodeficiency virus (HIV) infection (n = 11) or exposure (n = 2) or combined (n = 2), and herpes simplex virus (HSV) infection (n = 1). The represented MRI-based WM imaging methods included structural MRI and diffusion-weighted and diffusion tensor MRI (DWI/ DTI). Regions with the most frequently reported diffusion metric group differences included the cerebellar region, corticospinal tract and association fibre WM tracts in both children with HIV infection and children who are HIV-exposed uninfected. In qualitative imaging studies, WM hyperintensities were the most frequently reported brain abnormality in children with CMV infection and children with HSV infection.ConclusionThere was evidence that WM imaging techniques can play a role as diagnostic and evaluation tools assessing the impact of congenital infections and perinatal viral exposures on the developing brain. The high sensitivity for identifying WM hyperintensities suggests structural brain MRI is a useful neurodiagnostic modality in assessing children with congenital CMV infection, while the DTI changes associated with HIV suggest metrics such as fractional anisotropy have the potential to be specific markers of subtle impairment or WM damage in neuroHIV.

Dysregulation of fetal-derived cochlear resident tissue macrophage mediate CMV-associated sensorineural hearing loss

Abstract Cytomegalovirus (CMV) is the most common congenital viral infection in the developed world and leading cause of non-genetic sensorineural hearing loss (SNHL) in children. Here we investigated the role of fetal-derived resident tissue macrophages (RTMs) in normal cochlear development and their role in CMV-associated SNHL. Using genetic fate mapping, we uncovered dual sources of fetal-derived RTMs from yolk sac (YS) and fetal liver (FL) hematopoiesis. YS-derived RTMs naturally recede after cochlea maturity while FL-derived RTMs expand, revealing a temporal layering of RTMs. Additionally YS-derived and FL-derived RTMs demonstrate spatial specificity, seeding distinct cochlear tissues. Both anti-CSF1R depletion of fetal-RTMs and embryonic genetic deletion of YS-derived RTMs by CSF1R-flox lead to SNHL and impaired cochlear tissue development, revealing the requirement for fetal RTMs in normal cochlear development. During CMV infection, scRNAseq and fate-mapping analysis revealed an infiltration of bone marrow-derived macrophages at the expense of yolk-sac derived RTMs, indicating that CMV infection disrupted the normal temporal layering of fetal-derived RTMs in the cochlea. Fetal-derived RTMs also upregulated inflammation-associated pathways and downregulated pathways critical for inner ear development, such as FGF and TGFb signaling. Together these data reveal perturbation of developing RTMs that regulate normal cochlear development as a mechanism underlying CMV-mediated SNHL.

Neurobehavioral outcomes of neonatal asymptomatic congenital cytomegalovirus infection at 12-months

BackgroundCongenital cytomegalovirus (cCMV) is the most common congenital viral infection in the United States. Symptomatic infections can cause severe hearing loss and neurological disability, although ~ 90% of cCMV infections are asymptomatic at birth. Despite its prevalence, the long-term neurobehavioral risks of asymptomatic cCMV infections are not fully understood. The objective of this work was to evaluate for potential long-term neurobehavioral sequelae in infants with asymptomatic cCMV.MethodsInfants with cCMV were identified from a universal newborn cCMV screening study in a metropolitan area in the midwestern United States. Asymptomatic infants with cCMV were enrolled in a longitudinal neurodevelopmental study (N = 29). Age- and sex-matched healthy control infants (N = 193) were identified from the Baby Connectome Project (BCP), a longitudinal study of brain and behavioral development. The BCP sample supplemented an additional group of healthy control infants (N = 30), recruited from the same participant registry as the BCP specifically for comparison with infants with asymptomatic cCMV. Neurobehavioral assessments and parent questionnaires, including the Mullen Scales of Early Learning, the Repetitive Behavior Scales for Early Childhood (RBS-EC), and the Infant Toddler Social Emotional Assessment (ITSEA) were administered at 12 months of age. Neurobehavioral scores were compared between infants with asymptomatic cCMV and all identified healthy control infants.ResultsInfants with asymptomatic cCMV performed equivalently compared to healthy control infants on the neurobehavioral measures tested at 12 months of age.ConclusionsThese results indicate that at 12 months of age, infants with asymptomatic cCMV are not statistically different from controls in a number of neurobehavioral domains. Although follow-up is ongoing, these observations provide reassurance about neurobehavioral outcomes for infants with asymptomatic cCMV and inform the ongoing discussion around universal screening. Additional follow-up will be necessary to understand the longer-term outcomes of these children.

Ophthalmic Zika virus disease: ocular findings in two Costa Rican newborns with microcephaly render a new insight of the illness

Zika virus infection is a vectorial tropical illness which has only recently been reported in Costa Rica. Inoculation by this flavivirus can cause a mild fever and rash in the general population. However, when contracted by pregnant women it may result in severe brain abnormalities and cognitive impairment of the newborn. We present the first two reported cases of combined microcephaly with retinopathy presumably due to this congenital viral infection. The ocular findings in both infants consisted in extensive chorioretinal atrophy and pigmented mottling throughout the macula. Despite both newborn turning in a positive result for Zika virus, only one of the mothers reported flu-like symptoms during pregnancy. We must consider the great threat this disease may pose on our health system since it generates a profound disability in the infant and will be therefore associated with long-term healthcare costs.

Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections.

Congenital virus infections inflict substantial morbidity and devastating disease in neonates worldwide, and hearing loss is a common outcome. It has been difficult to study viral infections of the human hearing apparatus because it is embedded in the temporal bone of the skull. Recent technological advances permit the differentiation of otic progenitor cells (OPCs) from human-induced pluripotent stem cells. This paper is important for demonstrating that inner ear virus infections can be modeled in vitro using OPCs. We infected OPCs with two viruses associated with congenital hearing loss: human cytomegalovirus (HCMV), a DNA virus, or Zika virus (ZIKV), an RNA virus. An important result is that the gene expression and cytokine production profiles of HCMV/ZIKV-infected OPCs are markedly dissimilar, suggesting that mechanisms of hearing loss are also distinct. The specific molecular regulatory pathways identified in this work could suggest important targets for therapeutics.

Review Article] Cytomegalovirus Infection

Cytomegalovirus (CMV) is a common viral pathogen. Most people who have acute CMV will have an undetectable infection. It is known that cytomegalovirus (CMV) is the most prevalent congenital viral infection in individuals and a significant factor in morbidity and mortality in immunosuppressed hosts, as well as a significant factor in neurodevelopmental disabilities and sensorineural hearing loss. In order to screen for congenital CMV infection, PCR assays are currently being evaluated.

Review Article] Cytomegalovirus Infection

Cytomegalovirus (CMV) is a common viral pathogen. Most people who have acute CMV will have an undetectable infection. It is known that cytomegalovirus (CMV) is the most prevalent congenital viral infection in individuals and a significant factor in morbidity and mortality in immunosuppressed hosts, as well as a significant factor in neurodevelopmental disabilities and sensorineural hearing loss. In order to screen for congenital CMV infection, PCR assays are currently being evaluated.

A-324 Incorporating the Screening for Congenital Cytomegalovirus into a Newborn Genetic Testing Performed on Saliva Swab: An Intersection between Human Genetics and Infectious Diseases

Abstract Background Newborn genetic testing is a powerful tool for improving the future healthcare of infants because of its potential to screening for a wide range of disorders with a single test. The assay can be performed in non-invasive sample such as saliva swabs. Hundreds of genes associated to disorders with significant morbidity and mortality (if undiagnosed) are analyzed. Despite the knowledge that infectious disorders such as congenital cytomegalovirus virus (cCMV) infection also has potential to cause serious illness to newborns (10–15% of apparently asymptomatic infants with cCMV may develop hearing loss) most of the newborn genetic testing does not test the saliva for cCMV. This validation aims to compare two laboratory-developed PCR-based CMV tests in saliva samples to add the cCMV screening into our newborn genetic testing. Methods Saliva swabs (OCR-100, DNA Genotek) from infants of our NGS-based newborn genetic testing were enrolled (n = 171). Parent signed informed consent agreeing with the used of the left-over specimens. Infants age ranged from 0 to 10 years. Saliva DNA was extracted by using QIAsymphony and DSP DNA mini kit (Qiagen). CMV was tested by two independent qPCR assays performed on LightCycler 480II using LightCycler Multiplex DNA Master (Roche). Each assays target two separated regions of the CMV genome (UL55 + UL123 and UL34 + UL80.5). A third assay targeting human CPOX gene was used as process control. The assays limits of detection were calculated by applying probit regression to the qualitative results returned from a serial dilution (1:10) of a positive pool (2 310 000 UI/mL) into a negative pool of samples. The accuracies for CMV detection were estimated by the total, positive and negative agreement between the compared sets of assays. The assay with lower limit of detection were chosen and its precision was evaluated by testing a subset of 26 saliva swabs (6 positives and 20 negatives) during 3 distinct days. For accuracy and precision experiments, Cq values &amp;gt;35 (∼750 UI/mL) was considered as not detected. Results The limits of detections were 40.7 UI/mL (95% CI:19.2–62.27 UI/mL) for UL55 + UL123 and 184 UI/mL (95% CI:64–304 UI/mL) for UL34 + UL80.5. CMV was detected in 8 and not detected in 163 saliva swabs by either UL55 + UL123 and UL34 + UL80.5 resulting in total, positive and negative agreements of 100% (95% CI:97–100%), 100% (95% CI:67–100%) and 100% (95% CI:97–100%), respectively. The median (min-max) Cq values for UL55 + UL123 were 30.75 (21.39–34.42) and for UL34 + UL80.5 were 30.81 (20.53–34.1). In the assay precision evaluation, UL55 + UL123 returned the expected result in 26/26, 26/26 and 25/26 samples on day 1, 2 and 3, respectively. The exception was a borderline positive sample that reach the Cq cut-off value (&amp;gt;35) on day 3 evaluation. Conclusion The UL55 + UL123 assay had lower limit of detection for CMV compared UL34 + UL80.5 and was chosen to be used in our cCMV screening. Both assays showed complete agreement when applied to saliva swabs samples. UL55 + UL123 presented acceptable precisions for positive and negative results. The cCMV screening by qPCR is now performed in parallel to NGS in our newborn genetic testing. cCMV test is only performed for newborns with less than 21 days of life, as recommend by specific guidelines.

Genetic and Functional Characterization of Congenital HCMV Clinical Strains in Ex Vivo First Trimester Placental Model.

Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, leading to a variety of symptoms in the unborn child that range from asymptomatic to death in utero. Our objective was to better understand the mechanisms of placental infection by HCMV clinical strains, particularly during the first trimester of pregnancy. We thus characterized and compared the replication kinetics of various HCMV clinical strains and laboratory strains by measuring viral loads in an ex vivo model of first trimester villi and decidua, and used NGS and PCA analysis to analyze the genes involved in cell tropism and virulence factors. We observed that first trimester villi and decidua are similarly permissive to laboratory and symptomatic strains, and that asymptomatic strains poorly replicate in decidua tissue. PCA analysis allowed us to segregate our clinical strains based on their clinical characteristics, suggesting a link between gene mutations and symptoms. All these results bring forth elements that can help better understand the mechanisms that induce the appearance of symptoms or in the congenitally infected newborn.

Congenital Cytomegalovirus and Hearing Loss: The State of the Art.

In developed countries, congenital cytomegalovirus (cCMV) infection is the most common congenital viral infection, representing the leading non-genetic cause of sensorineural hearing loss (HL). Diagnosis of cCMV infection can be performed by detection of CMV DNA in urine or saliva within 2-3 weeks after birth, or later in dried blood samples on the Guthrie card. Currently, there are many controversies regarding the preventive, diagnostic, and therapeutic approaches to cCMV infection. HL secondary to cCMV is highly variable in onset, side, degree, audiometric configuration, and threshold changes over time. Therefore, it is of paramount importance to perform a long and thorough audiological follow-up in children with cCMV infection to ensure early identification and prompt treatment of progressive and/or late-onset HL. Early cochlear implantation appears to be a valid solution not only for children with bilateral profound HL, but also for those with single-sided deafness, improving localization ability and understanding speech in noisy environments. Moreover, the decision to apply a unilateral cochlear implant in children with cCMV is strengthened by the non-negligible possibility of hearing deterioration of the contralateral ear over time.

Interleukin 27 (IL-27): an immunoregulatory and antiviral cytokine at the maternal-fetal interface during congenital infection

Abstract Cytokines maintain homeostasis throughout pregnancy and have diverse responses to pathogens at the maternal-fetal interface. Interleukin 27 (IL-27) is a cytokine that is highly expressed in the placenta, however its functional role during pregnancy is unknown. In other contexts, IL-27 is a potent regulator of inflammation and has been shown to mediate antiviral immunity in the skin. Therefore, our objective was to determine how IL-27 contributes to immune responses at the maternal-fetal interface during congenital viral infection. To begin, we utilized an immunocompetent mouse model for Zika virus (ZIKV) infection to assess pregnancy and infection outcomes in the presence and absence of IL-27 signaling. At gestational day 13.5, we observed that the fetuses of IL-27-competent and -deficient dams had similar ZIKV burdens. However, we observed a significantly higher incidence of fetal pathology (resorption) in IL-27-deficient dams. To identify potential effectors of pathology, I evaluated IL-27 receptor (IL27RA) expression in placental tissues using flow cytometry and immunofluorescence and detected IL27RA+ immune cells throughout the maternal-fetal interface. Together these findings suggest that fetal pathology is independent of ZIKV viral burden in IL-27-deficient mice, and that IL-27 signaling may dampen pathologic immune cell responses during pregnancy. Interestingly, the placental tissues of infected, IL-27-deficient dams had significantly higher ZIKV burdens relative to IL-27-competent dams, indicating a potential antiviral role for IL-27 in the placenta. In conclusion, these data support novel antiviral and immunoregulatory roles for IL-27 at the maternal-fetal interface during congenital viral infection. This work was supported by the University of Pennsylvania Cell and Molecular Biology Training Grant T32 GM-07229. Additional funding provided by the Linda Pechenik Montague Investigator Award and the Pew Charitable Trusts Biomedical Scholars Program.

Dysregulation of fetal-derived cochlear resident tissue macrophages mediates CMV-associated sensorineural hearing loss

Abstract Cytomegalovirus (CMV) is the most common congenital viral infection in the developed world and the leading cause of non-genetic sensorineural hearing loss (SNHL) in children. Congenital CMV causes progressive SNHL long after acute infection has resolved, suggesting a lasting effect on the developing host immune response in the cochlea. Using fate-mapping models, we investigated the contribution of fetal-derived resident tissue macrophages (RTMs) to normal cochlear development and function, and their role in mediating CMV-associated SNHL. We uncovered dual contribution of fetal-derived cochlear RTMs (F4/80 hiCD11b lo) from yolk sac (YS) and fetal liver (FL) hematopoiesis at birth. YS-derived RTMs naturally recede postnatally after cochlea development, but remain in key tissues, such as the spiral ligament and stria vascularis, through adulthood. Depletion of fetal-derived RTMs by anti-CSF1R blocking Ab led to SNHL and impairments to cochlear architecture. Similarly, embryonic deletion of YS-derived RTMs by induced deletion of CSF1R leads to SNHL at high frequencies. During acute CMV infection, RTMs expand and become transcriptionally dysregulated in developmental programs, including tissue remodeling, chemorepulsion, otic vesicle morphogenesis, and FGF signaling. Importantly, analysis of CSF1R-Cre labeling suggests YS-derived RTMs retract in response to CMV infection, suggesting RTM expansion is caused by infiltration of BM-derived macrophages. Ongoing work examines spatial distribution of fetal-derived cochlear RTMs, transcriptional differences between YS, FL, and BM-derived RTMs in response to CMV, and how replacement of fetal-derived RTMs with BM-derived RTMs affects tissue function and response to CMV. Supported by grants from NIAID (T32 5T32AI138945) and University of Utah molecular medicine and immunology, inflammation and infectious disease (3i) initiative

Early arteriopathy in Aicardi-Goutières syndrome 5. Case report and review of literature.

Aicardi-Goutières syndrome (AGS) is an autosomal recessive disease that mimics congenital viral infection and mainly affects the brain, immune system, and skin. The dominant clinical symptom is the subacute onset of severe encephalopathy, which manifests as irritability, loss of ability, slowing of head growth, and poor nutrition. Arteriopathy in AGS is an uncommon manifestation usually associated with mutations in the SAMHD1 gene. We present a rare case of a 3-year-old male due to failure to thrive, global developmental delay, microcephaly, poor vision, upper and lower limbs spasticity, and gastroesophageal reflux disease (GERD), who harbored early stenotic lesions of the large and medium intracranial arteries with ischemic sequelae in the early postnatal life. Performed genetic testing confirmed homozygous gene mutation, SAMHD1 associated with AGS type 5. By reviewing the available literature, we were able to find only one patient whose arterial lesions were diagnosed after 6months.