Congenital Cytomegalovirus-Related Hearing Loss.

Congenital hearing loss is a significant global health concern that affects millions of newborns and infants worldwide, posing substantial challenges for affected individuals, their families, and healthcare systems. This condition, present at birth, can stem from genetic factors, in utero exposures, infections, or complications during pregnancy or childbirth. The spectrum of congenital hearing loss ranges from mild to profound, impacting the development of speech, language, and cognitive skills, thereby influencing educational achievements, social integration, and future employment opportunities. Early detection and intervention strategies, such as newborn hearing screenings, genetic counseling, and the use of hearing aids or cochlear implants, are crucial for mitigating these impacts. This review article aims to explore the diagnostic approaches and management strategies for congenital cytomegalovirus-related hearing loss, emphasizing the importance of interdisciplinary care and the potential for technological advances to improve outcomes for affected individuals.

Cytomegalovirus infection is associated with thymic dysfunction and chronic graft-versus-host disease after pediatric hematopoietic stem cell transplantation.

Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied. We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18-3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 106/L, P = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25highFOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 106/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023). These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.

Characterization of Natural Killer Cell Profile in a Cohort of Infected Pregnant Women and Their Babies and Its Relation to CMV Transmission.

Human cytomegalovirus (CMV) is a common herpesvirus causing lifelong latent infection in most people and is a primary cause of congenital infection worldwide. Given the role of NK cells in the materno-fetal barrier, we investigated peripheral blood NK cell behavior in the context of CMV infection acquired during pregnancy. We analyzed the NK phenotype and CD107a surface mobilization on PBMCs from CMV-transmitting and non-transmitting mothers and newborns with or without congenital infection. NK cells from non-transmitting mothers showed the typical phenotype of CMV-adaptive NK cells, characterized by higher levels of NKG2C, CD57, and KIRs, with reduced NKG2A, compared to transmitting ones. A significantly higher percentage of DNAM-1+, PD-1+, and KIR+NKG2A-CD57+PD-1+ CD56dim cells was found in the non-transmitting group. Accordingly, NK cells from congenital-CMV (cCMV)-infected newborns expressed higher levels of NKG2C and CD57, with reduced NKG2A, compared to non-congenital ones. Furthermore, they showed a significant expansion of CD56dim cells co-expressing NKG2C and CD57 or with a memory-like (KIR+NKG2A-CD57+NKG2C+) phenotype, as well as a significant reduction of the CD57-NKG2C- population. Degranulation assays showed a slightly higher CD107a geomean ratio in NK cells of mothers who were non-transmitting compared to those transmitting the virus. Our findings demonstrate that both CMV-transmitting mothers and cCMV newborns show a specific NK profile. These data can guide studies on predicting virus transmission from mothers and congenital infection in infants.

Exploring health disparities in congenital CMV (cCMV): a study in a Somali-American community to assess awareness of cCMV and facilitate understanding of universal cCMV screening.

Background: Congenital cytomegalovirus (cCMV) disproportionately impacts black and multiracial infants. While there have been strides made to address this health disparity, strategies to increase awareness and knowledge of cCMV have not been investigated in a Somali community. Methods: Two survey study strategies (in-person and online), consisting of a pre-survey test, educational intervention, and a post-survey, were designed to gauge knowledge and perceptions about cCMV among Somali women aged 18 to 40 years old. Results: 96 respondents partook in the online module, and 15 in the in-person event. On recruitment, < 45% of women were aware of cCMV. Following the pre-intervention survey, educational modules were conducted, and the survey repeated. For statistical comparisons, a point was assigned for each correct survey query, and the mean of correct responses tabulated for pre- and post-surveys. In the online intervention, mean scores changed from 55 to 87% (paired t-test, p = 0.001), whereas in the in-person intervention, mean scores changed from 65 to 87% (paired t-test, p = 0.007), demonstrating enhanced cCMV awareness upon completion of both interventions. Using multiple linear regression, the expected post-test score was 2% (95% CI [- 8%, 12%]) higher for the online module compared to the in-person module, adjusting for pre-test score. Conclusion: Both interventions were successful in enhancing knowledge about cCMV in this population, although there was no evidence either intervention was substantially better than the other. Educational efforts will be critical in enhancing the trust required to facilitate diagnostic evaluation and treatment of newborns identified with cCMV in this high-risk population.

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

BACKGROUND: Congenital 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. METHODS: Infants 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. RESULTS: Infants with asymptomatic cCMV performed equivalently compared to healthy control infants on the neurobehavioral measures tested at 12 months of age. CONCLUSIONS: These 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.

Ten-year epidemiology and risk factors of cytomegalovirus infection in hematopoietic stem cell transplantation patients in Taiwan.

BACKGROUND: Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for CMV infection and disease among HSCT recipients in Taiwan. METHODS: This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease. RESULTS: There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors. CONCLUSION: The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.

Multisystemic Disease in a Child and Successful Recovery With Antiviral Treatment.

Cytomegalovirus (CMV), a member of the Herpesviridae family, typically causes asymptomatic infections or mild mononucleosis-like syndromes in immunocompetent individuals. However, severe manifestations are well-documented in immunocompromised populations. This case report presents a previously healthy seven-year-old girl with a rare and complex presentation of primary CMV infection leading to severe multiorgan involvement, hepatosplenomegaly, cholestasis, bicytopenia, and a prolonged disease course. The patient's condition prompted an exhaustive diagnostic investigation, ruling out other potential causes. The diagnosis was confirmed by positive CMV IgM and IgG antibodies and a significantly elevated CMV DNA viral load. Treatment with intravenous ganciclovir resulted in a remarkable recovery. The case underscores the importance of considering CMV as a potential etiology of hepatitis, even in immunocompetent children, and the challenges of diagnosing complicated CMV infections. While guidelines for treating CMV in immunocompetent individuals are lacking, this report suggests that antiviral therapy may be beneficial in severe cases. Further research is needed to establish clear treatment protocols for such instances. This report contributes to the limited body of literature on severe CMV-induced hepatitis in immunocompetent children, emphasizing the need for heightened clinical awareness and timely interventions to prevent progression to acute liver failure.

TORCH (Toxoplasmosis, Other, Rubella, Cytomegalovirus, Herpes Simplex Virus) Infection and the Enigma of Anomalous Fetal Development: Pregnancy Puzzles.

The cytomegalovirus (CMV), a common DNA virus with a high global seroprevalence, is the primary cause of teratogenic congenital infections, which presents a serious risk to public health. Maternal CMV infection is linked to congenital CMV (cCMV), a major contributor to non-genetic sensorineural hearing loss, cognitive developmental impairments, and cerebral palsy in infants. Transmission might occur through direct contact with infected bodily fluids, with higher transmission rates after primary infection and an increased risk of severe fetal effects before 20 weeks. The mother and fetus do not get immunity from a prior infection. Fetal growth restriction, fetal loss, and cerebral or extra-cerebral abnormalities that can be detected by ultrasonography are possible presentations of cCMV. Specific antibody detection or seroconversion is required for the diagnosis of maternal CMV during pregnancy. Amniocentesis is used to diagnose fetal CMV during pregnancy after eight weeks of presumed maternal infection and 17 weeks of gestation. The main preventive measure is hygiene education, as the effectiveness of immunoglobulins, antiviral medications, and vaccines is still up for debate. The focus is particularly directed toward the anomalous fetal outcomes observed during the course of the pregnancy.

Cytomegalovirus immunoglobulin serology prevalence in patients with newly diagnosed multiple myeloma treated within the GMMG-MM5 phase III trial.

OBJECTIVES: The seroprevalence of antibodies against Cytomegalovirus (CMV) is an established poor prognostic factor for patients receiving an allogeneic stem cell transplantation. However, the impact of CMV serology on outcome after autologous stem cell transplantation remains unknown. METHODS: Here, we analyzed the CMV immunoglobulin (Ig) serology of 446 newly-diagnosed multiple myeloma (MM) patients of the GMMG-MM5 phase III trial with a median follow-up of 58 months. RESULTS: CMV IgG and IgM positivity was seen in 51% and 6% of the patients, respectively. In multivariate analysis CMV IgG and CMV IgM serology show an age-depending effect for PFS. We identified positive CMV IgG/positive CMV IgM serology as an age-depending beneficial factor on PFS. DISCUSSION: Younger patients with a positive CMV IgG/positive CMV IgM serology experienced a favorable effect on PFS, whereas a positive CMV IgG/positive CMV IgM serology at older age has a disadvantageous effect on PFS.

Decidual-tissue-resident memory T cells protect against nonprimary human cytomegalovirus infection at the maternal-fetal interface.

Congenital cytomegalovirus (cCMV) is the most common intrauterine infection, leading to infant neurodevelopmental disabilities. An improved knowledge of correlates of protection against cCMV is needed to guide prevention strategies. Here, we employ an ex vivo model of human CMV (HCMV) infection in decidual tissues of women with and without preconception immunity against CMV, recapitulating nonprimary vs. primary infection at the authentic maternofetal transmission site. We show that decidual tissues of women with preconception immunity against CMV exhibit intrinsic resistance to HCMV, mounting a rapid activation of tissue-resident memory CD8+ and CD4+ T cells upon HCMV reinfection. We further reveal the role of HCMV-specific decidual-tissue-resident CD8+ T cells in local protection against nonprimary HCMV infection. The findings could inform the development of a vaccine against cCMV and provide insights for further studies of the integrity of immune defense against HCMV and other pathogens at the human maternal-fetal interface.

Circular mRNA-based TCR-T offers a safe and effective therapeutic strategy for treatment of cytomegalovirus infection.

Circular mRNA (cmRNA) is particular useful due to its high resistance to degradation by exonucleases, resulting in greater stability and protein expression compared to linear mRNA. T cell receptor (TCR)-engineered T cells (TCR-T) represent a promising means of treating viral infections and cancer. This study aimed to evaluate the feasibility and efficacy of cmRNA in antigen-specific-TCR discovery and TCR-T therapy. Using human cytomegalovirus (CMV) pp65 antigen as a model, we found that the expansion of pp65-responsive T cells was induced more effectively by monocyte-derived dendritic cells transfected with pp65-encoding cmRNA compared with linear mRNA. Subsequently, we developed cmRNA-transduced pp65-TCR-T (cm-pp65-TCR-T) that specifically targets the CMV-pp65 epitope. Our results showed that pp65-TCR could be expressed on primary T cells for more than 7 days. Moreover, both in vitro killing and in vivo CDX models demonstrated that cm-pp65-TCR-T cells specifically and persistently kill pp65-and HLA-expressing tumor cells, significantly prolonging the survival of mice. Collectively, our results demonstrated that cmRNA can be used as a more effective technical approach for antigen-specific TCR isolation and identification, and cm-pp65-TCR-T may provide a safe, non-viral, non-integrated therapeutic approach for controlling CMV infection, particularly in patients who have undergone allogeneic hematopoietic stem cell transplantation.

Case Report: Toripalimab: a novel immune checkpoint inhibitor in advanced nasopharyngeal carcinoma and severe immune-related colitis.

Toripalimab, a specific immune checkpoint inhibitor targeting the programmed death 1 (PD-1) receptor, represents a novel immunotherapeutic approach for advanced nasopharyngeal carcinoma, showing promising curative potential. However, it is not without drawbacks, as some patients experience immune-related adverse events (irAEs) associated with this treatment, and there remains a limited body of related research. Here, we present a case of advanced nasopharyngeal carcinoma in a patient who developed colitis as an irAE attributed to Toripalimab. Subsequent to Toripalimab treatment, the patient achieved complete remission. Notably, the development of colitis was accompanied by inflammatory manifestations evident in colonoscopy and pathology results. Further investigation revealed cytomegalovirus (CMV) infection, detected through immunohistochemistry in 11 colon biopsies. Subsequent treatment with ganciclovir and steroids resulted in symptom relief, and colonoscopy indicated mucosal healing. Our case highlights the association between irColitis induced by Toripalimab and CMV infection. Toripalimab demonstrates remarkable efficacy in treating advanced nasopharyngeal carcinoma, albeit with a notable risk of irAEs, particularly in the form of colitis. The link between symptoms and endoscopic pathology findings in irColitis is noteworthy. Standardized biopsy procedures can effectively confirm the diagnosis of CMV infection. Our findings may provide valuable guidance for managing acute CMV infection and irAEs associated with Toripalimab in the treatment of nasopharyngeal carcinoma in the future.

ORAI1 defect in a patient with disseminated CMV infection and severe hypotonia.

BACKGROUND: A clinical presentation similar to severe combined immunodeficiency (SCID) with defective T cell activation but normal lymphocyte development occurs due to certain molecule defects including ORAI1- and STIM1. CASE: A four-month-old girl sufferd from fever, restlessness, diarrhea, and poor weight gain following the neonatal period. There was consanguinity and a positive family history. She had hypotonia and spontaneous opisthotonic posture. Refractory and extensive CMV infections were detected; immunological investigations revealed normal quantitative immunoglobulins and low numbers of CD3+, CD4+, and CD8+ cells. The next generation sequencing analysis revealed a mutation in the ORAI1 gene. CONCLUSIONS: The present patient`s history of refractory and widespread CMV infections shows a clinically substantial reduction in resistance against opportunistic microorganisms. This case emphasizes the importance of considering STIM1 and ORAI1 defects in patients with SCID phenotype and neurologic involvement, such as hypotonia.

Cytomegalovirus Infections in the Atypical Host: A Case Series of Clinical Conundra.

Background Cytomegalovirus (CMV) reactivation may occur as the shedding of the virus from various body sites or could represent an active disease that might be fatal if untreated. Distinguishing between the two states may prove very difficult. The role of the CMV disease in patients with hematological malignancies or transplant patients is more defined than that in other immunocompromised patients where neither anti-CMV prophylaxis is used nor plasma CMV levels are monitored. Here, we try to examine cases with CMV viremia in the latter group of patients in an attempt to make a distinction between CMV infection and disease to determine which patients would benefit from treatment. Methods Elderly patients, patients with rheumatological disorders, and patients with inflammatory bowel disease (IBD) and with clinical suspicion of CMV disease who were referred to the infectious diseases service at Sultan Qaboos University Hospital were examined from 1 January 2018 to 31 January 2023. We added a patient we found in our referral log book from 2012. Clinical, epidemiological, and laboratory data were retrieved from the hospital information system. Plasma CMV levels and CMV body fluid levels including pulmonary samples obtained from bronchoalveolar lavage (BAL) in suspected cases of CMV pneumonitis and gastrointestinal (GI) CMV levels obtained from stool and gastrointestinal tissue biopsies in suspected cases of gastrointestinal CMV disease were collected. COBAS® AmpliPrep/COBAS® TaqMan®assay (Roche Molecular Systems, Inc., Branchburg, NJ) was used to measure CMV copies per milliliter. Results A total of 28 patients were considered to have CMV disease, 12 of whom were elderly (≥60 years) and the rest were young and middle aged (Y/M). The most common comorbidities of the elderly included chronic kidney disease (CKD), hypertension (HTN), and diabetes mellitus (DM). In the Y/M group, seven patients had systemic lupus erythematosus (SLE), one had antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, four patients had IBD, two had IBD plus primary immunodeficiencies (one patient had agammaglobulinemia and one had combined deficiencies), and one patient had combined immunodeficiency. CKD was a common finding in the SLE patients. Diarrhea was the most common CMV presentation occurring in 19 patients (67.9%), being bloody in 10 patients. Four patients had pulmonary presentations, and four had hematological presentations in the form of anemia or pancytopenia. Nineteen patients were given CMV antiviral treatment, and one patient received it during the first episode but not in the second episode. Twenty-eight-day mortality in the treated group was 20% versus 55.5% in the untreated group. The majority of the deaths occurred in the SLE and elderly patients. Thrombocytopenia occurred in 60.7%, 70.6% of whom died signaling a potential predictive role for thrombocytopenia in early empirical CMV antiviral treatment and in prognosis. Conclusion The difficulty in distinguishing CMV infection from CMV disease remains a concern in the elderly and SLE patients. In our small study, there was a survival benefit in early screening for CMV and initiating preemptive CMV antiviral therapy in these two groups even before CMV disease is proven. This urgency was not observed for patients with IBD or primary immunodeficiencies. A major common factor for CMV disease was CKD, whereas thrombocytopenia was an indicator of disease and prognosis.

Two-sample Mendelian randomization study does not reveal a significant relationship between cytomegalovirus (CMV) infection and autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting ~ 2% of children worldwide and is characterized by repetitive, stereotypical behaviours and impaired expressive communication. Cytomegalovirus (CMV) is considered a risk factor for ASD; however, published studies are usually limited by covering too few events and have different conclusions, indicating that the relationship between CMV infection and ASD remains elusive. METHODS: To investigate the association between CMV infection and ASD, we conducted this 2-sample Mendelian randomization (MR) study using genome-wide association studies (GWAS) summary data from FinnGen and the IEU Open GWAS project. RESULTS: Our results showed no significant relationship between all 3 CMV infections (unspecified cytomegaloviral diseases, anti-CMV IgG levels, and maternal CMV) and ASD. CONCLUSIONS: Our results indicate that CMV infection does not significantly increase ASD risk. These results show that the relationship between CMV infection and ASD remains elusive and needs to be further clarified.

Prevention of Congenital Cytomegalovirus Infection: Review and Case Series of Valaciclovir versus Hyperimmune Globulin Therapy.

Cytomegalovirus (CMV) is the most common cause of congenital infections in developed countries because is capable of infecting the fetus after both primary and recurrent maternal infection, and because the virus may be spread for years through infected children. Moreover, CMV is the most serious congenital infection associated with severe neurological and sensorineural sequelae, which can occur at birth or develop later on. Hygienic measures can prevent CMV transmission, which mainly involve contact with children under 3 years of age and attending a nursery or daycare. In animal and human pregnancies, many observational and controlled studies have shown that CMV-specific hyperimmune globulin (HIG) is safe and can significantly decrease maternal-fetal transmission of CMV infection and, mostly, the occurrence of CMV disease. Recently, valaciclovir at the dosage of 8 g/day was also reported to be capable of decreasing the rates of congenital infection and disease. However, comparing the results of our two recent case series, the infants born to women treated with HIG showed significantly lower rates of CMV DNA positivity in urine (9.7% vs. 75.0%; p < 0.0001) and abnormalities after follow-up (0.0% vs. 41.7%; p < 0.0001). The implementation of CMV screening would enable primary prevention via hygiene counseling, improve the understanding and awareness of congenital CMV infection, and increase the knowledge of the potential efficacy of preventive or therapeutic HIG or antiviral administration.

Analysis of congenital hearing loss after neonatal hearing screening.

Introduction: Neonates undergo neonatal hearing screening to detect congenital hearing loss at an early stage. Once confirmed, it is necessary to perform an etiological workup to start appropriate treatment. The study objective was to assess the different etiologies, risk factors, and hearing results of infants with permanent hearing loss and to evaluate the efficacy and consequences of the different screening devices over the last 21 years. Methods: We conducted a single-center retrospective cohort analysis for all neonatal hearing screening program referrals and performed an etiological workup in case of confirmed hearing loss. We analyzed the evolution of the etiological protocols based on these results. Results: The governmental neonatal hearing screening program referred 545 infants to our center. Hearing loss was confirmed in 362 (66.4%) infants and an audiological workup was performed in 458 (84%) cases. 133 (24.4%) infants were diagnosed with permanent hearing loss. Ninety infants (56 bilateral and 34 unilateral) had sensorineural hearing loss, and the degree was predominantly moderate or profound. The most common etiology in bilateral sensorineural hearing loss was a genetic etiology (32.1%), and in unilateral sensorineural hearing loss, an anatomical abnormality (26.5%). Familial history of hearing loss was the most frequently encountered risk factor. Conclusion: There is a significant number of false positives after the neonatal hearing screening. Permanent hearing loss is found only in a limited number of infants. During the 21 years of this study, we noticed an increase in etiological diagnoses, especially genetic causes, due to more advanced techniques. Genetic causes and anatomical abnormalities are the most common etiology of bilateral and unilateral sensorineural hearing loss, respectively, but a portion remains unknown after extensive examinations.

Modeling of vertical transmission and pathogenesis of cytomegalovirus in pregnancy: Opportunities and challenges.

In addition to facilitating nutrient, oxygen, and waste transfer between developing fetus and mother, the placenta provides important immune barrier function against infection. Elucidation of the complexity of placental barrier function at the maternal-fetal interface has been greatly aided through experimental model organism systems. In this review, we focus on models of vertical transmission of cytomegalovirus (CMV), a ubiquitous double-stranded DNA viruses whose vertical transmission during pregnancy can lead to devastating neurological and obstetric sequelae. We review the current evidence related to guinea pig and murine models of congenital CMV infection, discuss the possible translatability of a non-human primate model, and conclude with recently developed technology using human placental organoids.