Shreya Gadagoju

Background: Cytomegalovirus (CMV) is the most common congenital viral infection in the United States and the leading cause of non-genetic sensorineural hearing loss (SNHL) in children.¹ The double-stranded DNA virus from the Herpesviridae family primarily affects immunocompromised individuals and infants who acquire the virus through direct placental transmission. Most infected infants are asymptomatic; however, a significant portion have multiple neurologic symptoms.^1,2,3 Epidemiological data from Northeastern US hospitals revealed that Hispanic and Black children had higher rates of congenital CMV diagnosis, demonstrating the disproportionate viral effects on disadvantaged ethnic minorities.⁴ Furthermore, of 129 CMV-diagnosed children with neurodevelopmental conditions, 56 (43%) also had hearing loss. This highlights that SNHL is only one aspect of the broader disease burden.⁴ Although the correlation between congenital CMV and hearing loss is well-established, a cellular mechanism has not been defined. Understanding this mechanism is essential for developing effective screening, treatment, and education tools.

Objectives: The goal is to understand a potential mechanism on how Congenital Cytomegalovirus causes sensorineural hearing loss.

Search Methods: All articles were ascertained on PubMed from 2019-2026 using search terms of “Congenital cytomegalovirus”, “Cytomegalovirus sensorineural hearing loss”, “sensorineural hearing loss”, “CMV IE2”, “CMV TSC-2”, and “CMV inner-ear mechanism.”

Results: Evidence shows that CMV can directly enter the cochlea and vestibular organs through multiple proteins. The pentameric complex binds to NRP2 receptors to enter non-fibroblast cells; gH/gL/gO triplex binds to PDGFRα receptors to enter fibroblast cells; and glycoprotein B binds to EGFR receptors for cell membrane fusion to enter all cell types. These cell types and receptors are expressed throughout the inner ear.⁵  After viral entry, CMV Immediate-Early 2 (IE2) plays a large role in mediating expression of early viral genes and modulates the host immune system.⁶ In 8-week-old IE2-expressing transgenic mice, there was significant elevation of auditory brainstem response thresholds at 32 kHz, along with cochlear inflammation and inner ear mitochondrial abnormalities, which were not seen in control or IE1 mice.⁷  To determine the mechanism behind these changes, western blot of IE2 mice’s inner ear mitochondria showed an overactivation of mTOR. Using AlphaFold protein modeling and an IP-pull down assay, researchers demonstrated direct IE2-TSC2 interaction. TSC2 is usually an inhibitor of mTOR. However, the IE2-TSC2 interaction prevents the usual TSC2 inhibition of mTOR. This leads to excessive mTOR expression and subsequent SNHL pathology.^7,8 Interestingly, studies have shown that using Rapamycin, an FDA-approved mTOR inhibitor, can partially restore the abnormally high auditory brainstem threshold and inner ear cell pathology of the IE2-expressing mice.⁷

Conclusion: Overall, scientists showed that CMV causes SNHL when IE2 binds with TSC2, causing abnormal upregulation of mTOR in mitochondria of the inner ear cells. Importantly, the Rapamycin recovery results have value to be a future therapy for CMV related SNHL. Given that marginalized communities bear a disproportionate burden of this condition, developing effective treatments is a critical health equity issue. These findings are valuable for physicians to help manage and prevent this developmentally impeding condition.

Works Cited:

1.  Kabani N, Ross SA. Congenital cytomegalovirus infection.
2. Njue A, Coyne C, Margulis AV, Wang D, Marks MA, Russell K, Das R, Sinha A. The role of congenital cytomegalovirus infection in adverse birth outcomes: A review of the potential mechanisms. Viruses. 2020, 13(1),20. https://doi.org/10.3390/v13010020. Accessed February 23, 2026.
3. Shave S, Botti C, Kwong K. Congenital sensorineural hearing loss. Pediatric Clinic North America. 2022,69, 221-234. https://doi.org/10.1016/j.pcl.2021.12.006. Accessed February 23, 2026.
4. Stout JC, Leung J, Kfoury P, Germiller JA, Park AH, Lanzieri TM. Hearing and neurodevelopmental outcomes among children with congenital cytomegalovirus. International Journal of Pediatric Otorhinolaryngology. 2025,195, 112408. Accessed March 29, 2026.
5. Grijpink LCM, van der Valk WH, van Beelen ESA, de Groot JCMJ, Locher H, Vossen, et al. Cytomegalovirus host receptor expression in the human fetal inner ear. PLoS ONE. 2025;20(3): e0320605. https://doi.org/10.1371/journal.pone.0320605. Accessed April 05, 2026.
6. Ball CB, Li M, Parida M, et al. Human cytomegalovirus IE2 both activates and represses initiation and modulates elongation in a context-dependent manner. mBio. 2022;13(3). https://doi.org/10.1128/mbio.00337-22. Accessed March 29, 2026.
7. Yu M, Wang Z, Wang Y, Zhang X, Wei Z, Wang B. HCMV immediate-early protein IE2 induces neurotoxicity and hearing loss by disrupting TSC2-mTOR signaling and metabolic homeostasis. Journal of Neuroinflammation. 2025,23(1),4. https://doi.org/10.1186/s12974-025-03646-6. Accessed March 29, 2026.
8. Rodríguez-Sánchez I, Schafer XL, Monaghan M, Munger J. The Human Cytomegalovirus UL38 protein drives mTOR-independent metabolic flux reprogramming by inhibiting TSC2. PLOS Pathogens. 2019,15(1): e1007569. https://doi.org/10.1371/journal.ppat.1007569. Accessed March 29, 2026.