Assistant Professor University of Toledo College of Medicine and Life Sciences Toledo, Ohio, United States
Disclosure(s):
Zachary T. Hilt, PhD: No financial relationships to disclose
Introduction/Rationale: Congenital cytomegalovirus (CMV) is a leading cause of hearing loss and neurological deficits. A risk factor for congenital CMV is primary exposure of pregnant individuals to the virus in bodily fluids. CMV infected adults stopped shedding virus in bodily fluids within ~6 months of seroconversion compared to children who continued shedding virus in bodily fluids for ~4 years after seroconversion.
Methods: Here we sought to replicate this phenomenon in a mouse model with the Murine strain of CMV by infecting neonatal and adult mice. We then examined the cellular intrinsic differences between neonatal and adult CD8+ T cells by performing adoptive co-transfers into congenic hosts. Our group utilized spectral flow cytometry, bulk RNA-sequencing and in vivo animal imaging to better characterize this phenomenon.
Results: Infected neonatal mice continued to shed virus for >12 weeks post-infection, while infected adult mice stopped shedding at 4 weeks post-infection. Both adult and neonatal CD8+ T cells upregulated CX3CR1 in response to CMV infection, however, neonatal CD8+ T cells terminally differentiated into a unique CX3CR1++ population that was functionally impaired in the ability to make IFNγ. This ‘dysfunctional’ CX3CR1++ population in neonates was specific to CMV, as neonatal CD8+ T cells in response to vaccinia made robust IFNγ. Higher expression of CX3CR1 on neonatal CD8+ T cells had a physiological role by promoting the T cells to stay vascularized, while adult CD8+ T cells were readily able to disseminate into the extravascular space of tissues.
Conclusion: This work provides the first identified mechanism that explains why the host immune response of neonates fails to control CMV viral replication and shedding.
