Biology subjects

Ezzell, J. A.

Publications and source records attributed to Ezzell, J. A..

3 recordsLinked to original sources

bioRxiv2026

Interferon lambda signaling to maternal dendritic cells protects against congenital Zika virus infection

Interferon lambda (IFN-{lambda}, type III IFN) mediates antiviral immunity at anatomic barriers, including the maternal-fetal interface. To investigate the effects of IFN-{lambda} during congenital Zika virus (ZIKV) infection, we infected mice lacking the IFN-{beta} receptor (Ifnar1-/-) or both the IFN-{beta} and IFN-{lambda} receptors (Ifnar1-/-Ifnlr1-/-) at E9 and found that loss of maternal IFN-{lambda} signaling resulted in greater transplacental transmission. We used HiPlex RNAscope on entire gravid uteruses and found that IFN-{lambda} was expressed more proximal to the site of ZIKV infection in Ifnar1-/- dams compared to Ifnar1-/-Ifnlr1-/- dams. We performed immunophenotyping of the placenta and uterus by flow cytometry and found a decrease in dendritic cells and NK cells in the uterus of Ifnar1-/-Ifnlr1-/- dams compared to Ifnar1-/- dams, but NK cell depletion did not impact fetal infection. Using conditional knockout mice, we identified maternal dendritic cells as the key IFN-{lambda} responsive cell type mediating protection against ZIKV congenital infection.

immunology↗

bioRxiv2024

TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.

cell biology↗

bioRxiv2023

Intermediate filament dysregulation and astrocytopathy in the human disease model of KLHL16 mutation in giant axonal neuropathy (GAN)

Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, a regulator of intermediate filament (IF) protein turnover. Previous neuropathological studies and our own examination of postmortem GAN brain tissue in the current study revealed astrocyte involvement in GAN. To study the underlying mechanisms, we reprogrammed skin fibroblasts from seven GAN patients carrying different KLHL16 mutations to iPSCs. Isogenic controls with restored IF phenotypes were derived via CRISPR/Cas9 editing of one patient carrying a homozygous missense mutation (G332R). Neural progenitor cells (NPCs), astrocytes, and brain organoids were generated through directed differentiation. All GAN iPSC lines were deficient for gigaxonin, which was restored in the isogenic control. GAN iPSCs displayed patient-specific increased vimentin expression, while GAN NPCs had decreased nestin expression compared to isogenic control. The most striking phenotypes were observed in GAN iPSC-astrocytes and brain organoids, which exhibited dense perinuclear IF accumulations and abnormal nuclear morphology. GAN patient cells with large perinuclear vimentin aggregates accumulated nuclear KLHL16 mRNA. In over-expression studies, GFAP oligomerization and perinuclear aggregation were potentiated in the presence of vimentin. As an early effector of KLHL16 mutations, vimentin may serve as a potential therapeutic target in GAN.

cell biology↗