BackgroundCumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine whether NRF2-deficient mice would develop AMD-like retinal pathology with aging and to explore the underlying mechanisms.Methods and FindingsEyes of both wild type and Nrf2−/− mice were examined in vivo by fundus photography and electroretinography (ERG). Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2−/− mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE). Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV) and sub-RPE deposition of inflammatory proteins were present in Nrf2−/− mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microcopy both within the RPE and in Bruch's membrane of aged Nrf2−/− mice.ConclusionsOur data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2−/− mice can provide a novel model for mechanistic and translational research on AMD.

Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli (APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1(+)) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1(+) cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.

BackgroundScrub typhus is a life-threatening disease, due to infection with O. tsutsugamushi, a Gram-negative bacterium that preferentially replicates in endothelial cells and professional phagocytes. Meningoencephalitis has been reported in scrub typhus patients and experimentally-infected animals; however, the neurological manifestation and its underlying mechanisms remain poorly understood. To address this issue, we focused on Orientia tsutsugamushi Karp strain (OtK), and examined host responses in the brain during lethal versus self-healing scrub typhus disease in our newly established murine models.Principle findingsFollowing inoculation with a lethal dose of OtK, mice had a significant increase in brain transcripts related to pathogen-pattern recognition receptors (TLR2, TLR4, TLR9), type-1 responses (IFN-γ, TNF-α, CXCL9, CXCR3), and endothelial stress/damage such as angiopoietins, but a rapid down-regulation of Tie2. Sublethal infection displayed similar trends, implying the development of type 1-skewed proinflammatory responses in infected brains, independent of time and disease outcomes. Focal hemorrhagic lesions and meningitis were evident in both infection groups, but pathological changes were more diffuse and frequent in lethal infection. At 6–10 days of lethal infection, the cortex and cerebellum sections had increased ICAM-1-positive staining in vascular cells, as well as increased detection of CD45+ leukocytes, CD3+ T cells, IBA1+ phagocytes, and GFAP+ astrocytes, but a marked loss of occludin-positive tight junction staining, implying progressive endothelial activation/damage and cellular recruitment in inflamed brains. Orientia were sparse in the brains, but readily detectable within lectin+ vascular and IBA-1+ phagocytic cells. These CNS alterations were consistent with type 1-skewed, IL-13-suppressed responses in lethally-infected mouse lungs.SignificanceThis is the first report of type 1-skewed neuroinflammation and cellular activation, accompanied with vascular activation/damage, during OtK infection in C57BL/6 mice. This study not only enhances our understanding of the pathophysiological mechanisms of scrub typhus, but also correlates the impact of immune and vascular dysfunction on disease pathogenesis.

PurposeEmerging evidence has shown that both congenital and adult Zika virus (ZIKV) infection can cause eye diseases. The goals of the current study were to explore mechanisms and pathophysiology of ZIKV-induced eye defects.MethodsWild-type or A129 interferon type I receptor–deficient mice were infected by either FSS13025 or Mex1-7 strain of ZIKV. Retinal histopathology was measured at different time points after infection. The presence of viral RNA and protein in the retina was determined by in situ hybridization and immunofluorescence staining, respectively. Growth curves of ZIKV in permissive retinal cells were assessed in cultured retinal pigment epithelial (RPE) and Müller glial cells.ResultsZIKV-infected mice developed a spectrum of ocular pathologies that affected multiple layers of the retina. A primary target of ZIKV in the eye was Müller glial cells, which displayed decreased neurotrophic function and increased expression of proinflammatory cytokines after infection. ZIKV also infected RPE; and both the RPE and Müller cells expressed viral entry receptors TYRO3 and AXL. Retinitis, focal retinal degeneration, and ganglion cell loss were observed after the clearance of viral particles.ConclusionsOur data suggest that ZIKV can infect infant eyes with immature blood–retinal barrier and cause structural damages to the retina. The ocular findings in microcephalic infants may not be solely caused by ZIKV-induced impairment of neurodevelopment.

Aging changes the subcellular localization and function of mTOR in the RPE. Increased mTORC1 inhibits POS degradation and may further exacerbate lysosome dysfunction of aged RPE.

Oxidative stress is a contributing factor to the development and progression of diabetic retinopathy, a leading cause of blindness in people at working age worldwide. Recent studies showed that Müller cells play key roles in diabetic retinopathy and produce vascular endothelial growth factor (VEGF) that regulates retinal vascular leakage and proliferation. Melatonin is a potent antioxidant capable of protecting variety of retinal cells from oxidative damage. In addition to the pineal gland, the retina produces melatonin. In the current study, we investigated whether melatonin protects against hyperglycemia-induced oxidative injury to Müller cells and explored the potential underlying mechanisms. Our results show that both melatonin membrane receptors, MT1 and MT2, are expressed in cultured primary Müller cells and are upregulated by elevated glucose levels. Both basal and high glucose-induced VEGF production was attenuated by melatonin treatment in a dose-dependent manner. Furthermore, we found that melatonin is a potent activator of Akt in Müller cells. Our findings suggest that in addition to functioning as a direct free radical scavenger, melatonin can elicit cellular signaling pathways that are protective against retinal injury during diabetic retinopathy.

Purpose To study the epidemiology of myopia in school-aged children in Tianjin and the relationship between visual acuity-based screening and refraction-based screening. Method This school-based prospective cohort study was performed on children from 42 elementary schools and 17 middle schools in Tianjin, China. Totally 14,551 children, ages ranging from 5 to 16 years, were included in this study. Uncorrected visual acuity (UCVA) was determined by logarithmic tumbling E chart. Non-cycloplegic photorefraction was examined by the Spot (v2.1.4) photoscreener. The relationship between the UCVA and refractive error was investigated for different age groups. Results The overall prevalence of myopia at this school based screen is 78.2%, ranged from 10% at age of 5 to 95% at age of 16. The most dramatic increase in prevalence is from age of 6 (14.8%) to age of 7 (38.5%). The overall prevalence of high myopia is 2.5%. UCVA is found corresponding to spherical equivalent refraction (SER) in a manner of normal distribution and is significantly affected by age. When using UCVA to estimate the prevalence of myopia, the overall sensitivity and specificity are 0.824 and 0.820, respectively. Age-dependent optimal cutoff points and 95% confident intervals of such estimation are reported. Conclusions Myopia is heavily affecting school-aged children in Tianjin, China. The refraction screening is preferable for myopia screening, whereas the UCVA screening results need to be interpreted in an age-dependent manner for myopia estimation.

The results suggest that the T cell-mediated immune responses played important roles in controlling the progression of AMD-like phenotype in Nrf2-deficient mice.