Compartmentalized ocular lymphatic system mediates eye-brain immunity.

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.

Single-cell analysis reveals inflammatory interactions driving macular degeneration.

Due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate therapies for neurodegenerative diseases, leading us to examine whether pathways of disease progression are shared across neurodegenerative conditions. Here we use single-nucleus RNA sequencing to profile lesions from 11 postmortem human retinas with age-related macular degeneration and 6 control retinas with no history of retinal disease. We create a machine-learning pipeline based on recent advances in data geometry and topology and identify activated glial populations enriched in the early phase of disease. Examining single-cell data from Alzheimer's disease and progressive multiple sclerosis with our pipeline, we find a similar glial activation profile enriched in the early phase of these neurodegenerative diseases. In late-stage age-related macular degeneration, we identify a microglia-to-astrocyte signaling axis mediated by interleukin-1ß which drives angiogenesis characteristic of disease pathogenesis. We validated this mechanism using in vitro and in vivo assays in mouse, identifying a possible new therapeutic target for AMD and possibly other neurodegenerative conditions. Thus, due to shared glial states, the retina provides a potential system for investigating therapeutic approaches in neurodegenerative diseases.

Health Management Workforce Capacity-Building in Liberia, Post-Ebola.

Following the Ebola crisis in Liberia in 2014-15, the Liberian Ministry of Health developed a strategy to build a fit-for-purpose health workforce, focusing on both health care providers and health managers. To help fulfill national capacity-building goals for health management, a team of faculty, staff, and practitioners from the Yale School of Medicine, the University of Liberia, the National Public Health Institute of Liberia, and the Ministry of Health collaboratively developed and launched the health management program in Liberia in July 2017. The team worked to build specific management and leadership competencies for healthcare workers serving in management and leadership roles in Liberia's health sector using two concurrent strategies-1) implementation of a hospital-based partnership-mentorship model in the two largest hospitals in the capital city of Monrovia, and 2) establishment of an executive education-style advanced Certificate in Health Systems Leadership and Management at the University of Liberia. Here we describe the health management program in Liberia, its focus, and its evolution from program launch in 2017 to the present, as well as ongoing efforts to transition program activities to local partner ownership by the end of 2021.