Person:

Wells, Michael

The recent emergence of Zika virus (ZIKV) in susceptible populations has led to an abrupt increase in microcephaly and other neurodevelopmental conditions in newborn infants. While mosquitos are the main route of viral transmission, it has also been shown to spread via sexual contact and vertical mother-to-fetus transmission. In this latter case of transmission, due to the unique viral tropism of ZIKV, the virus is believed to predominantly target the neural progenitor cells (NPCs) of the developing brain. Here a method for modeling ZIKV infection, and the resulting microcephaly, that occur when human cerebral organoids are exposed to live ZIKV is described. The organoids display high levels of virus within their neural progenitor population, and exhibit severe cell death and microcephaly over time. This three-dimensional cerebral organoid model allows researchers to conduct species-matched experiments to observe and potentially intervene with ZIKV infection of the developing human brain. The model provides improved relevance over standard two-dimensional methods, and contains human-specific cellular architecture and protein expression that are not possible in animal models.

A hexanucleotide repeat expansion in C9ORF72 is the most common genetic variant contributing to Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD)1,2. The C9ORF72 mutation acts through gain and loss of function mechanisms to induce pathways implicated in neural degeneration3–9. The expansion is transcribed into a long repetitive RNA, which may negatively sequester RNA binding proteins4 prior to its non-canonical translation into neural-toxic di-peptide proteins3,5. Failure of RNA-polymerase to read through the mutation also reduces abundance of the endogenous C9ORF72 gene product, which functions in endo-lysosomal pathways and suppresses systemic and neural inflammation6–9. Notably, effects of the repeat expansion act with incomplete penetrance in ALS/FTD families, indicating that either genetic or environmental factors modify each individual’s risk of disease. Identifying disease modifiers is of significant translational interest, as it could suggest strategies that diminish the risk of developing ALS/FTD, or that slow progression. Here, we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72 mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing microbial burden in mutants with broad spectrum antibiotics, as well as transplanting gut microflora from a protective environment attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial constituency of our gut plays an important role in brain health and can interact in surprising ways with well-known genetic risk factors for nervous system disorders.