Ouyang, P. | Search bioRxiv

bioRxiv2024

Microglia replacement effectively attenuates the disease progress of ALSP in the mouse model and human patient

Microglia play critical roles in the brain physiology and pathology. CSF1R is primarily expressed in microglia. The mono-allelic CSF1R mutation causes adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a lethal neurological disease and no rational cure in clinical trials. There are no animal models mimicking human ALSP. In this study, we first developed mouse models based on human ALSP hotspot mutations. We then utilized microglia replacement by bone marrow transplantation (Mr BMT) to replace the Csf1r-deficient microglia in ALSP mice by Csf1r-normal donor cells. With pathogenic gene correction, Mr BMT efficiently attenuated the pathologies. Previously, an ALSP patient received traditional bone marrow transplantation (tBMT) due to a misdiagnosis of metachromatic leukodystrophy. The disease progress was halted for 15 years with unknown reasons. We demonstrated that tBMT in ALSP is equivalent to or close to Mr BMT, achieving efficient microglia replacement and therefore attenuating the ALSP progress in the mouse model. Next, we applied tBMT to replace CSF1R-deficient microglia in human patients. Our clinical results show that after microglia replacement, the ALSP course is effectively halted. Together, microglia replacement corrects the pathogenic gene and thus halts the disease progress in the mouse model and human patients. This study strongly demonstrates clinical potentials of microglia replacement in neurological disease treatments.

neuroscience↗

bioRxiv2023

Metabolic Nutrient Preferences of Vibrio mimicus: Leveraging Nucleotides and Oligopeptides from Yellow Catfish for Enhanced Infectivity

In the context of host-microbe interactions, the microenvironment plays a critical role in facilitating microbial survival, and variations in these microenvironments may influence the pathogenicity of microorganisms. Vibrio mimicus, a major pathogen responsible for infections in aquatic animals, poses a substantial threat to yellow catfish (Pelteobagrus fulvidraco) and grass carp (Ctenopharyngodon idella), two naturally occurring hosts displaying markedly different susceptibility levels. This study aims to unravel the underlying mechanisms behind this susceptibility discrepancy in the two teleost species. Employing metabolomic analysis, we identified a distinctive microenvironment in yellow catfish, characterized by abundant purine nucleotides and oligopeptides. Furthermore, a total of 67 specific metabolites were identified from both yellow catfish and grass carp, with 33 displaying heightened expression on the body surface of yellow catfish, including nucleotides, amino acids, and gangliosides, while 34 were predominantly expressed on the body surface of grass carp, primarily comprising lipids. Subsequent investigations revealed that certain compounds related to nucleotides and oligopeptides exhibited significant growth-promoting effects and were utilized by V. mimicus as nutrients, with deoxyguanosine proving to be notably more than twice as effective as glucose. Moreover, during V. mimicus infection, numerous metabolites such as oligopeptides, purine nucleotides, and specific metabolites experienced considerable depletion in the skin of yellow catfish. Concurrently, several genes associated with nucleosidase and peptidase were upregulated in the skin and muscles of infected fish. These findings suggest that the microenvironment provided by different hosts plays a pivotal role in determining the infectivity of the pathogen. Additionally, our results indicate that the microenvironment on the surface of yellow catfish, characterized by an abundance of purine nucleotides and oligopeptides, indirectly enhances V. mimicus growth, ultimately augmenting its infectivity.

microbiology↗