Biology subjects

wu, h.

Publications and source records attributed to wu, h..

3 recordsLinked to original sources

bioRxiv2024

Recalibration of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion

Acute infection of the central nervous system is one of the most lethal diseases, yet the mechanisms by which intracellular bacteria infiltrate the brain remain poorly understood. Phagocytic cells are typically regarded as the primary site of conflict in the battle against intracellular bacteria; however, little is known about how the intracellular bacteria exploit infected phagocytes to gain access to the brain. In this study, we show that a novel CD36+ Fabp4+ Pparg+ macrophage subpopulation (CD36+macrophage) participates in penetration of the brain by intracellular bacteria without disruption of the blood-brain barrier. Biomechanical analysis reveals that the abundance of protrusions and adhesion molecules on CD36+ macrophages confers significant resistance to the mechanical stress of blood flow, thereby providing increased opportunities for these macrophages to adhere to the vascular endothelial surface. Metabolomics analysis identifies that macrophage lipid metabolism is dysregulated during bacterial neuroinvasion, and that {beta}-hydroxybutyrate promotes the formation and survival of CD36+ macrophages. Importantly, ketogenesis exacerbates symptoms during bacterial neuroinvasion, which could be halted by supplementing with physiological levels of glucose. Collectively, our findings elucidate a pathway by which intracellular bacteria hijack macrophages to invade the brain, suggesting that glycolipid metabolic homeostasis may play a role in the prevention or resolution of bacterial neuroinvasion. Highlights1. Intracellular bacteria hijack CD36+ M{varphi} for brain invasion without disrupting the BBB 2. CD36+ M{varphi} has enhanced adhesion to BMECs and increased resistance to shear flow 3. Ketogenesis promotes bacterial neuroinvasion that can be halted by glucose treatment 4. Accumulation of peripheral BHB and CD36+ M{varphi} fuels bacterial neuroinvasion in humans O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/582462v4_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@19fe27org.highwire.dtl.DTLVardef@7cf218org.highwire.dtl.DTLVardef@fa0d16org.highwire.dtl.DTLVardef@71366b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

microbiology↗

bioRxiv2023

Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure

Expansion of the glutamine tract (poly-Q) in the protein Huntingtin (HTT) causes the neurodegenerative disorder Huntingtons disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. 70Q introduction caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics and elevated resting energy expenditure. Elimination of the poly-Q tract of HTT normalized CHCHD2 expression and mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early intervention target for HD.

neuroscience↗

bioRxiv2021

Molecular Epidemiology and Microbiological Characteristics of Cryptococcus gattii VGII isolates from China

Cryptococcus gattii (C. gattii) is a fungal pathogen that once caused an outbreak of cryptococcosis on Vancouver Island, and had spread worldwide, while few data were available in China. In this study, seven clinical isolates of C. gattii VGII were collected from 19 hospitals, Multi-locus Sequence Typing (MLST) analysis and whole-genome sequencing (WGS) was performed, and combined with published data for phylogenetic analysis. In addition, in vitro antifungal susceptibility testing, phenotypic analysis, and in vivo virulence studies were performed, subsequently, histopathological analysis of lung tissue was performed. C.gattii VGII infected patients were mainly immunocompetent male, and most of them had symptoms of central nervous system (CNS) involvement. MLST results showed that isolates from china exhibited high genetic diversity, and sequence type (ST) 7 was the major ST among the isolates. Some clinical isolates showed a close phylogenetic relationship with strains from Australia and South America. All clinical isolates did not show resistance to antifungal drugs. In addition, there was no correlation between virulence factors (temperature, melanin production, and capsule size) and virulence while in vivo experiments showed significant differences in virulence among strains. Lung fungal burden and damage to lung tissue correlated with virulence, and degree of damage to lung tissue in mice may highlight differences in virulence. Our work seeks to provide useful data for molecular epidemiology, antifungal susceptibility, and virulence differences of C. gattii VGII in China. Author SummaryCryptococcus gattii is one of the life-threatening fungal pathogens that can infect immunocompetent individuals. C.gattii can be invaded through the respiratory tract and can be spread to the brain, causing meningoencephalitis and even death. In 1999, an outbreak of C. gattii VGII occurred on Vancouver Island in Canada and spread in the Pacific Northwest region, which attracted more attention. Compared with other nations, the data of C gattii VGII in China was limited. To better understand the molecular epidemiology and microbiological characteristics of C.gattii VGII isolates from China, Bioinformatics analysis and in vivo and in vitro experiments were performed for clinical strains. Multi-locus Sequence Typing and whole-genome sequencing reveal the genetic diversity of the isolates and genetic relationships with isolates from other countries. We also investigated the antifungal drug susceptibility and virulence differences of the isolates. The authors expect that our work can provide useful data for the prevention and control of C. gattii VGII in China and to draw attention to C. gattii.

microbiology↗