Biology subjects

Fong, V.

Publications and source records attributed to Fong, V..

3 recordsLinked to original sources

bioRxiv2026

Medulloblastoma Forms Symbiotic Metabolic Partnerships with Macrophages to Establish Leptomeningeal Metastases

Leptomeningeal metastases are the primary source of morbidity and mortality for pediatric medulloblastoma patients. Due to limited surgical sampling of metastases in patients, little is understood of the mechanisms of metastasis. Here, we identify biologically distinct quiescent small metastases (designated as micrometastases) and mitotically active larger metastases (macrometastases). Macrometastases are more metabolically active than micrometastases and contain higher levels of lipids, particularly cholesterol. Macrometastases secrete CXCL12, which attracts lipid-laden macrophages into the tumor. Lipid-laden macrophages upregulate the cholesterol transporter ABCG1, promoting the efflux of free cholesterol, which is then taken up by tumor cells via the HDL receptor SCARB1. CXCL12-driven macrophage recruitment and exogenous cholesterol are sufficient and necessary to drive progression of medulloblastoma leptomeningeal metastases in vivo. High fat diets drive metastatic progression in vivo. Dietary or pharmacological interventions targeting the CXCL12-SCARB1-cholesterol axis represent therapeutic strategies to either prevent or treat medulloblastoma leptomeningeal metastases.

cancer biology↗

bioRxiv2025

Neutralizing Activity of Cervicovaginal Secretions against Herpes Simplex Virus is Mediated by Mucosal IgG and Viral Glycoprotein E and Adversely Impacted by Vaginal Dysbiosis

Genital herpes simplex virus (HSV) recurrences are more common in women with bacterial vaginosis (BV). Prior studies demonstrated that genital tract secretions exhibit variable neutralizing activity against HSV, independent of serostatus, but the relationship of this activity to the vaginal microbiome and underlying mechanisms have not been defined. To test the hypothesis that cervicovaginal antiviral activity is lower in women with BV, we took advantage of cervicovaginal lavage (CVL) available from two studies conducted among women with symptomatic BV and healthy controls. CVL obtained from women with BV had significantly less antiviral activity than controls (p< 0.001). Inhibitory activity correlated negatively and most strongly with Shannon diversity index (p<0.0001). The innate activity did not differ comparing HSV-seropositive versus seronegative participants and no HSV-specific antibodies were detected in CVL. Activity was enriched in the immunoglobulin fraction but was lost when IgG (but not IgA) was depleted. Increasing doses of an anti-glycoprotein E (gE) monoclonal antibody overcame the neutralizing activity, suggesting that interactions between the Fc region of IgG and gE, a viral Fc gamma receptor (Fc{gamma}R), contribute. Consistent with this notion, CVL had less HSV inhibitory activity against a gE-null virus. Glycan analysis demonstrated a decrease in mature glycans in IgG from CVL with low antiviral activity and treatment of CVL with peptide N-glycanase F, which cleaves N-glycans in IgG, resulted in a loss of HSV inhibitory activity. We speculate that glycosidases elaborated by anaerobic bacteria cleave Fc glycans, resulting in decreased affinity for gE and a reduction in protective activity. IMPORTANCE: This study provides a mechanistic link for the increased risk of HSV infection and replication in the setting of symptomatic bacterial vaginosis and asymptomatic vaginal dysbiosis. Independent of Fab antigen specificity, the Fc region of mucosal IgG may neutralize HSV by binding to glycoprotein E, a viral Fc receptor. Vaginal dysbiosis leads to a loss of Fc glycans and a concomitant decrease in this innate antiviral activity. These findings suggest that viral Fc receptors, previously thought to function only in immune evasion, may also play a protective role. The results highlight the importance of developing and implementing strategies to protect against vaginal dysbiosis.

microbiology↗

bioRxiv2018

Single-cell RNA-seq reveals profibrotic macrophages in lung fibrosis

Myeloid cells localize to peripheral tissues in a wide range of pathologic contexts. However, appreciation of distinct myeloid subtypes has been limited by the signal averaging inherent to bulk sequencing approaches. Here we applied single-cell RNA sequencing (scRNA-seq) to map cellular heterogeneity in lung fibrosis induced by bleomycin injury in mice. We first developed a computational framework that enables unbiased, granular cell-type annotation of scRNA-seq. This approach identified a macrophage subpopulation that was specific to injured lung and notable for high expression of Cx3cr1+ and MHCII genes. We found that these macrophages, which bear a gene expression profile consistent with monocytic origin, progressively acquire alveolar macrophage identity and localize to sites of fibroblast accumulation. Probing their functional role, in vitro studies showed a trophic effect of these cells on fibroblast activation, and ablation of Cx3cr1-expressing cells suppressed fibrosis in vivo. We also found by gene set analysis and immunofluorescence that markers of these macrophages were upregulated in samples from patients with lung fibrosis compared with healthy controls. Taken together, our results uncover a specific pathologic subgroup of macrophages with markers that could enable their therapeutic targeting for fibrosis.

immunology↗