Male sex affects type I/type II interferon response of neutrophils during hepatic Amebiasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1011261 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25836800_1.fastq.gz | Fastqsanger.gz | |||
| SRR25836800_2.fastq.gz | Fastqsanger.gz | |||
| SRR25836801_1.fastq.gz | Fastqsanger.gz | |||
| SRR25836801_2.fastq.gz | Fastqsanger.gz | |||
| SRR25836802_1.fastq.gz | Fastqsanger.gz |
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Project description:Hepatic amebiasis, a serious complication caused by the parasite Entamoeba histolytica, predominantly affects men. Earlier research in the murine disease model indicated that testosterone modulates an intense immune reaction, triggering destructive immunopathological changes in the liver. Inflammatory monocytes expressing proinflammatory chemokines, crucial for neutrophil recruitment, worsen this process. This study examines sex-related variances in neutrophils during hepatic amebiasis in a mouse model. Male subjects exhibited higher levels and recruitment of neutrophils compared to females. Androgens directly contributed to this bias, enhancing neutrophil recruitment and retarding maturation in response to infection. Transcriptomic analysis revealed diminished type I and II interferon-stimulated gene expression and reduced activation pathways in male neutrophils versus female neutrophils. Upon ex-vivo stimulation, female human neutrophils showed higher expression of a key type I interferon-stimulated gene (viperin/RSAD2) at the protein level, which was similar in mice after infection, and suppressed by testosterone. In male mice with hepatic amebiasis, sex-dependent factors led to recruitment of less active neutrophils, intensifying immunopathological damage to liver tissue. This sex disparity and testosterone's impact on interferon-stimulated genes hold implications beyond hepatic amebiasis, potentially influencing broader areas, including viral infectious diseases
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Project description:Differences in immune response between men and women may influence the outcome of infectious diseases. Intestinal infection with Entamoeba histolytica leads to hepatic amebiasis, which is more common in males. Previously, we reported that innate immune cells contribute to liver damage in males in the murine model for hepatic amebiasis. Here, we focused on the influences of sex and androgens on neutrophils in particular. Infection associated with neutrophil accumulation in the liver was higher in male than in female mice and further increased after testosterone treatment in both sexes. Compared with female neutrophils, male neutrophils exhibit a more immature and less activated status, as evidenced by a lower proinflammatory N1-like phenotype and deconvolution, decreased gene expression of type I and type II interferon stimulated genes (ISGs) as well as downregulation of signaling pathways related to neutrophil activation. Neutrophils from females showed higher protein expression of the type I ISG viperin/RSAD2 during infection, which decreased by testosterone substitution. Moreover, ex vivo stimulation of human neutrophils revealed lower production of RSAD2 in neutrophils from men compared with women. These findings indicate that sex-specific effects on neutrophil physiology associated with maturation and type I IFN responsiveness might be important in the outcome of hepatic amebiasis.
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Project description:While critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during COVID-19 ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using scRNA-seq and plasma proteomics, we discovered that compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin (PG) signalling. Dexamethasone during severe COVID-19 depleted circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated gene, and activated IL1R2+ve neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils, preferential steroid-induced immature neutrophil expansion, and possibly different effects on outcome. Our single-cell atlas (www.biernaskielab.ca/COVID_neutrophil) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.
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