bims-inflin 2025-01-19 papers

Cell Rep. 2025 Jan 16. pii: S2211-1247(24)01567-5. [Epub ahead of print]44(1): 115216

Plasticity of cell death pathways ensures GSDMD activation during Yersinia pseudotuberculosis infection.

Felicia Hui Min Chan, Hui Wen Yeap, Zonghan Liu, Safwah Nasuha Rosli, Kay En Low, Isabelle Bonne, Yixuan Wu, Shu Zhen Chong, Kaiwen W Chen.

Macrophages express pattern recognition and cytokine receptors that mediate proinflammatory signal transduction pathways to combat microbial infection. To retaliate against such responses, pathogenic microorganisms have evolved multiple strategies to impede innate immune signaling. Recent studies demonstrated that YopJ suppression of TAK1 signaling during Yersinia pseudotuberculosis infection promotes the assembly of a RIPK1-dependent death-inducing complex that enables caspase-8 to directly cleave and activate gasdermin D (GSDMD). However, whether and how macrophages respond to Yersinia infection in the absence of YopJ or caspase-8 activity remains unclear. Here, we demonstrate that loss of YopJ or its catalytic activity triggers non-canonical inflammasome activation in macrophages and that caspase-11 is required to restrict the bacterial burden in vivo. Under conditions of low caspase-8 activity, wild-type Y. pseudotuberculosis invades macrophages and accesses the cytosol, leading to non-canonical inflammasome activation. Thus, our study highlights the plasticity of death pathways to ensure GSDMD activation during Yersinia infection.

Keywords: CP: Cell biology; CP: Immunology; CP: Microbiology; RIPK1; Yersinia; apoptosis; caspase-1; caspase-11; caspase-8; cell death; gasdermin; inflammasome; pyroptosis

DOI: https://doi.org/10.1016/j.celrep.2024.115216

Nat Commun. 2025 Jan 15. 16(1): 709

The Toxoplasma rhoptry protein ROP55 is a major virulence factor that prevents lytic host cell death.

Margarida T Grilo Ruivo, Ji-Hun Shin, Todd Lenz, Stephanie Y Matsuno, Katherine Olivia Yanes, Arnault Graindorge, Maguy Hamie, Laurence Berry-Sterkers, Mathieu Gissot, Hiba El Hajj, Karine G Le Roch, Melissa B Lodoen, Maryse Lebrun, Diana Marcela Penarete-Vargas.

Programmed-cell death is an antimicrobial defense mechanism that promotes clearance of intracellular pathogens. Toxoplasma counteracts host immune defenses by secreting effector proteins into host cells; however, how the parasite evades lytic cell death and the effectors involved remain poorly characterized. We identified ROP55, a rhoptry protein that promotes parasite survival by preventing lytic cell death in absence of IFN-γ stimulation. RNA-Seq analysis revealed that ROP55 acts as a repressor of host pro-inflammatory responses. In THP-1 monocytes ΔROP55 infection increased NF-κB p65 nuclear translocation, IL-1β production, and GSDMD cleavage compared to wild type or complemented parasites. ΔROP55 infection also induced RIPK3-dependent necroptosis in human and mouse primary macrophages. Moreover, ΔROP55 parasites were significantly impaired in virulence in female mice and prevented NF-κB activation and parasite clearance in mBMDM. These findings place ROP55 as a major virulence factor, dampening lytic cell death and enabling Toxoplasma to evade clearance from infected cells.

DOI: https://doi.org/10.1038/s41467-025-56128-x

Immunity. 2025 Jan 14. pii: S1074-7613(24)00571-5. [Epub ahead of print]58(1): 5-7

Mitochondria and NLRP3: To die or inflame.

Shuangshuang Yang, Guannan Huang, Jenny P-Y Ting.

Mitochondria play critical roles in intrinsic apoptosis and NLRP3 inflammasome activation, but how these processes are interconnected remains unclear. In this issue of Immunity, Saller et al. unveiled the complexity of NLRP3 activators, highlighting mitochondria's roles in switching apoptosis to NLRP3 inflammasome activation.

DOI: https://doi.org/10.1016/j.immuni.2024.12.007

Elife. 2025 Jan 16. pii: RP100922. [Epub ahead of print]13

Early and delayed STAT1-dependent responses drive local trained immunity of macrophages in the spleen.

Aryeh Solomon, Noa Bossel Ben-Moshe, Dotan Hoffman, Sébastien Trzebanski, Dror Yehezkel, Leia Vainman, Mihai G Netea, Roi Avraham.

Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette-Guérin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Salmonella Typhimurium (S.Tm). Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealing both early and delayed myeloid subsets with time-dependent, cell-type-specific STAT1 signatures. Using lineage tracing, we find that tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Early inhibition of STAT1 activation, using specific JAK-STAT inhibitors, reduces both RPM loss and recruitment of trained monocytes. Our study suggests a temporal window soon after BCG vaccination, in which STAT1-dependent activation of long-lived resident cells in the tissue mediates localized protection.

Keywords: BCG; Salmonella; immunology; inflammation; macrophages; mouse

DOI: https://doi.org/10.7554/eLife.100922