Re-defining granulomas: bacterial effectors, host circuits, and spatially resolved immunity

Area of Science:

• Immunology
• Cell Biology
• Microbiology

Background:

• Granulomas are immune cell aggregates formed when the host cannot eliminate persistent stimuli.
• Their dual role in controlling pathogen spread while enabling microbial survival presents a paradox.
• Traditional histopathological definitions are being expanded by high-throughput 'omics approaches.

Purpose of the Study:

• To integrate recent findings on granuloma cellular diversity and cytokine dynamics.
• To propose a unifying framework for understanding granuloma behavior in infection.
• To highlight the interplay between microbial effectors and host immune circuits.

Main Methods:

• Review of high-throughput 'omics data (genomics, transcriptomics, proteomics).
• Analysis of cellular diversity and cytokine gradients within granulomas.
• Integration of studies across diverse bacterial pathogens (Mycobacterium, Salmonella, Yersinia, Brucella).

Main Results:

• Granulomas exhibit unrecognized cellular diversity and cytokine gradients.
• Bacterial effector proteins actively remodel host macrophage activation and cytokine responses.
• Host immune programs involving IFN, regulatory cytokines, and fibroblasts shape the granuloma environment.
• Conserved cellular modules in granulomas mirror features of non-infectious inflammation.

Conclusions:

• Granulomas are adaptive, yet imperfect, host responses balancing protection and pathology.
• Understanding the joint influence of microbial and host factors is key to targeting granuloma-directed therapies.
• Reprogramming granulomatous inflammation could favor antimicrobial resolution.