The immune response to human tuberculosis (TB), particularly in the context of complex lung pathology, remains incompletely understood. Here, we employed whole-slide spatial proteomics to map immune c...

Tuberculosis (TB) outcomes vary widely, from asymptomatic infection to mortality, yet most animal models do not recapitulate human phenotypic and genotypic variation. The genetically diverse Collaborative Cross mouse panel models distinct facets of TB disease that occur in humans and allows identification of genomic loci underlying clinical outcomes. We previously mapped a TB susceptibility locus on mouse chromosome 2. Here, we identify cathepsin Z ( Ctsz ) as a lead candidate underlying this TB susceptibility and show that Ctsz ablation leads to increased bacterial burden, CXCL1 overproduction, and decreased survival in mice. Ctsz disturbance within murine macrophages enhances production of CXCL1, a known biomarker of TB severity. From a Ugandan household contact study, we identify significant associations between CTSZ variants and TB disease severity. Finally, we examine patient-derived TB granulomas and report CTSZ localization within granuloma-associated macrophages, placing human CTSZ at the host-pathogen interface. These findings implicate a conserved CTSZ-CXCL1 axis in humans and genetically diverse mice that mediates TB disease severity. ### Competing Interest Statement The authors have declared no competing interest.

B cells are major drivers of systemic immunity, but they also act locally in non-lymphoid organs. This Review highlights new insights into mechanisms of tissue B cell function as well as efforts to le...

The 2025 Gordon Research Conference on Tuberculosis Drug Discovery and Development will be held in Castelldefels, Barcelona Spain. Apply today to reserve your spot.

This study identifies 11 IFNAR1 alleles impairing IFN-α/ω responses but sparing IFN-β, including an allele common in Southern China (P335del). Heterozygous

The balance between protective and pathological immune responses shapes progression of Mycobacterium tuberculosis infection.

The 2025 Gordon Research Conference on Tuberculosis Drug Discovery and Development will be held in Castelldefels, Barcelona Spain. Apply today to reserve your spot.

Intestinal regionalization is characterized by robust and resilient structural cell states and the intestine can adapt to environmental stress in a spatially controlled manner through crosstalk betwee...

Loss-of-function mutations in LTBR result in a stromal defect, leading to dysfunctional secondary lymphoid organs and combined immunodeficiency in humans.