Tertiary lymphoid structures in pulmonary granulomas of cattle experimentally infected with aerosolized Mycobacterium bovis

Authors: Palmer, Mitchell; JONES, DOUGLAS - Iowa State University; BOCKENSTEDT, NICHOLAS - Iowa State University; Boggiatto, Paola

Submitted to: BMC Veterinary Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/4/2025
Publication Date: 6/5/2025
Citation: Palmer, M.V., Jones, D.E., Bockenstedt, N.J., Boggiatto, P.M. 2025. Tertiary lymphoid structures in pulmonary granulomas of cattle experimentally infected with aerosolized Mycobacterium bovis. BMC Veterinary Research. 21. Article 403. https://doi.org/10.1186/s12917-025-04804-x.
DOI: https://doi.org/10.1186/s12917-025-04804-x

Interpretive Summary: Mycobacterium bovis is the primary cause of tuberculosis in cattle known as bovine tuberculosis. Due to both animal and public health concerns, the USDA initiated a bovine tuberculosis eradication effort in 1917, which is still in place today. One obstacle to eradication is the lack of reliable diagnostic tests that would allow the removal of infected animals from a herd with confidence that no infected animal were missed, as well as an effective vaccine. Development of both accurate diagnostic assays and vaccines requires a foundational knowledge of the disease process. In order to better understand bovine tuberculosis development we examined tissue changes in lungs of cattle at various time points after infection to characterize specific immune cell types and immune related tissue changes. We found that specific immune related changes that closely mimic lymph glands develop in lungs of infected cattle at specific time points after infection. These changes may be critical in disease control Knowledge of these changes will aid the development of diagnostic assays and vaccine development.

Technical Abstract: Mycobacterium bovis is the primary cause of tuberculosis in animals, most notably cattle. In cattle and other susceptible hosts, the hallmark lesion of tuberculosis is the granuloma. Granulomas represent the host-pathogen interface where disease outcome is determined; therefore, it is critical to understand host-pathogen interactions at the granuloma level. Granulomas are highly structured lesions with distinct cellular compartments for T cells, macrophages, multinucleated giant cells, and B cells. A recognized but poorly understood morphologic feature of many granulomas is the presence of structures resembling follicular or germinal center-like arrangements of B cells known as tertiary lymphoid organs, or tertiary lymphoid structures. Pulmonary granulomas from cattle experimentally infected with M. bovis were collected at 15-, 30-, 90-, 180- and 270-days post-infection and examined for the presence of tertiary lymphoid-like structures. Follicle-like structures associated with granulomas were first seen 90 days after infection and persisted in later time points. Compartmentalization of T cells and B cells similar to follicles in germinal centers of lymph nodes was demonstrated using in situ hybridization. Additionally, the presence and arrangement of myeloid cells (CD11b, CD11c), markers for endothelial cells, T follicular helper cells, and chemokines (CXCL13, CCL21, CCL19) critical to tertiary lymphoid structure formation was shown to be similar to lymph node follicles and that described for tertiary lymphoid structures in other species. This represents the first demonstration of the similarities of follicle-like structures associated with bovine tuberculous granulomas to tertiary lymphoid structures in other species and follicles within secondary lymphoid organs such as lymph nodes.