Macrophage state and Mycobacterium avium subsp. paratuberculosis persistence in cattle: An evidence-to-claim framework.

Johne's disease is a chronic granulomatous enteritis of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). Macrophages are a major intracellular niche for MAP and a defining cellular component of bovine intestinal lesions, but results obtained from different tissues, donor groups, cell systems, MAP isolates, and time windows do not define one uniform macrophage state. This structured interpretive review applies an author-developed evidence-to-claim framework to MAP-macrophage research. The framework asks three separate questions: which biological context generated the observation, what relationship was directly tested, and how specifically the responsible host or bacterial factor was resolved. A separate check asks whether the conclusion matches the measured bacterial endpoint, such as uptake, assay-qualified viable burden or proportion, trafficking, tissue localization, host chronicity, or shedding. These questions and the endpoint check are recorded separately; they are not summed or used to rank studies. The reviewed evidence supports disease-history- and stage-associated differences in macrophage responsiveness, dissociation between inflammatory signaling and viable MAP control in defined models, altered lipid and phagosomal/endosomal readouts, and bacterial determinants of intracellular fitness. It does not yet establish a multidimensional macrophage-state atlas in natural bovine lesions, durable innate tolerance or trained immunity, or transmission-relevant persistence from macrophage experiments alone. A practical core design is to pair clearly defined macrophage phenotypes with uptake-aware, assay-qualified bacterial-fate endpoints in the same bovine model, then add perturbation, rescue, or tissue validation according to the strength of the intended claim.