Macrophage differences shape tuberculosis responses across humans and mice

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is fought first by immune cells in the lung called macrophages. These cells come in different types: alveolar macrophages (AMs) that live in the airway and monocyte-derived macrophages (MDMs) that arrive from the blood later in infection. Previous work has suggested AMs play a distinct role early in infection while MDMs are more active during later stages. To understand these differences across species, researchers led by corresponding author Alissa C. Rothchild combined data from human and mouse models to perform a cross-species analysis of how these macrophage types respond to Mtb. By directly comparing human AMs and MDMs with murine AMs and murine bone marrow-derived macrophages (BMDMs), the team aimed to find which responses are shared between species and which are unique. This approach helps clarify how laboratory mouse models reflect human biology and reveals which cellular pathways might be important at different stages of tuberculosis disease.

Using comparative analysis of human and mouse macrophage data, the study found that both AMs and MDMs in humans and mice mount a strong interferon response following Mtb infection. However, AMs in both species showed a weaker pro-inflammatory response than human MDMs or murine BMDMs, specifically in pathways described as TNFA signaling and inflammatory response pathways. Interestingly, AMs from mice that had been vaccinated with BCG (scBCG) or that came from a model of contained TB (coMtb) displayed Mtb responses that were more similar to human AMs than control mice, suggesting prior exposure or containment changes AM behavior. The analysis also uncovered species-specific differences: cholesterol-related pathways were altered differently in AMs between mouse and human, while MYC targets and Hedgehog signaling differed in MDMs/BMDMs. To probe downstream regulation, the team examined IL-10, an immunosuppressive cytokine induced by Type I Interferons, and c-Maf, a transcription factor required for IL-10 expression in myeloid cells, finding significantly lower expression of both IL-10 and c-Maf in AMs compared to MDMs in humans and mice.

These results illuminate the shifting landscape of innate immune responses during tuberculosis and show the value of comparing human and mouse data side by side. The conserved strong interferon response across species points to a common early defense signature, while the consistently lower pro-inflammatory signaling in AMs highlights functional differences that may matter for how infection is controlled or contained. The species-specific changes in cholesterol pathways and in MYC targets and Hedgehog signaling suggest caution when extrapolating some findings from mice to humans, and they identify molecular pathways for further study. The lower levels of c-Maf and IL-10 in AMs suggest one mechanism by which these cells can mount robust interferon-driven responses without triggering the same inflammatory programs seen in MDMs, which could affect disease progression. Overall, the study emphasizes how combining human and mouse analyses can reveal both shared mechanisms to target and unique features that need species-specific consideration for vaccine and therapeutic research.