Spatial transcriptomic analysis of HIV and tuberculosis coinfection in a humanized mouse model reveals specific transcription patterns, immune responses and early morphological alteration signaling

Mycobacterium tuberculosis ( Mtb ) and human immunodeficiency virus (HIV) coinfection is one of the biggest public health concerns worldwide. Both pathogens are adept at modulating immune response and, in the case of Mtb , even inducing structural modification of the affected tissue. The present study aimed at understanding the early phenotypical and functional changes in immune cell infiltration in the affected organ, using a humanized mouse model. The humanized mice were infected with either HIV or Mtb in single infection, or with both pathogens in coinfection. Three weeks after the infection, lung samples were collected, and spatial transcriptomics analysis was performed. This analysis revealed high infiltration of CD4 ⁺ T cells in Mtb infection, but not in HIV or coinfection. Coinfected mice also showed a minimal number of NK cells compared to the other groups. In addition to infection status, histological features also influenced the immune cell infiltration pattern in the lungs. Two distinct airway regions with distinct immune cell abundance patterns were detected by spatial transcriptome profiling. A lymphoid cell aggregate detected in coinfection lung exhibited distinct transcript profile. The cellular architecture in the lymphoid cell aggregate did not follow the spatial patterns seen in mature granulomas. However, lymphoid cell aggregates exhibited granuloma gene expression signatures, and pathways associated with reactive oxygen species production, oxidative phosphorylation, and TGFβ and interferon signaling similar to granulomas. This study revealed specific transcription patterns, immune responses and morphological alteration signaling in the early stage of HIV and Mtb infections.