Spatial transcriptomics reveals early immune responses in HIV and tuberculosis coinfection in humanized mice

Abstract Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) coinfection is a major public health concern, yet early immune and tissue changes during coinfection remain incompletely understood. Here we show, using a humanized mouse model and spatial transcriptomics of lung tissue, that early immune cell infiltration differs across single and combined infections. Mtb infection is associated with increased CD4 positive T cell infiltration, whereas this response is reduced in HIV infection and coinfection. Coinfected lungs also show lower natural killer cell abundance. Spatial profiling identifies distinct airway regions with different immune cell compositions and a lymphoid aggregate in coinfected lung with a distinct transcriptional profile. Although this aggregate lacks the cellular organization of a mature granuloma, it exhibits granuloma-associated gene expression signatures and pathways related to reactive oxygen species production, oxidative phosphorylation, transforming growth factor beta signaling, and interferon signaling. These findings define early spatial immune changes associated with coinfection.