CSF1-receptor signaling plays a vital role in immune control of Mycobacterium tuberculosis infection in rhesus macaques 3540

Abstract Description Macrophages play a central role during immune responses to Mycobacterium tuberculosis (Mtb) infection. Macrophage colony-stimulating factor receptor (CSF1R) is a primary regulator of the differentiation, maintenance, and function of macrophages. Here we show that the CSF1R ligands, M-CSF and IL-34, are abundant in tuberculosis granulomas and produced by a variety of cell types. Granuloma CD4 T cells are particularly a major source of M-CSF. To examine the role of CSF1R during Mtb infection, ten rhesus macaques were infected with Mtb and infused with a CSF1-receptor blocking or isotype control mAb beginning at week four post infection. 18FDG PET/CT imaging revealed a rapid progression of disease following CSF1R blockade that was not seen in control animals. This was characterized by the development of large consolidated lung lesions harboring high bacterial burdens as well as enhanced dissemination to extrapulmonary tissues in all treated animals. Single-cell RNA-seq analysis revealed a reduced number of macrophages within granulomas of treated animals, with a preferential loss of C1Q+ macrophages. The large, consolidated lesions in the treated animals also contained an elevated frequency of highly activated T cells. Collectively, these data show that CSF1R has a major role in host resistance to Mtb infection in rhesus macaques. Funding Sources Supported by the NIH/NIAID Division of Intramural Research Topic Categories Cytokines and Chemokines and Their Receptors (CCR)