Cutaneous leishmaniasis is caused by infection with the protozoan parasite Leishmania, which resides intracellularly in dermal macrophages (Mø), producing lesions. The skin lesions are characterized by proinflammatory cytokines and growth factors as well as inflammatory hypoxia, creating a stressful microenvironment for Mø. Of importance, not all Mø in lesions harbor parasites. To distinguish the influence of the parasite from the inflammatory microenvironment after Leishmania major (LM) infection on the Mø, we performed single-cell RNA sequencing and compared Mø associated with LM transcripts (or ‘infected' Mø) with Mø not associated with LM transcripts (or ‘bystander' Mø) within the lesions. Our findings show coordinated lysosomal expression and regulation signaling with increased cathepsin and H+-ATPase transcripts are upregulated in infected compared with bystander Mø. Additionally, eukaryotic initiation factor 2 (EIF2) signaling is downregulated in infected compared with bystander Mø, which includes many small and large ribosomal subunit (Rps and Rpl) transcripts being decreased in Mø harboring parasites. Furthermore, we also find EIF2 signaling including EIF, Rps, and Rpl transcripts being downregulated in bystander Mø compared with Mø from naïve skin. These data suggest that both the parasite and the inflammatory host microenvironment affect the transcription of ribosomal machinery in lesional Mø, thereby potentially affecting the ability of these cells to perform translation, protein synthesis, and thus function. Altogether, these results suggest that both the parasite and host inflammatory microenvironment independently drive transcriptional remodeling in Mø during LM infection in vivo.

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