The existence of constantly evolving dynamic interactions between the host and the pathogen determines their fate in this continuous arms race. Hence, identifying the molecular basis of processes that reinforce host defensive strategies to eliminate intracellular pathogens is of utmost significance. Pathogenic intrusion activates autophagy and phagocytic pathways that culminate in the lysosome, a vital organelle responsible for pathogen clearance. The transcription factor TFEB plays a pivotal role in autophagy-lysosomal function. Although TFEB is an emerging transcription factor in the field of immune signaling pathways, its role in infectious diseases remains contentious. Recent evidence suggests that infection with certain bacterial and viral pathogens causes TFEB, which is normally located in the cytoplasm, to translocate to the nucleus. There, it activates the transcription of genes that trigger the autophagy-lysosomal and inflammatory pathways to target intracellular pathogens. It is known that some pathogens modulate TFEB to establish themselves inside the host; in some cases, pathogens restrict TFEB to the cytoplasm, whereas in others, functional TFEB fuels pathogen survival and replication. However, the key regulators and molecular mechanisms that decide the outcome of TFEB function during intracellular infection are not clear. In this Review, we attempt to dissect the complex functions of TFEB in host–pathogen interactions and explore the suitability of TFEB as a therapeutic target of clinical relevance.

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