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How does the nematode Caenorhabditis elegans respond to natural pathogen infections with non-professional immune cells? To answer this question, we are studying the Intracellular Pathogen Response (IPR) – a host transcriptional response common to infection with molecularly diverse natural pathogens: microsporidia and the Orsay virus. In addition to intracellular pathogens, the IPR can be induced upon exposure to heat stress and proteasome inhibition. Mutant animals with constitutive IPR activation have increased intracellular pathogen resistance and thermotolerance, indicating that the IPR confers a protective response. The IPR involves transcriptional activation of 80 genes, some of which are predicted to encode ubiquitin ligase components. One of the most highly induced IPR genes is pals-5, which serves as a robust readout for the IPR activation. Using pals-5::GFP reporters, we identified the predicted bZIP transcription factor ZIP-1 as a positive regulator of the IPR in two reverse genetic screens. Our qRT-PCR and smFISH studies demonstrated that ZIP-1 controls pals-5 mRNA expression early after proteasome blockade, but not at later time points. We further performed an RNA-Seq analysis, which revealed that ZIP-1 is required for mRNA expression of multiple IPR components. Based on the type of transcriptional regulation, we have identified three distinct types of IPR genes: a) completely ZIP-1-dependent, b) partially ZIP-1-dependent and c) ZIP-1-independent. Importantly, we found that ZIP-1 is required for the increased resistance to microsporidia infection in mutants with constitutive IPR expression, suggesting that ZIP-1-dependent genes play an important role in innate immunity.