The innate immune system is an intricate network that communicates through signaling events to maintain immune balance. This system is activated through pattern recognition receptors (PRRs) that engage microbe pathogen-associated molecular patterns and host danger associated molecular patterns to induce or suppress an immune response, which is resolved once the danger is cleared. However, unresolved and dysregulated activation of these PRRs results in chronic inflammation that leads disease initiation and progression. Crosstalk between immunoreceptors and the host and microbial components play an imperative role in regulating these interactions. In Chapter 1, I wrote a comprehensive to understand the known crosstalk between immune receptors, microbes, and the host, with a focus on monocytes and macrophages, Toll-Like Receptors (TLRs), the Stimulator of Interferon Genes (STING) pathway, and the gut microbiome in the context of disease. In Chapter 2, I show that STING mediates TLR8-induced interferon (IFN) signaling and I hypothesize that this is mediated by activation of the kinase IKKε. Inhibition of STING significantly decreases IFN secretion in both primary and cell line human monocytes, which could serve as a therapeutic for IFN mediated diseases. In Chapter 3, we use novel technology to show macrophages have 11 different states and that health and disease-associated gut microbiome bacteria induce differential ratios of these states. We hypothesize that this is due to differential engagement with TLRs, particularly TLR4. We also find that these bacterial exposures have different functional outcomes as seen through changes in glycolysis. Lastly, in Chapter 4, I discuss the limitations, implications, and the future directions of my studies. The work of my thesis focuses on understanding the crosstalk between the host, health and disease-associated bacteria, and immune receptors that contribute to the field of host-microbe interactions. We found that TLR signaling is important to mediate autoimmune and host-microbe interactions. These findings provide insights and targets for future therapeutics and treatments for IFN autoimmune diseases and microbiome related diseases.