Sensing of microbes by the immune system depends on dedicated receptors (pathogen recognition receptors) that bind pathogen-associated molecular patterns (PAMPs). Activation of these receptors triggers immune responses, including inflammation, aimed at eliminating microbial infections. Pathogens, however, have evolved mechanisms that prevent activation of host receptors and downstream signalling pathways to promote their survival. Understanding how pathogens prevent effective immunity will enable the development of alternative strategies that rely on activating the immune system to treat infectious diseases. So far, targeted immune activation during established infection remains challenging due to the associated risks of immunopathology. Here, we discuss efforts to identify activators of pathogen recognition receptors to clear infections without inducing immunopathology in the Legionella lung infection model. We used established murine infections and tested available agonists of toll-like receptors to determine bacterial burdens, immune responses and cell numbers within the local and distal tissues and serum. We identified that the localized activation via Polyinosinic:polycytidylic acid (PolyIC), a double-stranded RNA analog, but not other agonists affected bacterial lung burdens. Spectral flow cytometry and cytokine arrays have identified that PolyIC alters innate immune responses in Legionella-infected lungs. We will discuss how the activation of host immune receptors affects intracellular pathogens and how this can be harnessed to treat infections.