We demonstrate that the mildly pathogenic Rickettsia parkeri, Rickettsia africae, and Rickettsia massiliae, all successfully proliferating in macrophages, trigger different proteome signatures in these cells and differentially impact critical components of innate immune responses by inducing different levels of beta interferon (IFN-β) and interleukin 1β (IL-1β) and different timing of pyroptotic events during infection. The gene discussed is IFNB1; the disease is infection.