In general, innate immune responses are beneficial to the host. However, under certain circumstances, such as coinfections, these responses may contribute to disease progression. For instance, an initial infection may induce an immune response that renders the host susceptible to a subsequent infection by a different pathogen. For years, it has been understood that Neisseria gonorrhoeae and HIV coinfection increase viral shedding and transmission (1). However, the molecular mechanisms that control this phenomenon have been unclear. Neisseria spp. release a factor that can activate the transcription factor nuclear factor κB (NF-κB) in host cells and drive HIV gene expression (2). On page 1251 of this issue, Gaudet et al. (3) reveal the identity of this bacterial-derived factor, as well as the signaling axis through which it drives innate immune gene expression. This detection pathway may constitute a previously unknown innate immune signaling response with broader implications in microbial defense, as well as the pathogenesis of HIV.