Different bacteria colonize different sites within the human body. To determine the role of site specificity in the upregulation of EGR1 several cell lines representing different body sites were infected by the same bacterial species. We selected a representative strain from each group; N. meningitidis serogroup C (Nm-C), S. pyogenes serogroup M6 (Sp-M6), H. pylori J99 (Hp-J99), N. gonorrheae (Ng), and S. enterica serovar Enteritidis (SE-3934). Remarkably, most bacteria could induce the strongest EGR1 response in the cell type of their natural niche and upregulation was low or absent in host cells that did not represent the natural colonization site (Figures 2A–E). An exception is the intestinal pathogen S. Enteritidis that induced a very strong response in the gastric epithelial cell line AGS (Figure 2E). Upregulation in other cell types sometimes showed different time kinetics, such as that observed for N. meningitidis where EGR1 levels peaked at 2 h in FaDu cells, which represents the natural colonization site of the nasopharynx, EGR1 expression peaked at 4h in ME180, a cervical cell line, and in the gastric epithelial cell line AGS (Figure 2A). Interestingly, infection with N. gonorrhoeae showed the same pattern (Figure 2D). This finding is not surprising, because these bacteria are closely related species that colonize both the pharynx and urogenital tract and therefore are likely to induce similar host responses. At 2 h post infection, S. pyogenes specifically triggered EGR1 expression in target FaDu cells, whereas after 6 h, EGR1 was unexpectedly induced in AGS cells (Figure 2B).