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Citrobacter rodentium infection is a mouse model for the important human diarrheal infection caused by enteropathogenic E. coli (EPEC). The pathogenesis of both species is very similar and depends on their unique ability to form intimately epithelium-adherent microcolonies, also known as “attachment/effacement” (A/E) lesions. These microcolonies must be dynamic and able to self-renew by continuous re-infection of the rapidly regenerating epithelium. It is unknown whether sustained epithelial A/E lesion pathogenesis is achieved through re-infection by planktonic bacteria from the luminal compartment or local spread of sessile bacteria without a planktonic phase. Focusing on the earliest events as C. rodentium becomes established, we show here that all colonic epithelial A/E microcolonies are clonal bacterial populations, and thus depend on local clonal growth to persist. In wild-type mice, microcolonies are established exclusively within the first 18 hours of infection. These early events shape the ongoing intestinal geography and severity of infection despite the continuous presence of phenotypically virulent luminal bacteria. Mechanistically, induced resistance to A/E lesion de-novo formation is mediated by TLR-MyD88/Trif-dependent signaling and is induced specifically by virulent C. rodentium in a virulence gene-dependent manner. Our data demonstrate that the establishment phase of C. rodentium pathogenesis in vivo is restricted to a very short window of opportunity that determines both disease geography and severity., Author summary The so-called “attaching and effacing” (A/E) pathogens enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) cause serious human diarrheal infections by adhering to and damaging the intestinal epithelium. Previous work on the mouse A/E pathogen Citrobacter rodentium has established that host adaptive immune response and intestinal microbiota cooperate to control the epithelial infection and colonization with this pathogen. We found that this is complemented by a rapid pathogen-induced mucosal innate immune response that is essential to prevent excessive pathogenesis before adaptive immunity takes effect. Its effectiveness is demonstrated by the fact that it normally limits the duration during which the bacteria can induce epithelial lesions to the first 18 hours of infection. Later, luminal virulent bacteria can no longer induce new A/E lesions, but those induced already in the first 18 hours of infection persist through localized epithelial re-infection. Severity of the disease at the peak of infection is consequently shaped by the early events of the first 18 hours. This information may be important for the development of effective therapies and vaccines.