A single Escherichia coli strain, designated sequence type 131 (ST131), has emerged in the U.S. over the past decade as the single most common E. coli strain in clinical laboratories and as the cause of most multidrug- resistant E. coli infection, particularly among veterans. To date, the ST131 epidemic has been recognized almost exclusively at the clinical level. Indeed, ST131 has caused huge numbers of infections, some of which have been strikingly severe, invasive, persistent, and/or problematically recurrent. However, multiple lines of evidence suggest that the substrate for this quite obvious clinical epidemic is an invisible, but much more extensive, epidemic of intestinal colonization and transmission involving ST131, whereby ST131 disseminates within the population, setting the stage for sporadic ST131 infections in colonized hosts. Effective management of the ST131 clinical epidemic will require attention to this underlying intestinal colonization epidemic. Thus, the over-arching study questions are (i) the extent of E. coli ST131 as a human intestinal colonizer, especially among veterans, which likely underlies ST131's recent explosive emergence as a disseminated multidrug- resistant pathogen, and (ii) whether an anti-ST131 vaccine can block this process. Therefore, the project will test the following hypotheses, through accomplishment of the following specific aims: Hypothesis 1: As an intestinal colonizer among veterans and their household contacts, ST131 is more prevalent than other fluoroquinolone-resistant E. coli (FQREC), and is associated with specific host characteristics and exposures.
Aim 1 : Define the extent of, and risk factors for, ST131 as an intestinal colonizer among veterans and their household contacts, compared with other FQREC. Hypothesis 2: ST131 is more capable of host colonization and/or transmission than are other antimicrobial- resistant E. coli. Specifically, it is more transmissible host-to-hos (which is associated with specific host characteristics), and once present tends to both out-compete and persist longer than other intestinal E. coli.
Aim 2 : Assess ST131's ability to colonize new hosts, spread among hosts, persist in colonized hosts, and achieve intestinal predominance, compared to other resistant E. coli, and identify associated risk factors. Hypothesis 3: Immunization of mice with ST131-derived antigens can engender a host mucosal IgA immune response that protects against intestinal colonization by an ST131 challenge strain.
Aim 3. 1: Define immunization conditions that yield strong intestinal IgA responses in mice to an ST131 vaccine strain.
Aim 3. 2: Assess the effect of such immunization on experimental gut colonization with an ST131 challenge strain in a humanized mouse model.
This project addresses an important new drug-resistant strain of E. coli, called ST131, which now causes most drug-resistant E. coli infections (e.g., urinary tract infections) in veterans. Because the silent spread of ST131 among uninfected individuals probably underlies the current ST131 epidemic, we will investigate the intestinal carrier state and person-to-person transmission of ST131, and will seek to develop a vaccine to block intestinal colonization with ST131. Specifically, we will (i) define the extent of intestinal ST131 carriage among veterans and risk factors for carrying ST131, (ii) determine whether ST131 is more transmissible and persists longer, or at higher densities, in colonized individuals, compared with other E. coli, and (iii) determine whether an ST131 vaccine can protect mice from becoming intestinally colonized with ST131 when challenged with it. This will lay the groundwork for developing and deploying future preventive interventions against ST131, to help control the ST131 epidemic.