Infectious diarrhea remains a leading cause of morbidity and mortality in children and immunocompromised patients. However, the lack of animal models that closely mirror the infection observed in these susceptible groups, including rapid pathogen colonization, systemic spread, persistence and/or lethality, has limited our understanding and treatment of disease.
Using mouse models with different age, genetic background or microbiota composition, our research aims to understand the virulence strategies by which enteric pathogens establish infection under different host conditions, leading to distinct disease severity and outcome. Likewise, we are interested in the mechanisms by which the gut microbiota and host immune responses prevent pathogen colonization or promote its eradication during infection.
We are currently working in the following projects:
Pathogen evasion of colonization resistance in the gut.
We reported that depletion of amino acids by the gut microbiota limits intestinal colonization by Citrobacter rodentium, a mouse pathogen broadly used to study enteric infection with the closely related human pathogen enteropathogenic Escherichia coli. In contrast, we found that C. rodentium induction of amino acid biosynthesis and increased dietary amino acids promote pathogen colonization in the gut. However, the role of conserved or strain-specific genetic factors in other pathogens during early intestinal expansion, and the differential colonization resistance conferred by the microbiota at different sites along the gastrointestinal tract, remain to be further explored.
Related publications:
Caballero-Flores, G., Pickard, J. M., Fukuda, S., Inohara, N., & Núñez, G. (2020). An enteric pathogen subverts colonization resistance by evading competition for amino acids in the gut. Cell host & microbe, 28(4), 526–533.e5.
Caballero-Flores, G., Pickard, J. M., & Núñez, G. (2023). Microbiota-mediated colonization resistance: Mechanisms and regulation. Nature reviews microbiology, 21, 347–360.
Host susceptibility factors to enteric infection during early life.
As observed for enteropathogenic E. coli human infections, young mice are also more susceptible to C. rodentium enteric infection than adults. This young mouse model of disease shows acute diarrhea, marked pathogen translocation and lethality. In contrast, adult animals exhibit only a mild, self-limiting disease that is fully resolved a few weeks after infection. However, the mechanisms underlying the increased susceptibility to enteric infection observed in the young group remain poorly understood. Thus, we are interested in identifying host factors contributing to severe enteric disease in the neonatal gut, aiming to harness them to promote protection during early life.
Related publications:
Caballero-Flores, G., Sakamoto, K., Zeng, M. Y., Wang, Y., Hakim, J., Matus-Acuña, V., Inohara, N., & Núñez, G. (2019). Maternal immunization confers protection to the offspring against an attaching and effacing pathogen through delivery of IgG in breast milk. Cell host & microbe, 25(2), 313–323.e4.
Pathogen adaptation to different host environments.
Various enteric pathogens can translocate from the gut to the systemic circulation and cause bacteremia in susceptible individuals. However, the virulence strategies allowing enteric pathogens to disseminate and/or thrive in different host environments outside the gut remain poorly understood. Therefore, we are interested in identifying pathogen factors promoting niche adaptation during distinct types or stages of infection in the host. This might lead to the discovery of new antimicrobial targets and/or the development of better treatment strategies for both enteric and systemic infections in humans.