What Is C. rodentium and Why Is It Important?

Citrobacter rodentium is a bacterial pathogen that naturally infects mice, causing inflammation and changes in the colon. As a mouse-specific pathogen, it serves as a research tool for studying infections caused by human pathogens like enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC). These human bacteria are a major cause of diarrheal diseases globally.

The value of this research model lies in its shared method of causing disease with EPEC and EHEC. All three bacteria create a distinct type of damage in the gut known as an “attaching and effacing” (A/E) lesion. This shared mechanism allows researchers to study the infection process in mice to gain insights into how similar infections develop in humans, which are often impractical to study directly.

Pathogenic Mechanisms of C. rodentium

Citrobacter rodentium infection forms attaching and effacing (A/E) lesions on intestinal epithelial cells. The bacterium binds to the host cell, altering its structure and destroying the microvilli—the finger-like projections that absorb nutrients. This process leads to a flattened cell surface at the site of bacterial attachment.

Central to this is the Type III Secretion System (T3SS), which acts like a microscopic syringe to inject bacterial effector proteins into host cells. This system is encoded by the Locus of Enterocyte Effacement (LEE), a gene cluster shared with human A/E pathogens. Injecting these proteins is a primary strategy the bacterium uses to colonize the gut.

Once inside, these effector proteins manipulate cellular functions. One of the first injected is the Translocated Intimin Receptor (Tir). Tir inserts into the host cell membrane and acts as a docking station for a bacterial surface protein called intimin, creating a strong attachment.

Other effector proteins disrupt the host cell’s cytoskeleton, the internal scaffolding that maintains cell shape, contributing to the effacement of the microvilli. Some effectors interfere with host signaling pathways to dampen the initial immune response and prevent the infected cell from undergoing programmed cell death. This manipulation allows C. rodentium to establish a protected niche where it can multiply, leading to colonic hyperplasia, or a thickening of the colon wall.

Host Immune Defenses Against C. rodentium

The mouse immune system mounts a multi-layered defense against C. rodentium. Part of this response involves type 3 immunity, which is suited for extracellular bacteria at mucosal surfaces like the intestine. This response is coordinated by the innate and adaptive branches of the immune system.

Early in the infection, innate lymphoid cells (ILCs) in the gut lining are first responders. A function of these ILCs is producing the cytokine Interleukin-22 (IL-22). IL-22 prompts intestinal epithelial cells to produce antimicrobial peptides and strengthens the gut’s physical barrier to prevent the infection from spreading.

As the infection progresses, the adaptive immune system activates, and Th17 cells become important. These cells produce the cytokine Interleukin-17 (IL-17). IL-17 helps recruit neutrophils, a type of white blood cell that destroys bacteria, to the infection site.

The immune response is also modulated by local signals. For instance, Retinoic Acid (RA), a derivative of Vitamin A, helps regulate immune cell function in the intestine. RA receptor signaling balances the immune response, ensuring it is strong enough to clear the pathogen without causing excessive tissue damage.

The Gut Environment’s Role in Infection

The gut ecosystem, where host, pathogens, and microbes interact, heavily influences C. rodentium infection. The existing gut bacteria, or microbiota, defend against pathogens through colonization resistance. A healthy microbiota can prevent C. rodentium from establishing itself by competing for nutrients and space.

The microbiota’s metabolic activity also shapes the gut’s chemical landscape. These microbes produce compounds like short-chain fatty acids (SCFAs) from fermenting dietary fiber. SCFAs can inhibit C. rodentium’s growth or suppress its disease-causing genes and also help maintain the gut barrier.

Conversely, C. rodentium can exploit and manipulate the gut environment. The inflammation from the infection alters the gut to favor C. rodentium over resident bacteria, contributing to dysbiosis (an imbalance in the microbiota). The pathogen also utilizes specific nutrients that become available during inflammation.

One such nutrient is sialic acid, a sugar released from host cells during inflammation. C. rodentium can metabolize sialic acid, giving it a competitive advantage in the inflamed gut. This highlights the dynamic interplay between the pathogen, microbiota, and the host.

C. rodentium in Scientific Research

Using C. rodentium in labs provides a tool to understand intestinal infections. Because the infection in mice mimics human EPEC and EHEC infections, researchers can study the entire disease course in a controlled way. This allows investigation into how these A/E pathogens cause disease and how the host fights back.

Researchers use different mouse models to answer specific questions. For example, germ-free mice, which lack a gut microbiota, are useful for studying the direct interaction between the pathogen and the host. This approach helps identify how the host immune system responds to the pathogen.

Genetically modified mice also allow for precise study of host defense mechanisms. Scientists can use mice missing a gene for a particular immune cell or signaling molecule like IL-22. Observing how this absence affects infection helps determine the component’s role in fighting the pathogen.

This model system has helped uncover T3SS functions, identify effector protein roles, and map immune pathways that clear the infection. Knowledge from studying C. rodentium in mice provides a foundation for understanding human enteric diseases. These insights aid the development of new strategies to treat diarrheal illnesses caused by EPEC and EHEC.