Citrobacter rodentium: Infection and Inflammation in Focus

Citrobacter rodentium is a bacterial pathogen that primarily infects mice, serving as a key model for studying gastrointestinal infections. It shares similarities with human pathogens like enteropathogenic and enterohemorrhagic Escherichia coli, making it valuable for understanding host-pathogen interactions and disease mechanisms.

Research on this bacterium has advanced knowledge of infectious processes and immune responses in the gut. Its ability to trigger inflammation provides insight into conditions such as colitis and other inflammatory bowel diseases.

Classification And Characteristics

Citrobacter rodentium belongs to the Enterobacteriaceae family, a diverse group of Gram-negative bacteria that includes several notable human and animal pathogens. It is a facultative anaerobe, meaning it can survive in both oxygen-rich and oxygen-deprived environments, enhancing its adaptability within the gastrointestinal tract. Unlike commensal gut bacteria, C. rodentium possesses virulence factors that enable it to colonize the intestinal epithelium and disrupt normal gut function.

Its classification as an attaching and effacing (A/E) pathogen places it in the same category as enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic Escherichia coli (EHEC), which cause diarrheal diseases in humans. The defining characteristic of C. rodentium is its ability to form A/E lesions on the intestinal lining. These lesions result from the bacterium’s capacity to adhere to enterocytes and induce cytoskeletal rearrangements, leading to the effacement of microvilli. This process is mediated by a type III secretion system (T3SS), a molecular syringe-like apparatus that injects bacterial effector proteins directly into host cells, manipulating signaling pathways to facilitate adherence and persistence while compromising epithelial barrier integrity.

Genomic analyses reveal significant homology between C. rodentium and EPEC and EHEC, particularly in genes responsible for host colonization and virulence. While C. rodentium lacks the Shiga toxin genes found in EHEC, it retains mechanisms for epithelial attachment and immune evasion. Its natural host restriction to mice eliminates ethical and biosafety concerns associated with studying human-specific pathogens in vivo, making it an effective model for A/E bacterial infections.

Infectious Cycle

The infection process of Citrobacter rodentium begins with oral ingestion, typically through contaminated food or water. Once inside the host, the bacterium traverses the acidic environment of the stomach before reaching the distal colon, where it establishes colonization. Unlike many enteric pathogens that rely on toxin production, C. rodentium employs a strategy centered on epithelial attachment and modification. Using its type III secretion system (T3SS), it injects effector proteins into host cells, disrupting tight junction integrity and promoting actin cytoskeletal rearrangements to facilitate adherence while compromising barrier function.

Following attachment, C. rodentium proliferates along the intestinal surface, forming dense microcolonies characteristic of A/E pathogens. The bacterium’s ability to generate these lesions is mediated by the locus of enterocyte effacement (LEE) pathogenicity island, which encodes multiple virulence determinants essential for colonization. These lesions destroy microvilli, reducing absorptive capacity and altering electrolyte balance, contributing to diarrhea and weight loss in infected mice. The pathogen’s persistence is supported by its ability to subvert host cellular responses, maintaining a foothold in the gut.

As C. rodentium expands within the colonic niche, it engages in metabolic adaptation to outcompete resident microbiota. Studies show that it exploits host-derived nutrients such as fucose and sialic acid, which are liberated from epithelial cells during infection. This metabolic flexibility, coupled with its ability to modulate host cell function, ensures prolonged colonization. Shedding occurs through fecal excretion, allowing for environmental dissemination and potential reinfection.

Immune-Mediated Inflammation

The inflammatory response triggered by Citrobacter rodentium is shaped by bacterial virulence factors and the immune system’s efforts to contain the infection. As the pathogen adheres to the colonic epithelium and disrupts barrier integrity, the host detects microbial-associated molecular patterns (MAMPs) through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). This recognition activates nuclear factor kappa B (NF-κB) and other transcription factors, leading to the upregulation of pro-inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). These mediators recruit immune cells to the site of infection, amplifying inflammation and contributing to tissue pathology.

As neutrophils and monocytes infiltrate the colonic mucosa, they release reactive oxygen species (ROS) and antimicrobial peptides to limit bacterial proliferation. However, this aggressive immune response can exacerbate epithelial damage, leading to crypt hyperplasia and mucosal thickening—hallmarks of C. rodentium-induced colitis. The recruitment of T-helper 17 (Th17) cells further intensifies inflammation through the secretion of interleukin-17 (IL-17) and interleukin-22 (IL-22), which enhance epithelial regeneration but also sustain immune-driven tissue remodeling. IL-22 plays a dual role, promoting epithelial repair while fostering an environment that C. rodentium exploits for persistence. The balance between protective and pathological inflammation influences disease severity, with excessive immune activation potentially leading to long-term gut dysbiosis.

Significance In Comparative Gastroenterology

The study of Citrobacter rodentium provides valuable insights into host-microbe interactions within the gastrointestinal tract. Its ability to colonize the murine gut and induce pathology mirrors the effects of certain human pathogens, making it a widely used model for understanding bacterial-driven intestinal disease. Unlike many opportunistic bacteria that establish transient infections, C. rodentium follows a defined course of colonization, proliferation, and clearance, allowing researchers to dissect the sequential stages of disease progression in a controlled manner.

Comparative gastroenterology benefits from C. rodentium research by highlighting species-specific differences in intestinal structure and microbial composition. While the murine gut shares core similarities with the human intestine, differences in immune architecture, microbiota diversity, and epithelial turnover rates influence bacterial colonization dynamics and disease susceptibility. The bacterium’s reliance on host-derived nutrients such as fucose and sialic acid underscores the role of metabolic competition in enteric infections. By examining how C. rodentium exploits these resources in mice, researchers can infer mechanisms that similar pathogens may use in humans, shedding light on factors that drive pathogen persistence and gut dysbiosis.