Candida albicans Colonizes and Disseminates to the Gastrointestinal Tract in the Presence of the Microbiota in a Severe Combined Immunodeficient Mouse Model

Abstract

Candida albicans is the leading cause of candidemia or other invasive candidiasis. Gastrointestinal colonization has been considered as the primary source of candidemia. However, few established mouse models that mimic this infection route are available. In the present study, we established a mouse model of disseminated candidiasis developed through the translocation of Candida from the gut. In this study, we developed a novel C. albicans GI colonization and dissemination animal model by using severe combined immunodeficient Rag2–/–IL2γc–/– (Rag2γc) mice, which lack functional T, B, NK cells, and IL2γc-dependent signaling. Rag2γc mice were highly susceptible to C. albicans gastrointestinal infection even in the presence of the gut microbiota. Within 4 weeks post infection, Rag2γc mice showed dose-dependent weight loss and disseminated candidiasis in more than 58% (7/12) of moribund mice. Histological analysis demonstrated abundant hyphae penetrating the mucosa, with significant neutrophilic infiltration in mice infected with wild-type C. albicans but not a filamentation-defective mutant. In moribund Rag2γc mice, the necrotic lesions and disrupted epithelial cells were associated with C. albicans hyphae. Notably, removal of the gut microbiota by antibiotics exacerbated the severity of fungal infection in Rag2γc mice, as demonstrated by elevated fungal burdens and accelerated weight loss and death. Furthermore, higher fungal burden and IL-1β expression were prominently noted in the stomach of Rag2γc mice. In fact, a significant increase in circulating proinflammatory cytokines, including IL-6, TNF-α, and IL-10, indicative of a septic response, was evident in infected Rag2γc mice. Additionally, Rag2γc mice exhibited significantly lower levels of IL-22 but not IFN-γ or IL-17A than wild-type B6 mice, suggesting that IL-22 plays a role in C. albicans gastrointestinal infection. Collectively, our analysis of the Rag2γc mouse model revealed features of C. albicans gastrointestinal colonization and dissemination without the interference from antibiotics or chemotherapeutic agents, thus offering a new investigative tool for delineating the pathogenesis of C. albicans and its cross-talk with the gut microbiota.

Microbiota signatures associated with invasive Candida albicans infection in the gastrointestinal tract of immunodeficient mice

“…In addition, obvious tissue damage, including epithelial hyperplasia and erosion accompanied by hyphal fungi, was found in the stomach of SC5314-infected mice, but neither hyperplasia nor tissue-associated fungi were observed in HLC54-infected mice ( Figure 1D ). Our data suggest that SC5314- but not HLC54-infected Rag2γc mice developed gastric candidiasis at 12 days post-infection, similar to our previous findings, which revealed that SC5314-infected Rag2γc mice exhibit signs of invasive infection, with 58% positive results in kidney/liver cultures within 2-3 weeks post-infection ( Pan et al., 2020 ).…”

“…To investigate the gut bacterial changes caused by C. albicans infection, we designed animal experiments according to previous reports ( Pan et al., 2020 ) and collected stool samples before infection and at 5 and 12 days post-infection (to represent the time of introduction and invasion, respectively) for bacterial 16S rRNA gene sequencing ( Figure 1A ). The colonization of C. albicans in the gut was confirmed by measuring the fungal counts in the feces.…”

“…We previously demonstrated successful colonization of C. albicans in the gut without antibiotic pretreatment using a severe immunodeficient mouse ( Rag2 -/- il2γc -/- ; Rag2γc), where indigenous C. albicans invasion is observed within 2-3 weeks after infection ( Pan et al., 2020 ). The high susceptibility of Rag2γc mice to C. albicans has been attributed to the impaired IL-17A and IL-22 response due to the absence of functional T, B, and NK cells ( Colucci et al., 1999 ), including type-3 innate lymphoid cells ( Van Maele et al., 2014 ).…”

From intestinal colonization to systemic infections: Candida albicans translocation and dissemination

“…These studies and others also show that invading C. albicans hyphae produce substantial host damage that allows for material to pass through the barrier, potentially leading to translocation via mechanical lesions. 13 , 14 , 59 This degree of epithelial damage during translocation in vivo is likely given that there is an expansion of Candida spp. just prior to bloodstream infections along with a decrease in the total bacterial burden.…”

The Role of Host and Fungal Factors in the Commensal-to-Pathogen Transition of Candida albicans

“…Several studies provide evidence that the human gastrointestinal (GI) tract serves as a source for systemic candidiasis [ 13 , 14 ••, 95 ]. This concept is supported by studies using mice, which demonstrate that C. albicans can translocate from the murine GI tract and establish systemic infection in severely immunocompromised animals [ 96 – 98 ]. In vitro interaction of C. albicans with enterocytes is similar to the interaction with other types of epithelial cells, with adhesion being followed by hypha formation, invasion, and damage driven by candidalysin [ 99 •].…”