Koh Lab

Research Projects


Role of Mucosal Immunity in Preventing Candida albicans Infections

Candida albicans is an ubiquitous fungus that colonizes 50-60% of humans and is now the 4th leading cause of hospital-acquired infections.   Surgical patients, premature babies, and cancer patients are particularly prone to developing


Commensal microbial flora play a critical role in maintaining homeostasis in the mammalian gut.  Recent studies have shown that certain populations of commensal bacteria are critical for inducing host gastrointestinal epithelial cells to produce antimicrobial peptides (AMP, such as RegIIIγ) that are essential for maintaining microbial population equlibrium and homeostasis.  When commensal bacterial populations are disrupted via antibiotic therapy, AMP production is markedly diminished and certain microbial populations can overgrow and subsequently cause invasive disease. 


Adult mice can not be natively gastrointestinally (GI) colonized with the fungi, Candida albicans, yet neonatal mice and adult mice pre-treated with antibiotics can be sustainably colonized in the GI tract.  We have preliminary evidence that the presence of select commensal anaerobic bacteria are essential for maintaining a GI environment that leads to C. albicans GI colonization resistance.  We are now in the process of elucidating both the direct bacterial-fungal and bacterial-host mechanisms that prevent C. albicans from colonizing the adult mice GI tract.  By gaining insight into these mechanisms, we hope to apply these findings to human patients with hopes of preventing invasive C. albicans infections.


Bacterial-Fungal Interactions in the Gastrointestinal Tract

Human Microbiome Project is in the process of characterizing the microbial communities found at several different sites on the human body, including nasal passages, oral cavities, skin, gastrointestinal tract, and urogenital tract, and to analyze the role of these microbes in human health and disease.  Although the majority of the GI human microbiome is composed of bacteria, fungi and viruses (as well as some parasites) are also inhabitants of human GI tract.  Our lab is interested in how bacteria and fungi interact within the GI tract and whether these interactions lead to changes in pathogen virulence and/or host immunity.  Using C. albicans (as our representative fungi) and Pseudomonas albicans (as a representative bacteria), we have found that when both organisms
co-colonize the murine GI tract that GI colonization levels are not affected but the ability of either organism to disseminate and cause invasive disease is significantly attenuated.  We are now in the process of trying to elucidate the exact mechanisms by which each pathogen affects the other’s virulence pathways. 




Role of Keratinocyte Growth Factor on the Virulence of Candida albicans

Recent studies have shown that human growth factors and hormones may directly affect bacterial signalling pathways (e.g. epinephrine and norepinephrine activate quorum sensing systems in E. coli).  Despite the fact that fungi are eukaryotes and share many common signalling pathways with higher eukaryotes, there is little know about the effects of human growth factors and hormones on fungal virulence pathways.  In initial experiments, we have found that keratinocyte growth factor (a member of the fibroblast growth factor that is produced in response to epithelial cell damage and induces a reparative and regenerative effect) increases the virulence of C. albicans in a murine model of GI colonization and dissemination. KGF ap
pears to bind to the surface of C. albicans, increases the organism’s ability to transmigrate through a GI epithelial monolayer, increases C. albicans’s cytotoxic activity on human GI cells, and may also activate a C. albicans MAPK pathway critical for

controlling such essential virulence factors as morphogenesis, invasion, and response to oxidative stress. We are in the process of elucidating the exact mechanism of KGF-induced increased virulence in C. albicans.Furthermore, we have begun investigating whether FGF-10, a homolog of KGF which also binds and activates KGF-R, also enhances the virulence of C. albicans. The information learned from these studies may be critical in furthering our understanding of the interplay between host and pathogen that allow C. albicans to cause disseminated disease.


Role of Commensal Flora in the Acute GI Graft Versus Host Disease

Hematopoietic stem cell transplantation (HSCT) is a therapeutic modality becoming increasingly utilized in the treatment of many hematologic malignancies. Despite the potentially curative effect, graft versus host disease (GVHD), a complex immune-mediated process, remains a major cause of morbidity and mortality encountered in those undergoing HSCT, and therefore limits its use. The commensal gut flora has been implicated in initiating and perpetuating acute GVHD, but its role remains controversial. Previous studies have shown that bacterial components activate the innate immune system, leading to cytokine release and subsequent inflammation. In murine transplant models, intestinal GVHD (iGVHD) was accompanied by a

shift in the gut flora as well as an upregulation of pro-inflammatory cytokine ( IL-17, IL-23, TNF-α) secretion. No study to date has been published evaluating intestinal bacterial shifts during iGVHD in a clinical context. We hypothesize that disruption of the commensal gut flora r
esults in dysregulation of homeostatic innate immune defenses thereby allowing select enteric microbial populations to overgrow in the GI tract and potentially contribute to the development of acute iGVHD.  We plan to collect fecal samples of cancer and HSCT patients at various time points during treatment and perform bacterial and fungal pyrosequencing.  We will also collect and analyze intestinal biopsy samples in patients with verified iGVHD.  By identifying potential bacterial and fungal exacerbators of iGVHD and the mechanism by which they exert their deleterious effects, therapy could be designed to target specific organisms and/or inhibit the subsequent inflammatory cascade.