Human defects in STAT3 promote oral mucosal fungal and bacterial dysbiosis

Abstract

Studies in patients with genetic defects can provide unique insights regarding the role of specific genes and pathways in humans. Patients with defects in the Th17/IL-17 axis, such as patients harboring loss-of-function STAT3 mutations (autosomal-dominant hyper IgE syndrome; AD-HIES) present with recurrent oral fungal infections. Our studies aimed to comprehensively evaluate consequences of STAT3 deficiency on the oral commensal microbiome. We characterized fungal and bacterial communities in AD-HIES in the presence and absence of oral fungal infection compared with healthy volunteers. Analyses of oral mucosal fungal communities in AD-HIES revealed severe dysbiosis with dominance of Candida albicans (C. albicans) in actively infected patients and minimal representation of health-associated fungi and/or opportunists. Bacterial communities also displayed dysbiosis in AD-HIES, particularly in the setting of active Candida infection. Active candidiasis was associated with decreased microbial diversity and enrichment of the streptococci Streptococcus oralis (S. oralis) and S. mutans, suggesting an interkingdom interaction of C. albicans with oral streptococci. Increased abundance of S. mutans was consistent with susceptibility to dental caries in AD-HIES. Collectively, our findings illustrate a critical role for STAT3/Th17 in the containment of C. albicans as a commensal organism and an overall contribution in the establishment of fungal and bacterial oral commensal communities.

Integrated Analysis of Clinical and Microbiome Risk Factors Associated with the Development of Oral Candidiasis during Cancer Chemotherapy

“…Our findings suggest that when sufficiently abundant, these species might place this population at an increased risk for subsequent infection. There is mounting experimental and clinical evidence (observed by our group and others) of a pathogenic synergy or at least of a mutualistic relationship between C. albicans and the Mitis group streptococci [25,56,57,58]. However, this synergy is likely to be highly species-specific within members of this streptococcal group, since another Mitis group member ( S. infantis ) was less abundant in patients who later developed oral candidiasis.…”

The Dysbiosis and Inter-Kingdom Synergy Model in Oropharyngeal Candidiasis, a New Perspective in Pathogenesis

“…It is also worth noting that the effect of certain bacteriome members on infection risk was greater than the effect of the baseline proportions of C. albicans in the oral microbiome. Finally, in a recent study oral bacterial dysbiosis was implicated in oropharyngeal candidiasis in humans with hyper-IgE inflammatory syndrome, with S. oralis identified as the top abundant bacterial species during infection [55].…”

MicroRNA-127 Promotes Anti-microbial Host Defense through Restricting A20-Mediated De-ubiquitination of STAT3

“…Next, we sought to understand the mechanism exploited by miR-127 to regulate the production of anti-microbial effector molecules by macrophages. Because STAT3 signaling played an essential role in triggering IL-22 and subsequently AMPs production (Abusleme et al, 2018;Choi et al, 2013;Frey-Jakobs et al, 2018;Zhao et al, 2018), we wondered whether miR-127 would enhance anti-microbial response via modulating STAT3 activity. Indeed, our data demonstrated that miR-127 treatment significantly enhanced phosphorylation of STAT3, whereas knockdown of miR-127 suppressed its activation ( Figures 4A and 4B).…”

“…In response to infectious or inflammatory signals, STAT3 undergoes phosphorylation, homo-dimerization, and nuclear translocation to initiate the transcription of IL-22 and IL-17 (Ciofani et al, 2012). Loss-of-functional mutation of STAT3 led to impaired IL-17 and IL-22 expression and rendered hosts more susceptible to candidiasis and staphylococcal infection (Abusleme et al, 2018;Choi et al, 2013). In mice, myeloid STAT3 deficiency was causatively associated with chronic enterocolitis and endotoxic shock (Gao et al, 2018).…”