Skin microbiome imbalance in patients with STAT1/STAT3 defects impairs innate host defense responses

Abstract

Background: Chronic mucocutaneous candidiasis (CMC) and hyper-IgE syndrome (HIES) are primary immunodeficiencies mainly caused by mutations in STAT1 and STAT3, respectively. CMC and HIES patients have an increased risk for skin and mucosal infections with fungal pathogens and Staphylococcus aureus. However, it is unknown whether the genetic defects in these patients also affect the skin and mucosal microbiome, which in turn may influence host defense mechanisms.

Methods: The skin and oral microbiome of CMC and HIES patients was compared to that of healthy controls at five body sites using 16S rRNA sequencing. The influence of skin colonizers on the immune response was investigated using in vitro experiments.

Results: The microbiome of CMC and HIES patients contained more Gram-negative bacteria, especially Acinetobacter spp., and less of the normal Corynebacterium spp. compared to healthy controls. Exposure of human primary leukocytes to Acinetobacter suppressed the cytokine response to Candida albicans and S. aureus, while the normal corynebacteria did not suppress cytokine responses.

Discussion: These results demonstrate that central mediators of immune responses like STAT1 and STAT3 not only directly influence immune responses, but also result in changes in the skin microbiome that in turn can amplify the defective immune response against fungal and microbial pathogens.

Fig. 1

Covariance of skin and oral microbial community structure with disease subtype in immunodeficient patients. The variation in microbial diversity of 35 skin (a) and 21 oral samples (b) from healthy controls (green squares), and patients with CMC (red circles) and HIES (blue triangles). The principal coordinate plot uses the weighted UniFrac β-diversity metric, with the covariance of selected microbial taxa overlaid as a biplot. Organisms characteristic for the healthy skin samples are Staphylococcus and Corynebacterium spp., with Moraxellaceae spp. driving the different communities in disease.

Fig. 2

CMC and HIES patients are colonized by relatively little Gram (G)-positive bacteria. Mean percentage of Gram-positive and -negative bacteria per body site per group. Bars represent means + SEM from 1-10 subjects. HC = Healthy controls.

Fig. 3

Selected associations of microbial clade abundance with body site and disease subtype. A subset of taxa that significantly differs in relative abundance as determined by LEfSe between disease subtypes at skin (a) or oral body sites (b). Subclasses of disease subtype are separated, with specific body sites differentially colored. The mean and median relative abundance of the taxa are indicated with solid and dashed lines, respectively (LEfSe * p < 0.05).

Fig. 4

Acinetobacter suppress typical immune responses. PBMC of healthy volunteers were prestimulated for 24 h with RPMI, Corynebacterium, Acinetobacter or Staphylococcus, and stimulated with C. albicans or S. aureus for 1 or 7 days. Cytokine concentrations were measured in cell culture supernatants using ELISA. Bars represent means + SEM of 10 healthy volunteers (Wilcoxon * p < 0.05, ** p < 0.01).

Fig. 5

Acinetobacter suppresses TNF-α, IFNγ and IL-22. Proposed model of typical interactions between the microbiome and the immune system in healthy individuals (a) and STAT1/STAT3 immunodeficient patients (b).