Streptococcal species with high protease activity promote IL-4 expression and correlate with atopic dermatitis severity in infants

Summary: Abstract Body: The composition of the human skin microbiome in atopic dermatitis (AD) has been characterized almost exclusively in adults and has mainly focused on staphylococcal species such as S. aureus. While Streptococcus pyogenes commonly causes infections in children, and has been isolated from some children with AD, it has been shown that other streptococcal species are common isolates from the skin and mucosa of children under 6. It is unclear if these non-pyogenes species offer protection against or if they potentially contribute to AD flares. To evaluate this, skin swabs were collected from the face of 19 pediatric subjects with AD and 16 healthy controls. Swabs were then processed and analyzed using culture-based colony counting, qPCR, 16S rRNA community sequencing, and shotgun metagenomics. All techniques showed the absolute abundance of staphylococcal and streptococcal species was higher at AD-lesional skin compared to normal controls (p-value=0.0014). Further, functional analysis of live culture isolates revealed a strong correlation between disease severity and the presence of several different streptococcal species with high protease activity including the Zn-metalloprotease (gelE+) (P=0.0019). In a Balb/c MC903 AD mouse model, the application of streptococcal species with gelE+ activity induced elevated expression of both IL-17A and IL-4 mRNA (75.2-fold increase). In addition, streptococcal species with high gelE+ activity inhibited AMP expression (Camp) (43.6-fold decrease) compared to strains of the same streptococcal species without gelE- activity. These data suggest that in children, colonization with Streptococcal species other than S. pyogenes may contribute to AD flares by producing a metalloprotease that promotes its own survival, enhances the survival of other streptococcal species, and induces a potent type 2 inflammatory response. Sydney Dong¹, Teruaki Nakatsuji¹, Yang Chen¹, Richard L. Gallo¹, George Hightower^{1, 2} 1. Dermatology, University of California San Diego, La Jolla, CA, United States. 2. Dermatology, Rady Children's Hospital San Diego, San Diego, CA, United States. Innate Immunity, Microbiology, and Microbiome