The Host-Microbiome Cross-Talks: the Role of T Cell Functional Diversity in Staphylococcal Colonization

Recent studies on the gut microbiota has revealed that the microbial community co-evolves with human hosts and contributes to the development of the host immune system, both locally and systematically.[2] For example, certain bacterial species was found to enhance the host resistance to Staphylococcal in the host lung tissue, decreasing associated host mortality.[3] On the contrary, how the skin microbiome interacts with the host immunity remains less explored. Meanwhile, psoriasis patients on therapeutic biologics can provide a suitable clinical model to observe the host immune responses to exogenous perturbations and how such disturbance subsequently leads to changes in the skin microbiota and dominant colonizing pathogens such as Staphylococcus aureus (S. aureus). Ustekinumab is an IL12/23 monocloncal antibody and has been approved by FDA for the treatment of moderate to severe psoriasis in 2009.[4] Nevertheless, how Ustekinumab influences other immune correlates, such as Th1- or Th2-axis functions and the proliferation or differentiation of keratinocytes remains unknown.[5] Previous studies have shown that, Th1 and Th17 cells derived from peripheral blood of healthy volunteers would generate IL12/IL23 upon exposure to Staphylococcal cell wall component,[6] which could lead to the subsequent secretion of anti-inflammatory cytokine such as IL17A and IL22;[7, 8] the latter two would further stimulate keratinocytes for an increased production of antimicrobial peptide (AMP) and neutrophil influx to the inflamed epithelial layers for pathogen killing.[9] Despite the continual efforts on developing anti-staphylococcal vaccines, most vaccine trials have failed due to prior focus on the host humoral rather than cellular immunity against bacterial surface antigens and toxins.[6, 10] An accumulating body of knowledge on Th17 cells has suggested its importance for protective immunity against S. aureus.[10] The advancement of high-throughput sequencing technology and relevant computing algorithm for parsing out T cell receptor sequence reads from targeted RNA sequencing experiments has enabled investigators to examine and compare the functional diversity of immune cell repertoire within each individual.[13] In the proposed work, we aim to compare, in psoriasis patients before and after the treatment with Ustekinumab, the following temporal changes in (1) the functional diversity of T cell receptor repertoire; (2) the differentiation/ proliferation of keratinocytes and its innate immune functions by quantifying relevant gene expression; (3) the structure and abundance of the skin microflora, as well as the inter-relationships among these key players. We hypothesize that, in psoriasis patients before treatment, we will observe a biased T cell functional repertoire with a reduced diversity, with a concomitantly lower microbial diversity because of a dominant colonizing pathogen. After treatment, we expect to see changes in keratinocyte differentiation and its antimicrobial function, followed by an altered T cell repertoire in response to dominant members of the re-established skin microbiota. Specifically, we hypothesize that the abovementioned sequential changes will differ by colonization status at the skin lesions.

Project ID:PC10601-0867
External Project ID:MOST105-2628-B182-006-MY2