Reconstituting systemic immunity with hematopoietic stem cell transplantation remodels the human skin microbiome in DOCK8 deficiency

Summary: Abstract Body: The human skin microbiome (bacteria, fungi, viruses) exists in equilibrium with skin immunity. Studies have elucidated microbial influences on immunity, yet understanding how altered immunity perturbs the equilibrium remains limited. We investigated the dual impact of immune deficiency and hematopoietic stem cell transplantation (HSCT) on skin microbiomes in DOCK8 deficiency (n=24), a rare inborn error of immunity with impaired innate and adaptive immunity, eczema, chronic systemic/skin infections, and increased cancer risk. Analyzing 590 shotgun metagenomic and 534 16S rDNA sequencing samples before and after HSCT, we observed disrupted microbiota pre-HSCT (median eukaryotic viruses 67.6% vs. 0.04% in controls), with unique viral compositions and highly diverse human papillomaviruses (HPV) and polyomaviruses – including oncogenic viruses. Specific bacterial species also markedly changed. DNA euk. viral relative abundances markedly decreased (79.7%±28.3% to 4.9%±8.6%; P<0.01) 12 mos. post-HSCT, demonstrating the reconstituted immune system's role in viral control. Recovered microbial communities were relatively stable through 1-year follow-up with clearance of oncogenic HPV and without convergence with transplant donors’ microbiomes. Spatial transcriptomics of warts from a patient showed increased immune cell populations and activation of IFN-α/β and IFN-γ pathways post-HSCT, suggesting a robust immune response and decreased viral susceptibility. These results highlight the immune system’s critical role in restoring the skin microbial-host equilibrium. You Che¹, Jungmin Han¹, Catriona Harkins¹, Peng Hou¹, Sean Conlan¹, Clay Deming¹, Adel Amirkhani¹, Molly Bingham¹, Cassandra Holmes¹, Hanna Englander¹, Zeyang Shen¹, Leslie Castelo-Soccio¹, Stefania Pittaluga¹, Chen Zhao¹, Stefania Dell'Orso¹, Sung-Yun Pai¹, Dennis Hickstein¹, Steven Holland¹, Isaac Brownell¹, Keisuke Nagao¹, Corina Gonzalez¹, Nirali Shah¹, Alexandra Freeman¹, Helen Su¹, Julia Segre¹, Heidi H. Kong¹ 1. National Institutes of Health, Bethesda, MD, United States. Innate Immunity, Microbiology, and Microbiome