Biology subjects

Amatullah, H.

Publications and source records attributed to Amatullah, H..

3 recordsLinked to original sources

bioRxiv2022

Immune chromatin reader SP140 regulates microbiota and risk for inflammatory bowel disease

Inflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Epigenetics facilitate integration of environmental cues for transcriptional output. However, evidence of epigenetic dysregulation directly causing host-commensal dysbiosis and IBD is lacking. Speckled Protein 140 (SP140) is an immune-restricted chromatin reader with homology to Autoimmune Regulator (AIRE). SP140 mutations associate with three immune diseases: Crohns disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL), but disease-causing mechanisms remain undefined. Here we identify a critical immune-intrinsic role for SP140 in preventing expansion of inflammatory Proteobacteria, including Helicobacter in mice and Enterobacteriaceae in humans. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis which was transmissible upon co-housing and ameliorated with antibiotics. SP140 was critical for calibration of macrophage microbicidal responses required for normal host-commensal crosstalk and elimination of invasive pathogens. Mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by the microbiome, such as IBD and MS.

immunology↗

bioRxiv2021

Human enteric viruses shape disease phenotype through divergent innate immunomodulation

Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found virus like particles (VLPs) enriched from normal human colon resections, containing eukaryotic viruses and bacteriophages (collectively, the virome), actively elicited atypical anti-inflammatory innate immune programs. Conversely, IBD patient VLPs provoked inflammation, which was successfully dampened by healthy VLPs. The IBD colon tissue virome was perturbed, including enriched Picornovirus Enterovirus B, not previously observed in fecal virome studies. Mice with humanized healthy colon tissue viromes had attenuated intestinal inflammation while those with IBD-derived viromes exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD-associated MDA5 loss-of-function on patient intestinal epithelial cells exposed to healthy or IBD viromes. Our results demonstrate that innate recognition of either healthy or IBD human viromes autonomously influences disease phenotypes in IBD. Harnessing the virome may offer therapeutic and biomarker potential. One Sentence SummaryHuman viromes divergently shape host immunity and disease

immunology↗

bioRxiv2021

Identification of topoisomerase as a precision-medicine target in chromatin reader SP140-driven Crohns disease

How mis-regulated chromatin directly impacts human immunological disease is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing chromatin reader whose loss-of-function associates with Crohns disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). However, mechanisms underlying SP140-driven pathogenicity and therapeutic approaches that rescue SP140 remain unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOP) that maintains heterochromatin and immune cell fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, genome instability, severely compromised lineage-defining and microbe-inducible innate transcriptional programs and defective bacterial killing. Pharmacological inhibition of TOP1 or TOP2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1 or TOP2 inhibitors in Sp140-/- mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a repressor of topoisomerases and reveal repurposing of TOP inhibition as a precision strategy for reversing SP140-driven immune disease.

immunology↗