Biology subjects

Heaney, T.

Publications and source records attributed to Heaney, T..

3 recordsLinked to original sources

bioRxiv2026

Type I and III interferons synergize with TNF to promote virally-triggered damage to the intestinal epithelium

Excessive cell death in the epithelium due to prolonged immune activation is associated with intestinal diseases such as Crohns disease. Mice with mutations in the Crohns disease susceptibility gene Atg16l1 are susceptible to inflammation associated with intestinal epithelial cell (IEC) death, including loss of antimicrobial Paneth cells triggered by infection with murine norovirus (MNV). Here, we show that intestinal disease downstream of MNV depends on IFN-/{beta} and IFN-{lambda} signaling in IECs. In mouse organoids, IFNs synergize with TNF to induce RIPK1-dependent cell death, amplified by ATG16L1 deficiency. We further show that human intestinal organoids harboring the ATG16L1 risk allele exhibit heightened sensitivity to TNF and IFN co-stimulation and to serum from severe COVID-19 patients. Our findings reveal that virally triggered cytokines including IFNs exacerbate epithelial vulnerability in genetically predisposed hosts.

immunology↗

bioRxiv2023

Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization

Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA. Microbiota sensing by NOD2 in myeloid cells mediated IL-1{beta} secretion and increased the proportion of IL-22-producing CD4+ T helper cells and innate lymphoid cells. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.

immunology↗

bioRxiv2020

Enteric viruses evoke broad host immune responses resembling bacterial microbiome

Contributions of the viral component of the microbiome, the virome, to the development of innate and adaptive immunity are largely unknown. Here, we systematically defined the host response in mice to a panel of eukaryotic enteric viruses representing six different families. Most of these viruses asymptomatically infected the mice, the magnitude and duration of which was dependent on the microbiota. Flow cytometric and transcriptional profiling of mice mono-associated with these viruses unveiled general adaptations by the host, such as lymphocyte differentiation and IL-22 signatures in the intestine as well as numerous viral strain-specific responses that persist. Comparison with a dataset derived from analogous bacterial mono-association mice identified bacterial species that evoke an immune response comparable to the viruses we examined. These results expand an understanding of the immune space occupied by the enteric virome and underscore the importance of viral exposure events.

microbiology↗