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NIH grant 1K99AI202747-01: Defining how Bacterial-Sensing Caspases Regulate RNA Metabolism and Immunity
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Christopher Bourne. Award: $147166.
Start: 2026-09-25T00:00:00.
PROJECT SUMMARY AND ABSTRACT
The innate immune system serves as the first line of defense against pathogenic infections, but many gaps in
our knowledge of innate immune signaling pathways remain. Gram-negative bacteria, like Salmonella or E. coli
contain lipopolysaccharide (LPS) in their cell walls that can induce septic shock and provide antibiotic
resistance. When a human cell is invaded by gram-negative bacteria, the LPS-sensing caspases -4 and -5
(CASP4/5) are activated and cleave protein substrates to induce innate immunity. The full repertoire of
substrates for CASP4/5 remains poorly characterized. Dr. Bourne has discovered a novel mechanism of host
defense in which human CASP4/5, cleave the RNA-binding protein (RBP) heterogenous nuclear
ribonucleoprotein K (hnRNPK) during gram-negative bacterial infections. Furthermore, CASP5 demonstrates a
unique ability to cleave multiple other RBPs that CASP4 cannot, providing the first ever evidence for a unique
function of CASP5. This is a paradigm-shifting discovery as RBPs were not previously recognized as CASP4/5
substrates. The central hypothesis of this proposal is that CASP4/5-mediated cleavage of RBPs is a critical
regulatory step in innate immune responses, modulating both RNA metabolism and cell fate to promote host
defense. Dr. Bourne will test this hypothesis through three specific aims: (1) Evaluate the functional impact of
RBP cleavage on RNA metabolism and immunity using CRISPR/Cas9-edited cell lines; (2) Determine the
molecular and structural mechanism of RBP recognition and processing by CASP4/5 using cryo-electron
microscopy; and (3) Uncover the unique role of human CASP5 in RBP cleavage and its contribution to immune
defense using a novel transgenic mouse model. The K99 phase will provide the necessary advanced training
and mentorship for Dr. Bourne to master advanced techniques in splicing profiling, transcriptomics and
structural biology, while the R00 phase will launch an independent research program focused on this new and
exciting area of inquiry at the intersection of RNA biology and immunology. Completion of this work will lay the
foundation for a new field of study and provide novel insights for developing effective therapeutic strategies
against infectious diseases like sepsis.document fetched 2026-10-04 02:43