[F31] Mucinases of Pathogenic Bacilli
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-08-07
Importo max: $50,114
Paese: US
Descrizione
Project Summary
Bacillus anthracis is the causative agent of gastrointestinal (GI) anthrax, a disease that affects all mammals
including humans, but whose pathogenesis is poorly understood. Specifically, the mechanism of invasion
across the protective mucus layers of the GI tract in order to disseminate is unknown. Examination of the
genome of B. anthracis revealed the presence of putative mucinases, proteases that are capable of degrading
the dense O-glycosylated sugars typically founded in mucus and the mucin-like glycosyl modifications integral
to eukaryotic cell surface receptors and some secreted immune effectors. We have so far characterized SmuA,
a mucinase of B. anthracis that is able to degrade a wide variety of mucin-like glycoproteins and purified GI
mucus from mice. Preliminary sequence analysis revealed a M60 peptidase domain and a single putative
mucin-/carbohydrate-binding domain. However, structural similarity search revealed the presence of two
additional carbohydrate binding domain (CBD) that we propose may play a role in substrate recognition. This
application seeks to further characterize SmuA to understand the substrate specificity of its three CBDs and
how this alters substrate specificity. In both subcutaneous and GI models of infection in mice, deletion of smuA
significantly promotes survival. However, the mechanism by which smuA deletion does this is still unknown.
Therefore, we seek to reveal how deletion of smuA in B. anthracis enables this defect in both models of
disease progression, but especially its role in initial invasion of the GI tract. Additionally, we propose expanding
this analysis to a putative mucinase found in a close neighbor of B. anthracis, another anthrax-causing strain
called Bacillus cereus G9241. This bacterium was isolated from a welder in Louisiana suffering from pulmonary
anthrax and sequence analysis revealed the presence of a putative mucinase that we named Bc-SmuB.
Interestingly, we identified the remnant of a smuB pseudogene in B. anthracis. Therefore, we propose to begin
the characterization of Bc-SmuB in a similar manner to SmuA and compared our findings. The ultimate goal of
this research is to characterize important effectors of B. anthracis that promote the progression of anthrax
infections.
Istituzione: UNIVERSITY OF CHICAGO
PI: Amanda Blocker
Progetto: 1F31AI203055-01
Settori: National Institute of Allergy and Infectious Diseases
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