UMMS Affiliation

Department of Microbiology and Physiological Systems; Program in Microbiome Dynamics; Department of Pathology; Horae Gene Therapy Center; Department of Molecular, Cell and Cancer Biology

Publication Date


Document Type



Amino Acids, Peptides, and Proteins | Bacterial Infections and Mycoses | Digestive System Diseases | Pathogenic Microbiology | Translational Medical Research


Shigella spp. are highly adapted pathogens that cause bacillary dysentery in human and nonhuman primates. An unusual feature of Shigella pathogenesis is that this organism invades the colonic epithelia from the basolateral pole. Therefore, it has evolved the ability to disrupt the intestinal epithelial barrier to reach the basolateral surface. We have shown previously that the secreted serine protease A (SepA), which belongs to the family of serine protease autotransporters of Enterobacteriaceae, is responsible for the initial destabilization of the intestinal epithelial barrier that facilitates Shigella invasion. However, the mechanisms used by SepA to regulate this process remain unknown. To investigate the protein targets cleaved by SepA in the intestinal epithelium, we incubated a sample of homogenized human colon with purified SepA or with a catalytically inactive mutant of this protease. We discovered that SepA targets an array of 18 different proteins, including alpha-1 antitrypsin (AAT), a major circulating serine proteinase inhibitor in humans. In contrast to other serine proteases, SepA cleaved AAT without forming an inhibiting complex, which resulted in the generation of a neutrophil chemoattractant. We demonstrated that the products of the AAT-SepA reaction induce a mild but significant increase in neutrophil transepithelial migration in vitro. Moreover, the presence of AAT during Shigella infection stimulated neutrophil migration and dramatically enhanced the number of bacteria invading the intestinal epithelium in a SepA-dependent manner. We conclude that by cleaving AAT, SepA releases a chemoattractant that promotes neutrophil migration, which in turn disrupts the intestinal epithelial barrier to enable Shigella invasion.

IMPORTANCE Shigella is the second leading cause of diarrheal death globally. In this study, we identified the host protein targets of SepA, Shigella's major protein secreted in culture. We demonstrated that by cleaving AAT, a serine protease inhibitor important to protect surrounding tissue at inflammatory sites, SepA releases a neutrophil chemoattractant that enhances Shigella invasion. Moreover, SepA degraded AAT without becoming inhibited by the cleaved product, and SepA catalytic activity was enhanced at higher concentrations of AAT. Activation of SepA by an excess of AAT may be physiologically relevant at the early stages of Shigella infection, when the amount of synthesized SepA is very low compared to the concentration of AAT in the intestinal lumen. This observation may also help to explain the adeptness of Shigella infectivity at low dose, despite the requirement of reaching the basolateral side to invade and colonize the colonic epithelium.


Shigella, alpha-1 antitrypsin, chemotaxis, gut inflammation, neutrophils, UMCCTS funding

Rights and Permissions

Copyright © 2021 Meza-Segura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

DOI of Published Version



Meza-Segura M, Birtley JR, Maldonado-Contreras A, Mueller C, Simin KJ, Stern LJ, McCormick BA. SepA Enhances Shigella Invasion of Epithelial Cells by Degrading Alpha-1 Antitrypsin and Producing a Neutrophil Chemoattractant. mBio. 2021 Dec 21;12(6):e0283321. doi: 10.1128/mBio.02833-21. Epub 2021 Nov 2. PMID: 34724811; PMCID: PMC8561385. Link to article on publisher's site

Journal/Book/Conference Title


Related Resources

Link to Article in PubMed

PubMed ID


Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.