Mechanisms of bacillary dysentery: lessons learnt from infant rabbits

Abstract

The bacterial pathogen Shigella flexneri causes more than 250 million cases of bacillary dysentery (blood in stool) every year across the world. This human-specific disease is characterized by profuse bloody diarrhea, dramatic ulceration of the colonic epithelium and immune cell infiltration of the colonic tissue. A major challenge in understanding the mechanisms supporting bacillary dysentery is the reliance on animal models that do not fully recapitulate the symptoms observed in humans, including bloody diarrhea. Here we outline advances provided by a recently developed infant rabbit model of bacillary dysentery. The infant rabbit model defines bacillary dysentery as a critical combination of massive vascular lesions and dramatic epithelial fenestration due to intracellular infection and cell-to-cell spread, respectively. The infant rabbit model provides an unprecedented framework for understanding how the cell biology of Shigella flexneri infection relates to pathogenesis.

Keywords: Shigella flexneri; T3SS; bacillary dysentery; cell-to-cell spread; epithelial fenestration; rabbit; vascular lesion.

Figure 1.

The Cell Biology of S. flexneri. (a) (1) S. flexneri (blue) utilizes its T3SS to trigger its own uptake into epithelial cells (green). (2) S. flexneri escapes primary vacuoles and gains access to the cytosol. (3) S. flexneri hijacks cytoskeleton components and displays actin-based motility. (4) At cell-cell contacts, motile S. flexneri forms membrane protrusions that (5) resolve into secondary (double-membrane) vacuoles. (6) S. flexneri escapes secondary vacuoles and (7) gains access to the cytosol of adjacent cells, where (8) it resumes actin-based motility. (b) Top. Wild type S. flexneri (WT) invades epithelial cells, grows and divides. Concurrently, bacteria acquire actin-based motility and spread from cell to cell, leading to the formation of infection foci. Bottom. The spreading-defective mutant ΔicsA invades epithelial cells, grows and divides, similar to wild type bacteria. The ΔicsA mutant does not acquire actin-based motility and consequently does not spread from cell to cell.

Figure 2.

Connecting Cell Biology and pathogenesis. (a) Representative images of hematoxylin- and eosin-stained colonic mucosa of infant rabbit colon infected with wild type S. flexneri (top) and the ΔicsA mutant (bottom). EC, epithelial cell; RBC red blood cell. Dotted lines delineate crypts. Scale bar, 50 μm. (b) Top. Wild type S. flexneri (blue) invades the colonic epithelium (green). Middle. Wild type bacteria spread from cell to cell. Intracellular infection leads to vascular lesions and red blood cell infiltration (red). Bottom. The combination of epithelial fenestration due to cell-to-cell spread and red blood cell infiltration leads to bloody diarrhea. (c) Top. The ΔicsA mutant (blue) invades the colonic epithelium (green). Middle. The ΔicsA mutant does not spread from cell to cell and grows as macro-colonies. Intracellular infection leads to vascular lesions and red blood cell infiltration (red). Bottom. In absence of cell-to-cell spread, cells infected with the ΔicsA mutant are eliminated, presumably through extrusion. The epithelial structure remains intact, and the animals do not experience bloody diarrhea, or any signs of illness.