Shiga Toxins as Multi-Functional Proteins: Induction of Host Cellular Stress Responses, Role in Pathogenesis and Therapeutic Applications

Abstract

Shiga toxins (Stxs) produced by Shiga toxin-producing bacteria Shigella dysenteriae serotype 1 and select serotypes of Escherichia coli are primary virulence factors in the pathogenesis of hemorrhagic colitis progressing to potentially fatal systemic complications, such as hemolytic uremic syndrome and central nervous system abnormalities. Current therapeutic options to treat patients infected with toxin-producing bacteria are limited. The structures of Stxs, toxin-receptor binding, intracellular transport and the mode of action of the toxins have been well defined. However, in the last decade, numerous studies have demonstrated that in addition to being potent protein synthesis inhibitors, Stxs are also multifunctional proteins capable of activating multiple cell stress signaling pathways, which may result in apoptosis, autophagy or activation of the innate immune response. Here, we briefly present the current understanding of Stx-activated signaling pathways and provide a concise review of therapeutic applications to target tumors by engineering the toxins.

Membrane assembly of Shiga toxin glycosphingolipid receptors and toxin refractiveness of MDCK II epithelial cells

“…Shiga toxins (Stxs) from pathogenic Stx-producing Escherichia coli (STEC) bind to lipid raft-associated GSL receptors on the surface of target cells, followed by endocytosis and retrograde transport to intracellular targets (32)(33)(34). Stx is the primary virulence factor of STEC that provokes life-threatening systemic complications and makes this pathogen a public health problem of serious concern (35)(36)(37)(38).…”

“…Furthermore, Stxs are capable of activating multiple cell stress signaling pathways (38,42). Protection of cells against Stxs can be provided either by inhibiting binding of the toxin to cells or by interfering with any of the subsequent steps required for its toxic effect (43).…”

Importance of flagella in acute and chronic Pseudomonas aeruginosa infections

“…Some highly pathogenic microorganisms pursue the strategy to express a few but very effective virulence factors (Lee et al, 2016;Chandrasekaran and Lacy, 2017;Fowler et al, 2017). In contrast, the success of the opportunistic pathogen P. aeruginosa can be attributed to a highly complex virulence-regulatory network (Balasubramanian et al, 2013).…”

Tumor necrosis factor-α modifies the effects of Shiga toxin on glial cells

“…In our present in vitro study, the combination of STX and TNF-α caused much greater damage to glial cells than TNF-α alone or STX alone (Fig.2-5). STX is multifunctional protein inducing protein biosynthesis inhibition and endoplasmic reticulum (ER) stress response [18]. ER stress is widely reported to induce apoptotic cell death [19].…”