Research ArticleHost-Pathogen Interactions

The Vibrio cholerae MARTX toxin silences the inflammatory response to cytoskeletal damage before inducing actin cytoskeleton collapse

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Science Signaling  14 Jan 2020:
Vol. 13, Issue 614, eaaw9447
DOI: 10.1126/scisignal.aaw9447

Why Vibrio cholerae infection is noninflammatory

The MARTX toxin of Vibrio cholerae (MARTXVc) forms a pore in the plasma membrane and translocates multiple toxin effector domains into intestinal epithelial cells (IECs). These include an actin cross-linking domain (ACD), a Rho inactivation domain (RID), and an α/β hydrolase domain (ABH), as well as a protease that releases these effectors into the host cytoplasm. Using human IECs in an in vitro model of infection, Woida and Satchell found that RID and ABH suppressed proinflammatory signaling that would otherwise have been activated by the cytoskeleton-damaging effects of ACD. These results reveal how the MARTXVc effector domains simultaneously promote virulence and suppress inflammatory responses and may explain why cholera is a noninflammatory disease.

Abstract

Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are pore-forming bacterial toxins that translocate multiple functionally independent effector domains into a target eukaryotic cell. Vibrio cholerae colonizes intestinal epithelial cells (IECs) and uses a MARTX toxin with three effector domains—an actin cross-linking domain (ACD), a Rho inactivation domain (RID), and an α/β hydrolase domain (ABH)—to suppress innate immunity and enhance colonization. We investigated whether these multiple catalytic enzymes delivered from a single toxin functioned in a coordinated manner to suppress intestinal innate immunity. Using cultured human IECs, we demonstrated that ACD-induced cytoskeletal collapse activated extracellular signal–regulated kinase, p38, and c-Jun amino-terminal kinase mitogen-activated protein kinase (MAPK) signaling to elicit a robust proinflammatory response characterized by the secretion of interleukin-8 (IL-8; also called CXCL8) and the expression of CXCL8, tumor necrosis factor (TNF), and other proinflammatory genes. However, RID and ABH, which are naturally delivered together with ACD, blocked MAPK activation through Rac1 and thus prevented ACD-induced inflammation. RID also abolished IL-8 secretion induced by heat-killed bacteria, TNF, or latrunculin A. Thus, MARTX toxins use enzymatic multifunctionality to silence the host response to bacterial factors and to the damage caused by the toxins. Furthermore, these data show how V. cholerae MARTX toxin suppresses intestinal inflammation and contributes to cholera being classically defined as a noninflammatory diarrheal disease.

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