Epsilon toxin–producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS immune privilege
Yinghua Ma, David Sannino, Jennifer R. Linden, Sylvia Haigh, Baohua Zhao, John B. Grigg, Paul Zumbo, Friederike Dündar, Daniel Butler, Caterina P. Profaci, Kiel Telesford, Paige N. Winokur, Kareem R. Rumah, Susan A. Gauthier, Vincent A. Fischetti, Bruce A. McClane, Francisco A. Uzal, Lily Zexter, Michael Mazzucco, Richard Rudick, David Danko, Evan Balmuth, Nancy Nealon, Jai Perumal, Ulrike Kaunzner, Ilana L. Brito, Zhengming Chen, Jenny Z. Xiang, Doron Betel, Richard Daneman, Gregory F. Sonnenberg, Christopher E. Mason, Timothy Vartanian
Yinghua Ma, David Sannino, Jennifer R. Linden, Sylvia Haigh, Baohua Zhao, John B. Grigg, Paul Zumbo, Friederike Dündar, Daniel Butler, Caterina P. Profaci, Kiel Telesford, Paige N. Winokur, Kareem R. Rumah, Susan A. Gauthier, Vincent A. Fischetti, Bruce A. McClane, Francisco A. Uzal, Lily Zexter, Michael Mazzucco, Richard Rudick, David Danko, Evan Balmuth, Nancy Nealon, Jai Perumal, Ulrike Kaunzner, Ilana L. Brito, Zhengming Chen, Jenny Z. Xiang, Doron Betel, Richard Daneman, Gregory F. Sonnenberg, Christopher E. Mason, Timothy Vartanian
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Research Article Autoimmunity Microbiology

Epsilon toxin–producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS immune privilege

Abstract

Multiple sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specific causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin–producing (ETX-producing) strains of C. perfringens within their gut microbiomes compared with individuals who are healthy controls (HCs). Isolates derived from patients with MS produced functional ETX and had a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution seen in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.

Authors

Yinghua Ma, David Sannino, Jennifer R. Linden, Sylvia Haigh, Baohua Zhao, John B. Grigg, Paul Zumbo, Friederike Dündar, Daniel Butler, Caterina P. Profaci, Kiel Telesford, Paige N. Winokur, Kareem R. Rumah, Susan A. Gauthier, Vincent A. Fischetti, Bruce A. McClane, Francisco A. Uzal, Lily Zexter, Michael Mazzucco, Richard Rudick, David Danko, Evan Balmuth, Nancy Nealon, Jai Perumal, Ulrike Kaunzner, Ilana L. Brito, Zhengming Chen, Jenny Z. Xiang, Doron Betel, Richard Daneman, Gregory F. Sonnenberg, Christopher E. Mason, Timothy Vartanian

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Figure 5

ETX-EAE is characterized by multifocal demyelination in the CNS.

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ETX-EAE is characterized by multifocal demyelination in the CNS. (A) ETX...
(A) ETX-EAE mice developed atypical EAE, which is characterized by ataxia, along with classical EAE symptoms defined by ascending paralysis. Same treatment conditions as in Figure 4, CFA/MOG35-55 followed by ETX (ETX-EAE) or PTX (PTX-EAE). (B) ETX targets broader brain regions compared with PTX including cerebellum (Ceb) and corpus callosum (cc). ETX-EAE mice (left column) exhibit more focal demyelinating lesions (arrowheads and red dashed circles) in the cerebellum and corpus callosum within WM tracts when compared with PTX-EAE mice (right column). Asterisk in lower row indicates demyelinated cc. Black arrows indicate borders of a cc lesion, which is also framed with a red dashed rectangle. A corresponding location in PTX- EAE mice (right column) is indicated by white arrows. Regions framed with black boxes are shown at high magnification in inserts. (C) Quantification of lesions in the cerebellum and corpus collosum. Data in A are mean ± SEM, and data in C represent median ± range; Kruscal-Wallis test (nonparametric). n = 4 mice for PBS > PTX and PBS > ETX-Hi controls, n = 6 mice for MOG > ETX-Lo, and n = 8 mice for groups including MOG > PTX and MOG > ETX-Hi. NS, not significant. Scale bars: 1 mm in B and 100 μm in the inserts. Similar results were achieved in 2 independently repeated experiments.