Pro-Inflammatory Cytokines Enhanced In Vitro Cytotoxic Activity of Clostridioides difficile Toxin B in Enteric Glial Cells: The Achilles Heel of Clostridioides difficile Infection?

被引:2
作者
Fettucciari, Katia [1 ]
Spaterna, Andrea [2 ]
Marconi, Pierfrancesco [1 ]
Bassotti, Gabrio [3 ,4 ]
机构
[1] Univ Perugia, Dept Med & Surg, Biosci & Med Embryol Sect, I-06132 Perugia, Italy
[2] Univ Camerino, Sch Biosci & Vet Med, I-62024 Macerata, Italy
[3] Univ Perugia, Dept Med & Surg, Gastroenterol Hepatol & Digest Endoscopy Sect, I-06132 Perugia, Italy
[4] Santa Maria Della Misericordia Hosp, Gastroenterol & Hepatol Unit, I-06129 Perugia, Italy
关键词
Clostridioides difficile; Clostridioides difficile toxin B; apoptosis; necrosis; pro-inflammatory cytokines; tumor necrosis factor alpha; interferon gamma; inflammation; cytotoxicity; cell death; APOPTOSIS; TCDB;
D O I
10.3390/ijms25020958
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Bacterial infections are characterized by an inflammatory response, which is essential for infection containment but is also responsible for negative effects on the host. The pathogen itself may have evolved molecular mechanisms to antagonize the antimicrobial effects of an inflammatory response and to enhance its pathogenicity using inflammatory response mediators, such as cytokines. Clostridioides difficile (C. difficile) infection (CDI) causes gastrointestinal diseases with markedly increasing global incidence and mortality rates. The main C. difficile virulence factors, toxin A and B (TcdA/TcdB), cause cytopathic/cytotoxic effects and inflammation. We previously demonstrated that TcdB induces enteric glial cell (EGC) apoptosis, which is enhanced by the pro-inflammatory cytokine tumor necrosis factor alpha plus interferon gamma (CKs). However, it is unknown whether CKs-enhanced TcdB cytotoxicity (apoptosis/necrosis) is affected by the timing of the appearance of the CKs. Thus, we simulated in vitro, in our experimental model with TcdB and EGCs, three main situations of possible interactions between TcdB and the timing of CK stimulation: before TcdB infection, concomitantly with infection, or at different times after infection and persisting over time. In these experimental conditions, which all represent situations of possible interactions between C. difficile and the timing of CK stimulation, we evaluated apoptosis, necrosis, and cell cycle phases. The CKs, in all of these conditions, enhanced TcdB cytotoxicity, which from apoptosis became necrosis when CK stimulation persisted over time, and was most relevant after 48 h of TcdB:EGCs interaction. Particularly, the enhancement of apoptosis by CKs was dependent on the TcdB dose and in a less relevant manner on the CK stimulation time, while the enhancement of necrosis occurred always independently of the TcdB dose and CK stimulation time. However, since in all conditions stimulation with CKs strongly enhanced the TcdB cytotoxicity, it always had a negative impact on C. difficile pathogenicity. This study might have important implications for the treatment of CDI.
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共 55 条
[1]   Immune Profiling To Predict Outcome of Clostridioides difficile Infection [J].
Abhyankar, Mayuresh M. ;
Ma, Jennie Z. ;
Scully, Kenneth W. ;
Nafziger, Andrew J. ;
Frisbee, Alyse L. ;
Saleh, Mahmoud M. ;
Madden, Gregory R. ;
Hays, Ann R. ;
Poulter, Mendy ;
Petri, William A. Jr Jr .
MBIO, 2020, 11 (03)
[2]   Clostridium difficile Toxin Biology [J].
Aktories, Klaus ;
Schwan, Carsten ;
Jank, Thomas .
ANNUAL REVIEW OF MICROBIOLOGY, VOL 71, 2017, 71 :281-307
[3]   A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling [J].
Alphonse, Noemie ;
Wanford, Joseph J. ;
Voak, Andrew A. ;
Gay, Jack ;
Venkhaya, Shayla ;
Burroughs, Owen ;
Mathew, Sanjana ;
Lee, Truelian ;
Evans, Sasha L. ;
Zhao, Weiting ;
Frowde, Kyle ;
Alrehaili, Abrar ;
Dickenson, Ruth E. ;
Munk, Mads ;
Panina, Svetlana ;
Mahmood, Ishraque F. ;
Llorian, Miriam ;
Stanifer, Megan L. ;
Boulant, Steeve ;
Berchtold, Martin W. ;
Bergeron, Julien R. C. ;
Wack, Andreas ;
Lesser, Cammie F. ;
Odendall, Charlotte .
CELL, 2022, 185 (13) :2354-+
[4]   Global burden of Clostridium difficile infections: a systematic review and meta-analysis [J].
Balsells, Evelyn ;
Shi, Ting ;
Leese, Callum ;
Lyell, Iona ;
Burrows, John ;
Wiuff, Camilla ;
Campbell, Harry ;
Kyaw, Moe H. ;
Nair, Harish .
JOURNAL OF GLOBAL HEALTH, 2019, 9 (01)
[5]   Enteric glial cells and their role in gastrointestinal motor abnormalities: Introducing the neuro-gliopathies [J].
Bassotti, Gabrio ;
Villanacci, Vincenzo ;
Fisogni, Simona ;
Rossi, Elisa ;
Baronio, Paola ;
Clerici, Carlo ;
Maurer, Christoph A. ;
Cathomas, Gieri ;
Antonelli, Elisabetta .
WORLD JOURNAL OF GASTROENTEROLOGY, 2007, 13 (30) :4035-4041
[6]   Enteric glial cells: new players in gastrointestinal motility? [J].
Bassotti, Gabrio ;
Villanacci, Vincenzo ;
Antonelli, Elisabetta ;
Morelli, Antonio ;
Salerni, Bruno .
LABORATORY INVESTIGATION, 2007, 87 (07) :628-632
[7]   Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections [J].
Carter, Glen P. ;
Chakravorty, Anjana ;
Tu Anh Pham Nguyen ;
Mileto, Steven ;
Schreiber, Fernanda ;
Li, Lucy ;
Howarth, Pauline ;
Clare, Simon ;
Cunningham, Bliss ;
Sambol, Susan P. ;
Cheknis, Adam ;
Figueroa, Iris ;
Johnson, Stuart ;
Gerding, Dale ;
Rood, Julian I. ;
Dougan, Gordon ;
Lawley, Trevor D. ;
Lyras, Dena .
MBIO, 2015, 6 (03)
[8]   The role of toxins in Clostridium difficile infection [J].
Chandrasekaran, Ramyavardhanee ;
Lacy, D. Borden .
FEMS MICROBIOLOGY REVIEWS, 2017, 41 (06) :723-750
[9]   Toxins A and B from Clostridium difficile differ with respect to enzymatic potencies, cellular substrate specificities, and surface binding to cultured cells [J].
ChavesOlarte, E ;
Weidmann, M ;
vonEichelStreiber, C ;
Thelestam, M .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (07) :1734-1741
[10]   Clostridium difficile Toxins TcdA and TcdB Cause Colonic Tissue Damage by Distinct Mechanisms [J].
Chumbler, Nicole M. ;
Farrow, Melissa A. ;
Lapierre, Lynne A. ;
Franklin, Jeffrey L. ;
Lacy, D. Borden .
INFECTION AND IMMUNITY, 2016, 84 (10) :2871-2877