Posttranslational Regulation of IL-23 Production Distinguishes the Innate Immune Responses to Live Toxigenic versus Heat-Inactivated <named-content content-type="genus-species">Vibrio cholerae</named-content>
ABSTRACT Vibrio cholerae infection provides long-lasting protective immunity, while oral, inactivated cholera vaccines (OCV) result in more-limited protection. To identify characteristics of the innate immune response that may distinguish natural V. cholerae infection from OCV, we stimulated differe...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2019-08-01
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| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSphere.00206-19 |
| _version_ | 1819041651555827712 |
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| author | Ana A. Weil Crystal N. Ellis Meti D. Debela Taufiqur R. Bhuiyan Rasheduzzaman Rashu Daniel L. Bourque Ashraful I. Khan Fahima Chowdhury Regina C. LaRocque Richelle C. Charles Edward T. Ryan Stephen B. Calderwood Firdausi Qadri Jason B. Harris |
| author_facet | Ana A. Weil Crystal N. Ellis Meti D. Debela Taufiqur R. Bhuiyan Rasheduzzaman Rashu Daniel L. Bourque Ashraful I. Khan Fahima Chowdhury Regina C. LaRocque Richelle C. Charles Edward T. Ryan Stephen B. Calderwood Firdausi Qadri Jason B. Harris |
| author_sort | Ana A. Weil |
| collection | DOAJ |
| description | ABSTRACT Vibrio cholerae infection provides long-lasting protective immunity, while oral, inactivated cholera vaccines (OCV) result in more-limited protection. To identify characteristics of the innate immune response that may distinguish natural V. cholerae infection from OCV, we stimulated differentiated, macrophage-like THP-1 cells with live versus heat-inactivated V. cholerae with and without endogenous or exogenous cholera holotoxin (CT). Interleukin 23A gene (IL23A) expression was higher in cells exposed to live V. cholerae than in cells exposed to inactivated organisms (mean change, 38-fold; 95% confidence interval [95% CI], 4.0 to 42; P < 0.01). IL-23 secretion was also higher in cells exposed to live V. cholerae than in cells exposed to inactivated V. cholerae (mean change, 5.6-fold; 95% CI, 4.4 to 11; P < 0.001). This increase in IL-23 secretion was more marked than for other key innate immune cytokines (e.g., IL-1β and IL-6) and dependent on exposure to the combination of both live V. cholerae and CT. While IL-23 secretion was reduced following stimulation with either heat-inactivated wild-type V. cholerae or a live isogenic ctxAB mutant of V. cholerae, the addition of exogenous CT restored IL-23 secretion in combination with the live isogenic ctxAB mutant V. cholerae, but not when it was paired with stimulation by heat-inactivated V. cholerae. The posttranslational regulation of IL-23 under these conditions was dependent on the activity of the cysteine protease cathepsin B. In humans, IL-23 promotes the differentiation of Th17 cells to T follicular helper cells, which maintain and support long-term memory B cell generation after infection. Based on these findings, the stimulation of IL-23 production may be a determinant of protective immunity following V. cholerae infection. IMPORTANCE An episode of cholera provides better protection against reinfection than oral cholera vaccines, and the reasons for this are still under study. To better understand this, we compared the immune responses of human cells exposed to live Vibrio cholerae with those of cells exposed to heat-killed V. cholerae (similar to the contents of oral cholera vaccines). We also compared the effects of active cholera toxin and the inactive cholera toxin B subunit (which is included in some cholera vaccines). One key immune signaling molecule, IL-23, was uniquely produced in response to the combination of live bacteria and active cholera holotoxin. Stimulation with V. cholerae that did not produce the active toxin or was killed did not produce an IL-23 response. The stimulation of IL-23 production by cholera toxin-producing V. cholerae may be important in conferring long-term immunity after cholera. |
| first_indexed | 2024-12-21T09:28:23Z |
| format | Article |
| id | doaj.art-4866f94033c54f77908b6cc981567724 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-12-21T09:28:23Z |
| publishDate | 2019-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-4866f94033c54f77908b6cc9815677242022-12-21T19:08:50ZengAmerican Society for MicrobiologymSphere2379-50422019-08-014410.1128/mSphere.00206-19Posttranslational Regulation of IL-23 Production Distinguishes the Innate Immune Responses to Live Toxigenic versus Heat-Inactivated <named-content content-type="genus-species">Vibrio cholerae</named-content>Ana A. Weil0Crystal N. Ellis1Meti D. Debela2Taufiqur R. Bhuiyan3Rasheduzzaman Rashu4Daniel L. Bourque5Ashraful I. Khan6Fahima Chowdhury7Regina C. LaRocque8Richelle C. Charles9Edward T. Ryan10Stephen B. Calderwood11Firdausi Qadri12Jason B. Harris13Infectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USAInfectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USAInfectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USAInfectious Diseases Division, International Center for Diarrheal Disease and Research, Bangladesh (icddr,b), Dhaka, BangladeshInfectious Diseases Division, International Center for Diarrheal Disease and Research, Bangladesh (icddr,b), Dhaka, BangladeshInfectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USAInfectious Diseases Division, International Center for Diarrheal Disease and Research, Bangladesh (icddr,b), Dhaka, BangladeshInfectious Diseases Division, International Center for Diarrheal Disease and Research, Bangladesh (icddr,b), Dhaka, BangladeshInfectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USAInfectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USAInfectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USAInfectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USAInfectious Diseases Division, International Center for Diarrheal Disease and Research, Bangladesh (icddr,b), Dhaka, BangladeshDepartment of Medicine, Harvard Medical School, Boston, Massachusetts, USAABSTRACT Vibrio cholerae infection provides long-lasting protective immunity, while oral, inactivated cholera vaccines (OCV) result in more-limited protection. To identify characteristics of the innate immune response that may distinguish natural V. cholerae infection from OCV, we stimulated differentiated, macrophage-like THP-1 cells with live versus heat-inactivated V. cholerae with and without endogenous or exogenous cholera holotoxin (CT). Interleukin 23A gene (IL23A) expression was higher in cells exposed to live V. cholerae than in cells exposed to inactivated organisms (mean change, 38-fold; 95% confidence interval [95% CI], 4.0 to 42; P < 0.01). IL-23 secretion was also higher in cells exposed to live V. cholerae than in cells exposed to inactivated V. cholerae (mean change, 5.6-fold; 95% CI, 4.4 to 11; P < 0.001). This increase in IL-23 secretion was more marked than for other key innate immune cytokines (e.g., IL-1β and IL-6) and dependent on exposure to the combination of both live V. cholerae and CT. While IL-23 secretion was reduced following stimulation with either heat-inactivated wild-type V. cholerae or a live isogenic ctxAB mutant of V. cholerae, the addition of exogenous CT restored IL-23 secretion in combination with the live isogenic ctxAB mutant V. cholerae, but not when it was paired with stimulation by heat-inactivated V. cholerae. The posttranslational regulation of IL-23 under these conditions was dependent on the activity of the cysteine protease cathepsin B. In humans, IL-23 promotes the differentiation of Th17 cells to T follicular helper cells, which maintain and support long-term memory B cell generation after infection. Based on these findings, the stimulation of IL-23 production may be a determinant of protective immunity following V. cholerae infection. IMPORTANCE An episode of cholera provides better protection against reinfection than oral cholera vaccines, and the reasons for this are still under study. To better understand this, we compared the immune responses of human cells exposed to live Vibrio cholerae with those of cells exposed to heat-killed V. cholerae (similar to the contents of oral cholera vaccines). We also compared the effects of active cholera toxin and the inactive cholera toxin B subunit (which is included in some cholera vaccines). One key immune signaling molecule, IL-23, was uniquely produced in response to the combination of live bacteria and active cholera holotoxin. Stimulation with V. cholerae that did not produce the active toxin or was killed did not produce an IL-23 response. The stimulation of IL-23 production by cholera toxin-producing V. cholerae may be important in conferring long-term immunity after cholera.https://journals.asm.org/doi/10.1128/mSphere.00206-19IL-23Vibrio choleraecholera |
| spellingShingle | Ana A. Weil Crystal N. Ellis Meti D. Debela Taufiqur R. Bhuiyan Rasheduzzaman Rashu Daniel L. Bourque Ashraful I. Khan Fahima Chowdhury Regina C. LaRocque Richelle C. Charles Edward T. Ryan Stephen B. Calderwood Firdausi Qadri Jason B. Harris Posttranslational Regulation of IL-23 Production Distinguishes the Innate Immune Responses to Live Toxigenic versus Heat-Inactivated <named-content content-type="genus-species">Vibrio cholerae</named-content> mSphere IL-23 Vibrio cholerae cholera |
| title | Posttranslational Regulation of IL-23 Production Distinguishes the Innate Immune Responses to Live Toxigenic versus Heat-Inactivated <named-content content-type="genus-species">Vibrio cholerae</named-content> |
| title_full | Posttranslational Regulation of IL-23 Production Distinguishes the Innate Immune Responses to Live Toxigenic versus Heat-Inactivated <named-content content-type="genus-species">Vibrio cholerae</named-content> |
| title_fullStr | Posttranslational Regulation of IL-23 Production Distinguishes the Innate Immune Responses to Live Toxigenic versus Heat-Inactivated <named-content content-type="genus-species">Vibrio cholerae</named-content> |
| title_full_unstemmed | Posttranslational Regulation of IL-23 Production Distinguishes the Innate Immune Responses to Live Toxigenic versus Heat-Inactivated <named-content content-type="genus-species">Vibrio cholerae</named-content> |
| title_short | Posttranslational Regulation of IL-23 Production Distinguishes the Innate Immune Responses to Live Toxigenic versus Heat-Inactivated <named-content content-type="genus-species">Vibrio cholerae</named-content> |
| title_sort | posttranslational regulation of il 23 production distinguishes the innate immune responses to live toxigenic versus heat inactivated named content content type genus species vibrio cholerae named content |
| topic | IL-23 Vibrio cholerae cholera |
| url | https://journals.asm.org/doi/10.1128/mSphere.00206-19 |
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