Research ArticleImmunologyInfectious disease Open Access | 10.1172/JCI179563

Chih-Ming Tsai,1 Irshad A. Hajam,1 J.R. Caldera,1 Austin W.T. Chiang,2 Cesia Gonzalez,1 Xin Du,1 Biswa Choudhruy,3 Haining Li,4 Emi Suzuki,5,6 Fatemeh Askarian,7 Ty’Tianna Clark,8 Brian Lin,1 Igor H. Wierzbicki,9 Angelica M. Riestra,8 Douglas J. Conrad,10 David J. Gonzalez,9 Victor Nizet,7,9 Nathan E. Lewis,4,7 and George Y. Liu1,11

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

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1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

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1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

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1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

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1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

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1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

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1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

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1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Li, H. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Suzuki, E. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Askarian, F. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Clark, T. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Lin, B. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Wierzbicki, I. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Riestra, A. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Conrad, D. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Gonzalez, D. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Nizet, V. in: JCI | PubMed | Google Scholar |

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Lewis, N. in: JCI | PubMed | Google Scholar |

1Division of Infectious Diseases, Department of Pediatrics, University of California, La Jolla, California, USA.

2Immunology Center of Georgia and Department of Medicine, Augusta University, Augusta, Georgia, USA.

3Glycobiology Research and Training Center, UCSD, La Jolla, California, USA.

4Department of Bioengineering, University of California, La Jolla, California, USA.

5Division of Gastroenterology, Department of Pediatrics, UCSD, La Jolla, California, USA.

6Division of Gastroenterology, Rady Children’s Hospital, San Diego, California, USA.

7Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California, USA.

8Department of Biology, San Diego State University, San Diego, California, USA.

9Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA.

10Division of Pulmonary, Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.

11Division of Infectious Diseases, Rady Children’s Hospital, San Diego, California, USA.

Address correspondence to: George Y. Liu, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4119, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.2465830; Email: gyliu@health.ucsd.edu. Or to: Chih-Ming Tsai, Division of Infectious Diseases, Department of Pediatrics, UCSD, BRF2 Room 4220, Bay C, Gilman Drive, Mail Code 0760, La Jolla, California 92093, USA. Phone: 858.8225993; Email: c8tsai@health.ucsd.edu.

Find articles by Liu, G. in: JCI | PubMed | Google Scholar

Published December 16, 2024 - More info

Published in Volume 134, Issue 24 on December 16, 2024
J Clin Invest. 2024;134(24):e179563. https://doi.org/10.1172/JCI179563.
© 2024 Tsai et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published December 16, 2024 - Version history
Received: January 23, 2024; Accepted: October 9, 2024 View PDF Related article:

Abstract

Despite many attempts, there is currently no approved vaccine to prevent Staphylococcus aureus infections. Preclinical vaccination models have failed to predict vaccine efficacy in humans as S. aureus exposure in humans imprints an immune response that is lacking in naive animals. In this issue of the JCI, Tsai and colleagues identify the cytokine IL-10 as the driver of humoral imprinting by S. aureus. Upon vaccination, S. aureus–experienced animals produced copious levels of IL-10, resulting in the hyper-α2,3 sialylation of antibodies, which interfered with the phagocytic-promoting properties of the vaccine-elicited anti–S. aureus antibodies. These findings correlate with the observation that hyperproduction of IL-10 in humans also induces hyper-α2,3 sialylation of antibodies and provide a possible mechanism for previous vaccine failures.

Authors

× Abstract

The pathobiont Staphylococcus aureus (Sa) induces nonprotective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which Sa modifies antibody activity is not clear. Herein, we demonstrate that IL-10 is the decisive factor that abrogates antibody protection in mice. Sa-induced B10 cells drive antigen-specific vaccine suppression that affects both recalled and de novo developed B cells. Released IL-10 promotes STAT3 binding upstream of the gene encoding sialyltransferase ST3gal4 and increases its expression by B cells, leading to hyper-α2,3sialylation of antibodies and loss of protective activity. IL-10 enhances α2,3sialylation on cell-wall–associated IsdB, IsdA, and MntC antibodies along with suppression of the respective Sa vaccines. Consistent with mouse findings, human anti-Sa antibodies as well as anti-pseudomonal antibodies from cystic fibrosis subjects (high IL-10) are hypersialylated, compared with anti–Streptococcus pyogenes and pseudomonal antibodies from normal individuals. Overall, we demonstrate a pathobiont-centric mechanism that modulates antibody glycosylation through IL-10, leading to loss of staphylococcal vaccine efficacy.

Introduction

Staphylococcus aureus (Sa) is a leading agent of human bacterial skin, soft tissue, and invasive infections. The continual spread of antibiotic resistance, particularly in association with methicillin-resistant Sa (MRSA), has prompted a concerted effort to devise a viable human vaccine (1, 2). Despite the demonstrated efficacy of numerous anti-Sa vaccine candidates in naive mice, approximately 30 human clinical trials have failed to yield a functional vaccine (1, 2), for unclear reasons. Laboratory animals are predominantly naive to human Sa, which stands in stark contrast to humans who encounter Sa from early infancy onward (3). As a superbly adapted “pathobiont,” Sa has evolved intricate mechanisms facilitating its coexistence with the host (4–7).

Our prior work has revealed that Sa modification of its own surface peptidoglycan blunts the host’s development of anti-staphylococcal Th17 immunity, thereby permitting subsequent Sa infections to proceed without a reduction in pathogen burden (8). Consequently, we posit that anti-Sa vaccines developed in naive rodents may inadequately recapitulate trial outcomes in human who have prior exposure to Sa. In a recent investigation, we demonstrated that prior infections induced by i.p., i.v., or s.c. Sa administration impede the effectiveness of the subsequently administered IsdB vaccine (9). Our findings indicated that Sa infections generate nonprotective antibody imprints that, upon IsdB vaccination, lead to suboptimal vaccine responses (9). Furthermore, we have extended these observations to vaccines targeting 5 other Sa cell-wall–associated antigens (9, 10). Thus, imprinting emerges as a plausible explanation for the widespread failure of Sa vaccines.

While we had established that humoral imprinting interferes with effective vaccination, the mechanism by which the pathobiont Sa renders anti-Sa antibodies ineffectual across a spectrum of vaccines remained unclear. Our prior study found that IsdB antibodies exhibited nonprotective characteristics, primarily as they preferentially targeted the nonneutralizing NEAT1 domain of IsdB (9). Additionally, IsdB antibodies displayed elevated α2,3 sialylation, which impeded opsonophagocytosis (9).

Glycosylation of the IgG-Fc plays a pivotal role in regulating antibody function through Fc-mediated effector functions (11). Generally, IgGs lacking galactose (agalactosylated), fucose (afucosylated), or carrying bisecting GlcNAc modifications are associated with enhanced proinflammatory properties. In contrast, galactosylated and sialylated IgGs are correlated with attenuated inflammatory responses (12, 13). Moreover, sialylated IgG is linked to immunosuppressive effector functions (14–16). Modified IgG glycosylation is linked to autoimmunity and persistent infection and has a reported role in modulating the inflammatory cytokine profile (17). Some reports have demonstrated a direct role of cytokines in antibody glycosylation that leads to functional consequences. For example, IL-23 directs antibody glycosylation that promotes inflammation (18). Conversely, in CD8+ T cells, IL-10 enhances N-glycan branching to decrease antigen sensitivity in a cytomegalovirus infection model (19).

Given the broad effect of cytokines and their reported roles in the regulation of glycan expression, we investigate here the hypothesis that a cytokine induced by Sa regulates antibody glycosylation, thereby promoting a generalized inefficacy of Sa vaccines.

Results

Sa-induced IL-10 impacts IsdB antibody protective function. To investigate our hypothesis linking a Sa-induced cytokine response to antibody glycosylation, we initially examined the cytokine milieu associated with effective and noneffective vaccine antibody responses in naive and Sa-exposed mice, respectively. For this analysis, we used the well-characterized