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933 results on '"Mekalanos, John J."'

2. Gut complement induced by the microbiota combats pathogens and spares commensals

Author

Wu, Meng, Zheng, Wen, Song, Xinyang, Bao, Bin, Wang, Yuanyou, Ramanan, Deepshika, Yang, Daping, Liu, Rui, Macbeth, John C., Do, Elyza A., Andrade, Warrison A., Yang, Tiandi, Cho, Hyoung-Soo, Gazzaniga, Francesca S., Ilves, Marit, Coronado, Daniela, Thompson, Charlotte, Hang, Saiyu, Chiu, Isaac M., Moffitt, Jeffrey R., Hsiao, Ansel, Mekalanos, John J., Benoist, Christophe, and Kasper, Dennis L.

Published
2024
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3. CBASS Immunity Uses CARF-Related Effectors to Sense 3′–5′- and 2′–5′-Linked Cyclic Oligonucleotide Signals and Protect Bacteria from Phage Infection

Author

Lowey, Brianna, Whiteley, Aaron T, Keszei, Alexander FA, Morehouse, Benjamin R, Mathews, Ian T, Antine, Sadie P, Cabrera, Victor J, Kashin, Dmitry, Niemann, Percy, Jain, Mohit, Schwede, Frank, Mekalanos, John J, Shao, Sichen, Lee, Amy SY, and Kranzusch, Philip J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Amino Acid Sequence, Bacteria, Bacterial Proteins, Bacteriophages, CRISPR-Cas Systems, Deoxyribonuclease I, Immunity, Ligands, Mutagenesis, Nucleotidyltransferases, Oligonucleotides, Protein Binding, Second Messenger Systems, Signal Transduction, CARF, CBASS antiphage immunity, CD-NTase, SAVED, nucleotide second messenger, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzymes are immune sensors that synthesize nucleotide second messengers and initiate antiviral responses in bacterial and animal cells. Here, we discover Enterobacter cloacae CD-NTase-associated protein 4 (Cap4) as a founding member of a diverse family of >2,000 bacterial receptors that respond to CD-NTase signals. Structures of Cap4 reveal a promiscuous DNA endonuclease domain activated through ligand-induced oligomerization. Oligonucleotide recognition occurs through an appended SAVED domain that is an unexpected fusion of two CRISPR-associated Rossman fold (CARF) subunits co-opted from type III CRISPR immunity. Like a lock and key, SAVED effectors exquisitely discriminate 2'-5'- and 3'-5'-linked bacterial cyclic oligonucleotide signals and enable specific recognition of at least 180 potential nucleotide second messenger species. Our results reveal SAVED CARF family proteins as major nucleotide second messenger receptors in CBASS and CRISPR immune defense and extend the importance of linkage specificity beyond mammalian cGAS-STING signaling.

Published
2020

4. Structure and Mechanism of a Cyclic Trinucleotide-Activated Bacterial Endonuclease Mediating Bacteriophage Immunity

Author

Lau, Rebecca K, Ye, Qiaozhen, Birkholz, Erica A, Berg, Kyle R, Patel, Lucas, Mathews, Ian T, Watrous, Jeramie D, Ego, Kaori, Whiteley, Aaron T, Lowey, Brianna, Mekalanos, John J, Kranzusch, Philip J, Jain, Mohit, Pogliano, Joe, and Corbett, Kevin D

Subjects
Infectious Diseases, Emerging Infectious Diseases, Infection, Allosteric Regulation, Bacterial Proteins, Bacteriophage lambda, CRISPR-Cas Systems, DNA Cleavage, DNA Restriction Enzymes, Deoxyribonuclease I, Escherichia coli, Genome, Viral, Protein Multimerization, Second Messenger Systems, CD-NTase, Endonuclease, abortive infection, bacteriophage immunity, second messenger signaling, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Bacteria possess an array of defenses against foreign invaders, including a broadly distributed bacteriophage defense system termed CBASS (cyclic oligonucleotide-based anti-phage signaling system). In CBASS systems, a cGAS/DncV-like nucleotidyltransferase synthesizes cyclic di- or tri-nucleotide second messengers in response to infection, and these molecules activate diverse effectors to mediate bacteriophage immunity via abortive infection. Here, we show that the CBASS effector NucC is related to restriction enzymes but uniquely assembles into a homotrimer. Binding of NucC trimers to a cyclic tri-adenylate second messenger promotes assembly of a NucC homohexamer competent for non-specific double-strand DNA cleavage. In infected cells, NucC activation leads to complete destruction of the bacterial chromosome, causing cell death prior to completion of phage replication. In addition to CBASS systems, we identify NucC homologs in over 30 type III CRISPR/Cas systems, where they likely function as accessory nucleases activated by cyclic oligoadenylate second messengers synthesized by these systems' effector complexes.

Published
2020

8. A live vaccine rapidly protects against cholera in an infant rabbit model

Author

Hubbard, Troy P, Billings, Gabriel, Dörr, Tobias, Sit, Brandon, Warr, Alyson R, Kuehl, Carole J, Kim, Minsik, Delgado, Fernanda, Mekalanos, John J, Lewnard, Joseph A, and Waldor, Matthew K

Subjects
Digestive Diseases, Infectious Diseases, Vaccine Related, Prevention, Biodefense, Foodborne Illness, Biotechnology, Emerging Infectious Diseases, Immunization, 3.4 Vaccines, Prevention of disease and conditions, and promotion of well-being, Infection, Good Health and Well Being, Adaptive Immunity, Animals, Cholera, Disease Progression, Kinetics, Models, Theoretical, Rabbits, Vaccines, Attenuated, Biological Sciences, Medical and Health Sciences
Abstract

Outbreaks of cholera, a rapidly fatal diarrheal disease, often spread explosively. The efficacy of reactive vaccination campaigns-deploying Vibrio cholerae vaccines during epidemics-is partially limited by the time required for vaccine recipients to develop adaptive immunity. We created HaitiV, a live attenuated cholera vaccine candidate, by deleting diarrheagenic factors from a recent clinical isolate of V. cholerae and incorporating safeguards against vaccine reversion. We demonstrate that administration of HaitiV 24 hours before lethal challenge with wild-type V. cholerae reduced intestinal colonization by the wild-type strain, slowed disease progression, and reduced mortality in an infant rabbit model of cholera. HaitiV-mediated protection required viable vaccine, and rapid protection kinetics are not consistent with development of adaptive immunity. These features suggest that HaitiV mediates probiotic-like protection from cholera, a mechanism that is not known to be elicited by traditional vaccines. Mathematical modeling indicates that an intervention that works at the speed of HaitiV-mediated protection could improve the public health impact of reactive vaccination.

Published
2018

17. Cholera toxin promotes pathogen acquisition of host-derived nutrients

Author

Rivera-Chávez, Fabian and Mekalanos, John J.

Subjects
Cholera toxin -- Physiological aspects -- Research, Host-bacteria relationships -- Research -- Physiological aspects, Microbiological research -- Research -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Vibrio cholerae is the causative agent of cholera, a potentially lethal enteric bacterial infection.sup.1. Cholera toxin (CTX), a protein complex that is secreted by V. cholerae, is required for V. cholerae to cause severe disease. CTX is also thought to promote transmission of the organism, as infected individuals shed many litres of diarrhoeal fluid that typically contains in excess of 10.sup.11 organisms per litre. How the pathogen is able to reach such high concentrations in the intestine during infection remains poorly understood. Here we show that CTX increases pathogen growth and induces a distinct V. cholerae transcriptomic signature that is indicative of an iron-depleted gut niche. During infection, bacterial pathogens need to acquire iron, which is an essential nutrient for growth.sup.2. Most iron in the mammalian host is found in a chelated form within the porphyrin structure of haem, and the ability to use haem as a source of iron is genetically encoded by V. cholerae.sup.3. We show that the genes that enable V. cholerae to obtain iron via haem and vibriobactin confer a growth advantage to the pathogen only when CTX is produced. Furthermore, we found that CTX-induced congestion of capillaries in the terminal ileum correlated with an increased bioavailability of luminal haem. CTX-induced disease in the ileum also led to increased concentrations of long-chain fatty acids and l-lactate metabolites in the lumen, as well as the upregulation of V. cholerae genes that encode enzymes of the tricarboxylic acid (TCA) cycle that contain iron-sulfur clusters. Genetic analysis of V. cholerae suggested that pathogen growth was dependent on the uptake of haem and long-chain fatty acids during infection, but only in a strain capable of producing CTX in vivo. We conclude that CTX-induced disease creates an iron-depleted metabolic niche in the gut, which selectively promotes the growth of V. cholerae through the acquisition of host-derived haem and fatty acids. Cholera toxin selectively promotes the growth of Vibrio cholerae through the acquisition of nutrients, including haem and fatty acids, from the host gut., Author(s): Fabian Rivera-Chávez [sup.1] , John J. Mekalanos [sup.1] Author Affiliations: (1) Department of Microbiology, Harvard Medical School, Boston, USA Main The enterotoxin activity of CTX was first reported in [...]

Published
2019
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42. Complete Genomes of Two Clinical Staphylococcus aureus Strains: Evidence for the Rapid Evolution of Virulence and Drug Resistance

Author

Feil, Edward J., Lindsay, Jodi A., Peacock, Sharon J., Enright, Mark C., Foster, Tim J., Moore, Catrin E., Hurst, Laurence, Atkin, Rebecca, Barron, Andrew, Bason, Nathalie, Bentley, Stephen D., Chillingworth, Carol, Chillingworth, Tracey, Churcher, Carol, Clark, Louise, Corton, Craig, Cronin, Ann, Doggett, Jon, Dowd, Linda, Feltwell, Theresa, Hance, Zahra, Harris, Barbara, Hauser, Heidi, Holroyd, Simon, Jagels, Kay, James, Keith D., Lennard, Nicola, Line, Alexandra, Mayes, Rebecca, Moule, Sharon, Mungall, Karen, Ormond, Douglas, Quail, Michael A., Rabbinowitsch, Ester, Rutherford, Kim, Sanders, Mandy, Sharp, Sarah, Simmonds, Mark, Stevens, Kim, Whitehead, Sally, Barrell, Bart G., Spratt, Brian G., Parkhill, Julian, and Mekalanos, John J.

Published
2004

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