Harvard Catalyst Profiles

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Matthew K Waldor, M.D., Ph.D.

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Biography
1979
Phi Beta Kappa
1980
Belknap Prize for excellence in biology
1980
BS summa cum laude with departmental honors
1980
Nicholas Cup for academic achievement
1981
Medical Student Scholars Program
1981 - 1983
Viets Fellowship for Research on Myasthenia Gravis
1983 - 1985
Neurosciences USPHS pre-doctoral traineeship
1992 - 1995
Howard Hughes Post-Doctoral Fellowship
1995
ICCAC Young Investigator Award
1995
Maxwell Finland Young Investigator Award
1998
Pew Scholar in Biomedical Sciences
1999
Presidential Early Career Award for Scientists and Engineers
2000
Distinguished Faculty Award
2002
Nestle Award,*best paper in bacteriophage biology in the Journal of Bacteriology*
2002
Squibb
2005
Zucker Award, Outstanding Research

Overview
The focus of my research has been on the plasticity and maintenance of the Vibrio cholerae genome. Lateral gene transfer has played a major role in the evolution of pathogenic bacteria because most virulence factors are encoded on mobile genetic elements. My work has focused on two virulence-linked mobile elements in Vibrio cholerae, the agent of cholera. My laboratory has defined several of the molecular steps in the life-cycles of two novel mobile genetic elements: 1) CTXƒÖ, an integrating filamentous phage that encodes cholera toxin, the principal virulence factor of Vibrio cholerae, and 2) SXT, a V. cholerae-derived integrating conjugative element (ICE) that encodes multiple antibiotic resistance genes.

CTXƒÖ infection of non-toxigenic V. cholerae strains can render them fully pathogenic. My laboratory has dissected many of the events in the CTXƒÖ lifecycle and demonstrated the profound dependence of CTXƒÖ on its host. Cellular factors directly mediate integration of the CTXƒÖ genome into the V. cholerae chromosome, secretion of viral particles, and regulation of phage gene transcription. Currently, we are defining the molecular features of the ¡¥genetic switch¡¦ that controls CTXƒÖ prophage induction to further knowledge of the molecular controls that govern cholera toxin gene transfer.

We are studying SXT, a V. cholerae-derived integrative conjugative element (ICE) that encodes resistance to multiple antibiotics, to learn about the environmental and genetic factors that control dissemination of antibiotic resistance genes and to define the key properties of this poorly understood but pervasive class of mobile elements. Like conjugative plasmids, ICEs are transferred between cells in a cell-contact dependent fashion; unlike plasmids, ICEs do not autonomously replicate but integrate into the chromosome of the new host. We have carried out genomic and functional analyses of the ~100kb SXT and identified many of the genes that mediate its integration, excision, and conjugation. My laboratory discovered that SXT is part of a family of closely related ICEs and, most importantly, defined some of the key components of a regulatory circuit that controls SXT transfer. Currently we are exploring the molecular mechanisms that mediate the generation of novel ICEs and investigating the mechanisms that limit SXT transfer.

Another focus of my research has been the study of the mechanisms that control and coordinate the replication and segregation of the two V. cholerae chromosomes. Studies of prokaryotic chromosome replication and segregation have focused almost exclusively on organisms with one chromosome. We defined and characterized the origins of replication of the two V. cholerae chromosomes, oriCIvc and oriCIIvc. OriCIIvc-based replication requires a hypothetical gene (designated rctB) that flanks oriCIIvc. RctB is conserved among diverse genera of the family Vibrionaceae and encodes an origin binding protein. Currently we are defining the biochemical activities of RctB and conducting high-throughput screens to identify small molecules inhibitors of this essential Vibrionaceae-specific replication factor.

We found that in all stages of the cell cycle, the two origins localize to distinct subcellular locations. The differences in localization and timing of segregation of oriCIvc and oriCIIvc suggest that distinct mechanisms govern the segregation of the two V. cholerae chromosomes. Currently, we are exploring the mechanisms that mediate the segregation of the two chromosomes.

Another area of my work has been the study of Vibrio cholerae sRNAs. Recently it has become clear from studies in E. coli that small untranslated RNAs (sRNAs) regulate many cellular processes. We have evidence that sRNAs regulate V. cholerae virulence. We developed a computer program, sRNAPredict, which enables the rapid identification of putative sRNAs in intergenic regions of bacterial genomes. Currently, we are investigating the targets and mechanisms of action of several of the V. cholerae sRNAs that were identified using this software and exploring the use of new high density sequencing technologies in sRNA discovery.

In addition, we are studying the pathogenicity of enterohemorrhagic Escherichia coli (EHEC). EHEC (E. coli O157), are important foodborne pathogens. In collaboration with David Friedman (U. Mich.), we showed that transcription of phage-borne genes encoding Shiga toxin (Stx), the principal EHEC virulence factor, is largely dependent on a phage promoter and that toxin release depends on phage mediated cell lysis. Our current goals are to explore Stx prophage induction within the intestine and to identify previously uncharacterized horizontally transmitted genes that influence EHEC intestinal colonization using an infant rabbit model of EHEC pathogenesis that we developed.

Mentoring
Available: 09/01/19, Expires: 08/31/23

The student will conduct a genome-wide screen to identify pathogen or host genes that contribute to pathogenesis of diseases caused by enteric pathogens. The student will be engaged in all steps of the project from creation of mutant libraries to analyses of the big data that screens generate. Some experience in molecular biology is preferable.

Available: 10/20/18, Expires: 09/30/23

Our lab studies the biology of Vibrio cholerae, the agent of cholera, and E. coli O157, a common cause of diarrheal disease in the USA. We are using a wide range of techniques to understand how these pathogens cause disease. We study both basic questions, such as how bacterial chromosomes replicate and segregate, and more applied issues such as development of new antibiotics and vaccines for diarrheal diseases.


Research
The research activities and funding listed below are automatically derived from NIH ExPORTER and other sources, which might result in incorrect or missing items. Faculty can login to make corrections and additions.
  1. R21AI067827 (WALDOR, MATTHEW K) Feb 1, 2006 - Jan 31, 2009
    NIH
    Intestinal colonization of Enterohemorrhagic E. coil
    Role: Principal Investigator
  2. R21AI059698 (WALDOR, MATTHEW K) Apr 1, 2004 - Mar 31, 2007
    NIH
    Role of Hfq in Vibrio cholerae virulence
    Role: Principal Investigator
  3. R01AI042347 (WALDOR, MATTHEW K) Jan 1, 1998 - May 31, 2022
    NIH
    Vibrio cholerae intestinal colonization and vaccine development
    Role: Principal Investigator
  4. R37AI042347 (WALDOR, MATTHEW K) Jan 1, 1998 - May 31, 2018
    NIH
    Molecular Biology and Virulence of CTX Phage
    Role: Principal Investigator
  5. K08AI001321 (WALDOR, MATTHEW K) Aug 1, 1995 - Jul 31, 1998
    NIH
    IDENTIFICATION OF VIRULENCE GENES IN VIBRIO CHOLERAE
    Role: Principal Investigator

Bibliographic
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
  1. Tomasi FG, Kimura S, Rubin EJ, Waldor MK. A tRNA modification in Mycobacterium tuberculosis facilitates optimal intracellular growth. bioRxiv. 2023 Feb 20. PMID: 36865327; PMCID: PMC9979996.
    Citations:    
  2. Campbell IW, Hullahalli K, Turner JR, Waldor MK. Quantitative dose-response analysis untangles host bottlenecks to enteric infection. Nat Commun. 2023 Jan 28; 14(1):456. PMID: 36709326; PMCID: PMC9884216.
    Citations:    Fields:    Translation:AnimalsCells
  3. Tomasi FG, Schweber JTP, Kimura S, Zhu J, Cleghorn LAT, Davis SH, Green SR, Waldor MK, Rubin EJ. Peptidyl tRNA Hydrolase Is Required for Robust Prolyl-tRNA Turnover in Mycobacterium tuberculosis. mBio. 2023 Feb 28; 14(1):e0346922. PMID: 36695586; PMCID: PMC9973355.
    Citations:    Fields:    
  4. Chou S, Guo H, Zingl FG, Zhang S, Toska J, Xu B, Chen Y, Chen P, Waldor MK, Zhao W, Mekalanos JJ, Mou X. Synthetic peptides that form nanostructured micelles have potent antibiotic and antibiofilm activity against polymicrobial infections. Proc Natl Acad Sci U S A. 2023 01 24; 120(4):e2219679120. PMID: 36649429; PMCID: PMC9942841.
    Citations:    Fields:    Translation:AnimalsCells
  5. Rubin DHF, Ma KC, Westervelt KA, Hullahalli K, Waldor MK, Grad YH. CanB is a metabolic mediator of antibiotic resistance in Neisseria gonorrhoeae. Nat Microbiol. 2023 01; 8(1):28-39. PMID: 36604513.
    Citations:    Fields:    Translation:HumansCells
  6. Rubin DHF, Zingl FG, Leitner DR, Ternier R, Compere V, Marseille S, Slater D, Harris JB, Chowdhury F, Qadri F, Boncy J, Ivers LC, Waldor MK. Reemergence of Cholera in Haiti. N Engl J Med. 2022 12 22; 387(25):2387-2389. PMID: 36449726; PMCID: PMC9901182.
    Citations: 2     Fields:    Translation:HumansPHPublic Health
  7. Sit B, Srisuknimit V, Bueno E, Zingl FG, Hullahalli K, Cava F, Waldor MK. Undecaprenyl phosphate translocases confer conditional microbial fitness. Nature. 2023 Jan; 613(7945):721-728. PMID: 36450355; PMCID: PMC9876793.
    Citations: 1     Fields:    Translation:Cells
  8. Matute JD, Duan J, Flak MB, Griebel P, Tascon-Arcila JA, Doms S, Hanley T, Antanaviciute A, Gundrum J, Mark Welch JL, Sit B, Abtahi S, Fuhler GM, Grootjans J, Tran F, Stengel ST, White JR, Krupka N, Haller D, Clare S, Lawley TD, Kaser A, Simmons A, Glickman JN, Bry L, Rosenstiel P, Borisy G, Waldor MK, Baines JF, Turner JR, Blumberg RS. Intelectin-1 binds and alters the localization of the mucus barrier-modifying bacterium Akkermansia muciniphila. J Exp Med. 2023 01 02; 220(1). PMID: 36413219; PMCID: PMC9683900.
    Citations:    Fields:    Translation:HumansAnimalsCells
  9. Kimura S, Srisuknimit V, McCarty KL, Dedon PC, Kranzusch PJ, Waldor MK. Sequential action of a tRNA base editor in conversion of cytidine to pseudouridine. Nat Commun. 2022 Oct 11; 13(1):5994. PMID: 36220828; PMCID: PMC9553926.
    Citations:    Fields:    
  10. Sit B, Fakoya B, Waldor MK. Emerging Concepts in Cholera Vaccine Design. Annu Rev Microbiol. 2022 09 08; 76:681-702. PMID: 35759873.
    Citations:    Fields:    
  11. Fakoya B, Hullahalli K, Rubin DHF, Leitner DR, Chilengi R, Sack DA, Waldor MK. Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of Protection. mBio. 2022 04 26; 13(2):e0053922. PMID: 35389261; PMCID: PMC9040834.
    Citations:    Fields:    Translation:HumansAnimalsCells
  12. Hounmanou YMG, Sit B, Fakoya B, Waldor MK, Dalsgaard A. Genomic and Phenotypic Insights for Toxigenic Clinical Vibrio cholerae O141. Emerg Infect Dis. 2022 03; 28(3):617-624. PMID: 35202520; PMCID: PMC8888207.
    Citations:    Fields:    Translation:HumansAnimalsCells
  13. Sit B, Fakoya B, Waldor MK. Animal models for dissecting Vibrio cholerae intestinal pathogenesis and immunity. Curr Opin Microbiol. 2022 02; 65:1-7. PMID: 34695646; PMCID: PMC8792189.
    Citations:    Fields:    Translation:AnimalsCells
  14. Zoued A, Zhang H, Zhang T, Giorgio RT, Kuehl CJ, Fakoya B, Sit B, Waldor MK. Proteomic analysis of the host-pathogen interface in experimental cholera. Nat Chem Biol. 2021 11; 17(11):1199-1208. PMID: 34675415.
    Citations: 1     Fields:    Translation:AnimalsCells
  15. Hullahalli K, Waldor MK. Pathogen clonal expansion underlies multiorgan dissemination and organ-specific outcomes during murine systemic infection. Elife. 2021 10 12; 10. PMID: 34636322; PMCID: PMC8545400.
    Citations: 1     Fields:    Translation:AnimalsCells
  16. Lazarus JE, Warr AR, Westervelt KA, Hooper DC, Waldor MK. A Genome-Scale Antibiotic Screen in Serratia marcescens Identifies YdgH as a Conserved Modifier of Cephalosporin and Detergent Susceptibility. Antimicrob Agents Chemother. 2021 11 17; 65(12):e0078621. PMID: 34491801; PMCID: PMC8597751.
    Citations:    Fields:    Translation:Cells
  17. Hullahalli K, Pritchard JR, Waldor MK. Refined Quantification of Infection Bottlenecks and Pathogen Dissemination with STAMPR. mSystems. 2021 Aug 31; 6(4):e0088721. PMID: 34402636; PMCID: PMC8407386.
    Citations: 3     
  18. Plaza N, Urrutia IM, Garcia K, Waldor MK, Blondel CJ. Identification of a Family of Vibrio Type III Secretion System Effectors That Contain a Conserved Serine/Threonine Kinase Domain. mSphere. 2021 08 25; 6(4):e0059921. PMID: 34346702; PMCID: PMC8386410.
    Citations: 1     Fields:    Translation:HumansCells
  19. Gensollen T, Lin X, Zhang T, Pyzik M, See P, Glickman JN, Ginhoux F, Waldor M, Salmi M, Rantakari P, Blumberg RS. Embryonic macrophages function during early life to determine invariant natural killer T cell levels at barrier surfaces. Nat Immunol. 2021 06; 22(6):699-710. PMID: 34040226; PMCID: PMC8171892.
    Citations: 4     Fields:    Translation:HumansAnimalsCells
  20. Elhenawy W, Hordienko S, Gould S, Oberc AM, Tsai CN, Hubbard TP, Waldor MK, Coombes BK. High-throughput fitness screening and transcriptomics identify a role for a type IV secretion system in the pathogenesis of Crohn's disease-associated Escherichia coli. Nat Commun. 2021 04 01; 12(1):2032. PMID: 33795670; PMCID: PMC8016931.
    Citations: 6     Fields:    Translation:HumansAnimalsCells
  21. Zhang T, Sasabe J, Hullahalli K, Sit B, Waldor MK. Increased Listeria monocytogenes Dissemination and Altered Population Dynamics in Muc2-Deficient Mice. Infect Immun. 2021 03 17; 89(4). PMID: 33431704.
    Citations: 2     Fields:    Translation:AnimalsCells
  22. Suzuki M, Sujino T, Chiba S, Harada Y, Goto M, Takahashi R, Mita M, Hamase K, Kanai T, Ito M, Waldor MK, Yasui M, Sasabe J. Host-microbe cross-talk governs amino acid chirality to regulate survival and differentiation of B cells. Sci Adv. 2021 03; 7(10). PMID: 33658193; PMCID: PMC7929512.
    Citations:    Fields:    Translation:AnimalsCells
  23. Baker-Austin C, Oliver JD, Alam M, Ali A, Waldor MK, Qadri F, Martinez-Urtaza J. Author Correction: Vibrio spp. infections. Nat Rev Dis Primers. 2021 Feb 19; 7(1):15. PMID: 33608543.
    Citations:    Fields:    
  24. Sit B, Fakoya B, Zhang T, Billings G, Waldor MK. Dissecting serotype-specific contributions to live oral cholera vaccine efficacy. Proc Natl Acad Sci U S A. 2021 02 16; 118(7). PMID: 33558237.
    Citations: 1     Fields:    Translation:AnimalsCells
  25. Del Peso Santos T, Alvarez L, Sit B, Irazoki O, Blake J, Warner BR, Warr AR, Bala A, Benes V, Waldor MK, Fredrick K, Cava F. BipA exerts temperature-dependent translational control of biofilm-associated colony morphology in Vibrio cholerae. Elife. 2021 02 12; 10. PMID: 33588990; PMCID: PMC7886329.
    Citations: 3     Fields:    Translation:Cells
  26. Warr AR, Kuehl CJ, Waldor MK. Shiga toxin remodels the intestinal epithelial transcriptional response to Enterohemorrhagic Escherichia coli. PLoS Pathog. 2021 02; 17(2):e1009290. PMID: 33529199.
    Citations: 4     Fields:    Translation:AnimalsCells
  27. Warr AR, Giorgio RT, Waldor MK. Genetic analysis of the role of the conserved inner membrane protein CvpA in EHEC resistance to deoxycholate. J Bacteriol. 2020 Dec 23. PMID: 33361192.
    Citations: 3     Fields:    
  28. Hu M, Zhang Y, Gu D, Chen X, Waldor MK, Zhou X. Nucleolar c-Myc recruitment by a Vibrio T3SS effector promotes host cell proliferation and bacterial virulence. EMBO J. 2021 01 15; 40(2):e105699. PMID: 33347626; PMCID: PMC7809790.
    Citations: 3     Fields:    Translation:HumansAnimalsCells
  29. Tian L, Wang XW, Wu AK, Fan Y, Friedman J, Dahlin A, Waldor MK, Weinstock GM, Weiss ST, Liu YY. Deciphering functional redundancy in the human microbiome. Nat Commun. 2020 12 04; 11(1):6217. PMID: 33277504.
    Citations: 27     Fields:    Translation:HumansCells
  30. Bueno E, Sit B, Waldor MK, Cava F. Genetic Dissection of the Fermentative and Respiratory Contributions Supporting Vibrio cholerae Hypoxic Growth. J Bacteriol. 2020 11 19; 202(24). PMID: 32631948.
    Citations: 4     Fields:    Translation:HumansAnimalsCells
  31. Fakoya B, Sit B, Waldor MK. Transient Intestinal Colonization by a Live-Attenuated Oral Cholera Vaccine Induces Protective Immune Responses in Streptomycin-Treated Mice. J Bacteriol. 2020 11 19; 202(24). PMID: 32540930.
    Citations: 4     Fields:    Translation:HumansAnimalsCells
  32. Charles RC, Kelly M, Tam JM, Akter A, Hossain M, Islam K, Biswas R, Kamruzzaman M, Chowdhury F, Khan AI, Leung DT, Weil A, LaRocque RC, Bhuiyan TR, Rahman A, Mayo-Smith LM, Becker RL, Vyas JM, Faherty CS, Nickerson KP, Giffen S, Ritter AS, Waldor MK, Xu P, Kovác P, Calderwood SB, Kauffman RC, Wrammert J, Qadri F, Harris JB, Ryan ET. Humans Surviving Cholera Develop Antibodies against Vibrio cholerae O-Specific Polysaccharide That Inhibit Pathogen Motility. mBio. 2020 11 17; 11(6). PMID: 33203761; PMCID: PMC7683404.
    Citations: 9     Fields:    Translation:HumansAnimalsCells
  33. Zhang H, Zoued A, Liu X, Sit B, Waldor MK. Type I interferon remodels lysosome function and modifies intestinal epithelial defense. Proc Natl Acad Sci U S A. 2020 11 24; 117(47):29862-29871. PMID: 33172989.
    Citations: 2     Fields:    Translation:HumansAnimalsCells
  34. Parker DJ, Lalanne JB, Kimura S, Johnson GE, Waldor MK, Li GW. Growth-Optimized Aminoacyl-tRNA Synthetase Levels Prevent Maximal tRNA Charging. Cell Syst. 2020 08 26; 11(2):121-130.e6. PMID: 32726597.
    Citations: 11     Fields:    Translation:Humans
  35. Kimura S, Srisuknimit V, Waldor MK. Probing the diversity and regulation of tRNA modifications. Curr Opin Microbiol. 2020 10; 57:41-48. PMID: 32663792; PMCID: PMC7722113.
    Citations: 4     Fields:    Translation:Cells
  36. Kimura S, Dedon PC, Waldor MK. Comparative tRNA sequencing and RNA mass spectrometry for surveying tRNA modifications. Nat Chem Biol. 2020 09; 16(9):964-972. PMID: 32514182; PMCID: PMC8172280.
    Citations: 14     Fields:    Translation:AnimalsCells
  37. Lipsitch M, Perlman S, Waldor MK. Testing COVID-19 therapies to prevent progression o