John Mekalanos

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John Mekalanos is a microbiologist who is primarily known for leading one of the first teams that reported the discovery of the type VI secretion system as well as his work on the pathogenicity of the bacterial species Vibrio cholerae , its toxin, and its secretion systems. Since 1998, he has been a member of the National Academy of Sciences. [1]

Contents

Education

He started his research studies as a graduate student in the labs of R. John Collier and William Robert Romig at UCLA where his research was focused on studying the genetic and biochemical analysis of the cholera toxin secreted by the bacterium Vibrio cholerae . [2] Highlights of his career during this time was, along with Romig, the development of a screening assay designed to isolate the tox mutants of Vibrio cholerae (strains with altered toxin production ability) [3] which led to the genetic mapping of the toxin-regulatory mutants in this bacterial species. [4]

He continued his work on cholera toxin as a post-doc at the Department of Microbiology and Molecular Genetics at Harvard Medical School with John R. Murphy, which was followed by his appointment as an assistant professor there. [5]

Career and Research

Early Research

His early work as an independent researcher led to the identification of toxR, a gene that affects the expression of the cholera toxin operon ctxAB, [6] the discovery that the Staphylococcus aureus enterotoxin A (entA) is a phage-encoded protein, [7] and finally, the demonstration of the presence of duplications of the toxin operon in different strains of Vibrio cholerae that could account for the variable toxinogenicity of the strains [8] which led to his promotion to Professor in 1986. [5] His continued strong research output led to his appointment as Chairman of the then Department of Microbiology and Molecular Genetics (now Microbiology) ten years later in 1996 and his election to the National Academy of Sciences in 1998. [5]

T6SS Discovery

In 2006, his group published the first account of the identification of a novel secretion system that they named the type VI secretion system, a system initially found to be capable of conferring increased virulence in non-O1/non-O139 strain strains of V. cholerae, [9] which was later however shown to be primarily responsible for interbacterial competition. [10]

Awards and honors

Related Research Articles

<span class="mw-page-title-main">Pilus</span> A proteinaceous hair-like appendage on the surface of bacteria

A pilus is a hair-like appendage found on the surface of many bacteria and archaea. The terms pilus and fimbria can be used interchangeably, although some researchers reserve the term pilus for the appendage required for bacterial conjugation. All conjugative pili are primarily composed of pilin – fibrous proteins, which are oligomeric.

<i>Vibrio cholerae</i> Species of bacterium

Vibrio cholerae is a species of Gram-negative, facultative anaerobe and comma-shaped bacteria. The bacteria naturally live in brackish or saltwater where they attach themselves easily to the chitin-containing shells of crabs, shrimp, and other shellfish. Some strains of V. cholerae are pathogenic to humans and cause a deadly disease called cholera, which can be derived from the consumption of undercooked or raw marine life species or drinking contaminated water.

<i>Vibrio</i> Genus of bacteria and the disease it can cause

Vibrio is a genus of Gram-negative bacteria, possessing a curved-rod (comma) shape, several species of which can cause foodborne infection, usually associated with eating undercooked seafood. Being highly salt tolerant and unable to survive in fresh water, Vibrio spp. are commonly found in various salt water environments. Vibrio spp. are facultative anaerobes that test positive for oxidase and do not form spores. All members of the genus are motile. They are able to have polar or lateral flagellum with or without sheaths. Vibrio species typically possess two chromosomes, which is unusual for bacteria. Each chromosome has a distinct and independent origin of replication, and are conserved together over time in the genus. Recent phylogenies have been constructed based on a suite of genes.

<span class="mw-page-title-main">Secretion</span> Controlled release of substances by cells or tissues

Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mechanism of cell secretion is via secretory portals at the plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures embedded in the cell membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

<span class="mw-page-title-main">Enterotoxin</span> Toxin from a microorganism affecting the intestines

An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines. They can be chromosomally or plasmid encoded. They are heat labile (>60⁰), of low molecular weight and water-soluble. Enterotoxins are frequently cytotoxic and kill cells by altering the apical membrane permeability of the mucosal (epithelial) cells of the intestinal wall. They are mostly pore-forming toxins, secreted by bacteria, that assemble to form pores in cell membranes. This causes the cells to die.

<span class="mw-page-title-main">Cholera toxin</span> Protein complex secreted by the bacterium Vibrio cholerae

Cholera toxin is an AB5 multimeric protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection. It is a member of the heat-labile enterotoxin family.

<span class="mw-page-title-main">Sambhu Nath De</span>

Sambhunath De ; was an Indian medical scientist and researcher, who discovered the cholera toxin, the animal model of cholera, and successfully demonstrated the method of transmission of cholera pathogen Vibrio cholerae.

Microbial toxins are toxins produced by micro-organisms, including bacteria, fungi, protozoa, dinoflagellates, and viruses. Many microbial toxins promote infection and disease by directly damaging host tissues and by disabling the immune system. Endotoxins most commonly refer to the lipopolysaccharide (LPS) or lipooligosaccharide (LOS) that are in the outer plasma membrane of Gram-negative bacteria. The botulinum toxin, which is primarily produced by Clostridium botulinum and less frequently by other Clostridium species, is the most toxic substance known in the world. However, microbial toxins also have important uses in medical science and research. Currently, new methods of detecting bacterial toxins are being developed to better isolate and understand these toxins. Potential applications of toxin research include combating microbial virulence, the development of novel anticancer drugs and other medicines, and the use of toxins as tools in neurobiology and cellular biology.

The RTX toxin superfamily is a group of cytolysins and cytotoxins produced by bacteria. There are over 1000 known members with a variety of functions. The RTX family is defined by two common features: characteristic repeats in the toxin protein sequences, and extracellular secretion by the type I secretion systems (T1SS). The name RTX refers to the glycine and aspartate-rich repeats located at the C-terminus of the toxin proteins, which facilitate export by a dedicated T1SS encoded within the rtx operon.

<span class="mw-page-title-main">Shah M. Faruque</span>

Shah Mohammad Faruque is a professor and the dean of the School of Environment and Life Sciences at Independent University Bangladesh (IUB). He is widely recognized for his research in Vibrio cholerae, the bacterium which causes the epidemic diarrhoeal disease Cholera. Among other positions, previously he was a professor at BRAC University; director of the Genomics Centre at the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), and formerly director of the Centre for Food and Water Borne Diseases in ICDDR,B. His areas of research interest include microbial genomics, bacteriophages, environmental microbiology, ecology, and evolution of bacterial pathogens, particularly those associated with waterborne and foodborne diseases. Faruque is primarily known for his work in genomics, epidemiology and ecology of the cholera pathogen, and its bacteriophages.

<span class="mw-page-title-main">Heat-labile enterotoxin family</span> Family of toxic protein complexes

In molecular biology, the heat-labile enterotoxin family includes Escherichia coli heat-labile enterotoxin and cholera toxin (Ctx) secreted by Vibrio cholerae.

The CTXφ bacteriophage is a filamentous bacteriophage. It is a positive-strand DNA virus with single-stranded DNA (ssDNA).

Vibrio campbellii is a Gram-negative, curved rod-shaped, marine bacterium closely related to its sister species, Vibrio harveyi. It is an emerging pathogen in aquatic organisms.

The type VI secretion system (T6SS) is molecular machine used by a wide range of Gram-negative bacterial species to transport effectors from the interior of a bacterial cell across the cellular envelope into an adjacent target cell. While often reported that the T6SS was discovered in 2006 by researchers studying the causative agent of cholera, Vibrio cholerae, the first study demonstrating that T6SS genes encode a protein export apparatus was actually published in 2004, in a study of protein secretion by the fish pathogen Edwardsiella tarda.

<span class="mw-page-title-main">Virstatin</span> Molecule that inhibits the activity of a cholera protein

Virstatin is a small molecule that inhibits the activity of the cholera protein, ToxT.

Rhs toxins belong to the polymorphic toxin category of bacterial exotoxins. Rhs proteins are widespread and can be produced by both Gram-negative and Gram-positive bacteria. Rhs toxins are very large proteins of usually more than 1,500 aminoacids with variable C-terminal toxic domains. Their toxic activity can either target eukaryotes or other bacteria.

Contact-dependent growth inhibition (CDI) is a phenomenon where a bacterial cell may deliver a polymorphic toxin molecule into neighbouring bacterial cells upon direct cell-cell contact, causing growth arrest or cell death.

<span class="mw-page-title-main">Bacterial secretion system</span> Protein complexes present on the cell membranes of bacteria for secretion of substances

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for secretion of substances. Specifically, they are the cellular devices used by pathogenic bacteria to secrete their virulence factors to invade the host cells. They can be classified into different types based on their specific structure, composition and activity. Generally, proteins can be secreted through two different processes. One process is a one-step mechanism in which proteins from the cytoplasm of bacteria are transported and delivered directly through the cell membrane into the host cell. Another involves a two-step activity in which the proteins are first transported out of the inner cell membrane, then deposited in the periplasm, and finally through the outer cell membrane into the host cell.

<span class="mw-page-title-main">Virginia L. Miller</span> American microbiologist

Virginia L. Miller is a microbiologist known for her work on studying the factors leading to disease caused by bacteria. Miller is an elected fellow of the American Academy of Microbiology (2003) and a former Pew Charitable Trust Biomedical Scholar (1989).

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References

  1. ↑ "John J. Mekalanos".
  2. ↑ "William Robert Romig".
  3. ↑ Mekalanos JJ, Collier RJ, Romig WR (1978). "Affinity filters, a new approach to the isolation of tox mutants of Vibrio cholerae". Proc Natl Acad Sci U S A. 75 (2): 941–5. doi: 10.1073/pnas.75.2.941 . PMC   411374 . PMID   345281.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ↑ Mekalanos JJ, Sublett RD, Romig WR (1979). "Genetic mapping of toxin regulatory mutations in Vibrio cholerae". J Bacteriol. 139 (3): 859–65. doi:10.1128/jb.139.3.859-865.1979. PMC   218032 . PMID   479110.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. 1 2 3 4 5 6 7 "John J. Mekalanos, PHD".
  6. ↑ Miller VL, Mekalanos JJ (1984). "Synthesis of cholera toxin is positively regulated at the transcriptional level by toxR". Proc Natl Acad Sci U S A. 81 (11): 3471–5. doi: 10.1073/pnas.81.11.3471 . PMC   345530 . PMID   6374658.
  7. ↑ Betley MJ, Mekalanos JJ (1985). "Staphylococcal enterotoxin A is encoded by phage". Science. 229 (4709): 185–7. doi:10.1126/science.3160112. PMID   3160112.
  8. ↑ Mekalanos JJ (1983). "Duplication and amplification of toxin genes in Vibrio cholerae". Cell. 35 (1): 253–63. doi: 10.1016/0092-8674(83)90228-3 . PMID   6627396.
  9. ↑ Pukatzki S, Ma AT, Sturtevant D, Krastins B, Sarracino D, Nelson WC; et al. (2006). "Identification of a conserved bacterial protein secretion system in Vibrio cholerae using the Dictyostelium host model system". Proc Natl Acad Sci U S A. 103 (5): 1528–33. doi: 10.1073/pnas.0510322103 . PMC   1345711 . PMID   16432199.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ↑ Hood RD, Peterson SB, Mougous JD (2017). "From Striking Out to Striking Gold: Discovering that Type VI Secretion Targets Bacteria". Cell Host Microbe. 21 (3): 286–289. doi:10.1016/j.chom.2017.02.001. PMC   6404758 . PMID   28279332.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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