Mycobacteriophage

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Mycobacteriophage Bxb1 Structure Bacteriophage Bxb1 Structure.jpg
Mycobacteriophage Bxb1 Structure

A mycobacteriophage is a member of a group of bacteriophages known to have mycobacteria as host bacterial species. While originally isolated from the bacterial species Mycobacterium smegmatis and Mycobacterium tuberculosis , [2] the causative agent of tuberculosis, more than 4,200 mycobacteriophage species have since been isolated from various environmental and clinical sources. 2,042 have been completely sequenced. [3] Mycobacteriophages have served as examples of viral lysogeny and of the divergent morphology and genetic arrangement characteristic of many phage types. [4]

Contents

All mycobacteriophages found thus far have had double-stranded DNA genomes and have been classified by their structure and appearance into siphoviridae or myoviridae. [5]

Discovery

A bacteriophage found to infect Mycobacterium smegmatis in 1947 was the first documented example of a mycobacteriophage. It was found in cultures of the bacteria originally growing in moist compost. [6] The first bacteriophage that infects M. tuberculosis was discovered in 1954. [7]

Diversity

Thousands of mycobacteriophage have been isolated using a single host strain, Mycobacterium smegmatis mc2155, over 1400 of which have been completely sequenced. [3] These are mostly from environmental samples, but mycobacteriophages have also been isolated from stool samples of tuberculosis patients, [8] although these have yet to be sequenced. [9] About 30 distinct types (called clusters, or singletons if they have no relatives) that share little nucleotide sequence similarity have been identified. Many of the clusters span sufficient diversity that the genomes warrant division into subclusters (Figure 1). [9]

There is also considerable range in overall guanine plus cytosine content (GC%), from 50.3% to 70%, with an average of 64% (M. smegmatis is 67.3%). Thus, phage GC% does not necessarily match that of its host, and the consequent mismatch of codon usage profiles does not appear to be detrimental. Because new mycobacteriophages lacking extensive DNA similarity with the extant collection are still being discovered, and as there are at least seven singletons for which no relatives have been isolated, we clearly have yet to saturate the diversity of this particular population. [9]

The collection of >50,000 genes can be sorted into >3,900 groups (so-called phamilies, i.e. phage protein families) according to their shared amino acid sequences. Most of these phamilies (~75%) do not have homologues outside of the mycobacteriophages and are of unknown function. Genetic studies with mycobacteriophage Giles show that 45% of the genes are nonessential for lytic growth. [10]

Figure 1. Diversity of mycobacteriophages. Sequenced genomes for 471 mycobacteriophages were compared according to their shared gene contents and overall nucleotide sequence similarity. Colored circles encompass Clusters A-T as indicated, and grey circles represent singleton genomes that have no close relatives. A1, A2, A3... indicate subclusters. Micrographs show the morphotypes of the myoviral Cluster C phages and the siphoviruses (all others) that primarily differ in tail length (scale bars: 100 nm). With the exception of DS6A (a singleton), all phages infect M. smegmatis mc2155. Cluster K phages and a subset of Cluster A phages also infect M. tuberculosis. From Hatfull 2014 Diversity of mycobacteriophages.png
Figure 1. Diversity of mycobacteriophages. Sequenced genomes for 471 mycobacteriophages were compared according to their shared gene contents and overall nucleotide sequence similarity. Colored circles encompass Clusters A–T as indicated, and grey circles represent singleton genomes that have no close relatives. A1, A2, A3... indicate subclusters. Micrographs show the morphotypes of the myoviral Cluster C phages and the siphoviruses (all others) that primarily differ in tail length (scale bars: 100 nm). With the exception of DS6A (a singleton), all phages infect M. smegmatis mc2155. Cluster K phages and a subset of Cluster A phages also infect M. tuberculosis. From Hatfull 2014

As of May 2023, the PhagesDB website lists 12579 reported mycobacteriophages, 2257 of which having been sequenced. Around one-third of the sequenced phages fall into cluster "A", which contains L5. [11]

Taxonomy

In line with the clustering results by phageDB, mycobacteriophages are split into many places on the ICTV's virus taxonomy tree. Some examples are:

Host range

Host range analysis shows that not all mycobacteriophages from M. smegmatis infect other strains and only phages in Cluster K and in certain subclusters of Cluster A efficiently infect M. tuberculosis (Figure 1). [15] However, mutants can be readily isolated from some phages that expand their host range to infect these other strains. [15] However, the molecular basis of host range depends on the behavior and presence of specific genes.  This raises the probability of a correlation between gene phamilies and the preferred host. [15]

The realms of mycobacteriophage infection are not understood in its entirety because it involves various mechanisms including receptor availability, restriction-modification, abortive infection, and more. These mechanisms can be mediated through several processes like Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPRs) and the translational apparatus being modified. Phages overcome these constraints by evolving, spontaneous mutation, and diversifying. [15]

Genome architecture

The first sequenced mycobacteriophage genome was that of mycobacteriophage L5 in 1993. [16] In the following years hundreds of additional genomes have been sequenced. [3] Mycobacteriophages have highly mosaic genomes. Their genome sequences show evidence of extensive horizontal genetic transfer, both between phages and between phages and their mycobacterial hosts. Comparisons of these sequences have helped to explain how frequently genetic exchanges of this type may occur in nature, as well as how phages may contribute to bacterial pathogenicity. [17]

A selection of 60 mycobacteriophages were isolated and had their genomes sequenced in 2009. These genome sequences were grouped into clusters by several methods in an effort to determine similarities between the phages and to explore their genetic diversity. More than half of the phage species were originally found in or near Pittsburgh, Pennsylvania, though others were found in other United States locations, India, and Japan. No distinct differences were found in the genomes of mycobacteriophage species from different global origins. [18] Mycobacteriophage genomes have been found to contain a subset of genes undergoing more rapid genetic flux than other elements of the genomes. These "rapid flux" genes are exchanged between mycobacteriophage more often and are 50 percent shorter in sequence than the average mycobacteriophage gene. [18]

Applications

Historically, mycobacteriophage have been used to "type" (i.e. "diagnose") mycobacteria, as each phage infects only one or a few bacterial strains. [19] In the 1980s phages were discovered as tools to genetically manipulate their hosts. [20] For instance, phage TM4 was used to construct shuttle phasmids that replicate as large cosmids in Escherichia coli and as phages in mycobacteria. [21] Shuttle phasmids can be manipulated in E. coli and used to efficiently introduce foreign DNA into mycobacteria.[ citation needed ]

Phages with mycobacterial hosts may be especially useful for understanding and fighting mycobacterial infections in humans. A system has been developed to use mycobacteriophage carrying a reporter gene to screen strains of M. tuberculosis for antibiotic resistance. [22] In the future, mycobacteriophage could be used to treat infections by phage therapy. [23] [24]

In 2019 it was reported that three mycobacteriophages were administered intravenously twice daily to a 15 year-old girl with cystic fibrosis and disseminated M. abscessus subsp. massiliense infection that occurred following lung transplant. [25] The patient had clear benefit from treatment, and the phage treatment combined with antibiotics was extended for several years. In 2022 it was reported that two mycobacteriophages were administered intravenously twice daily to a young man with treatment-refractory M. abscessus subsp. abscessus  pulmonary infection and severe cystic fibrosis lung disease. [26] Airway cultures for M. abscessus became negative after approximately 100 days of combined phage and antibiotic treatment, and a variety of biomarkers confirmed the therapeutic response. The individual received a bilateral lung transplant after 379 days of treatment, and cultures from the explanted lung tissue confirmed eradication of the bacteria.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Bacteriophage</span> Virus that infects prokaryotes

A bacteriophage, also known informally as a phage, is a virus that infects and replicates within bacteria and archaea. The term is derived from Ancient Greek φαγεῖν (phagein) 'to devour' and bacteria. Bacteriophages are composed of proteins that encapsulate a DNA or RNA genome, and may have structures that are either simple or elaborate. Their genomes may encode as few as four genes and as many as hundreds of genes. Phages replicate within the bacterium following the injection of their genome into its cytoplasm.

<span class="mw-page-title-main">Lambda phage</span> Bacteriophage that infects Escherichia coli

Enterobacteria phage λ is a bacterial virus, or bacteriophage, that infects the bacterial species Escherichia coli. It was discovered by Esther Lederberg in 1950. The wild type of this virus has a temperate life cycle that allows it to either reside within the genome of its host through lysogeny or enter into a lytic phase, during which it kills and lyses the cell to produce offspring. Lambda strains, mutated at specific sites, are unable to lysogenize cells; instead, they grow and enter the lytic cycle after superinfecting an already lysogenized cell.

<i>Mycobacterium tuberculosis</i> Species of pathogenic bacteria that causes tuberculosis

Mycobacterium tuberculosis, also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, M. tuberculosis can appear weakly Gram-positive. Acid-fast stains such as Ziehl–Neelsen, or fluorescent stains such as auramine are used instead to identify M. tuberculosis with a microscope. The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, it infects the lungs. The most frequently used diagnostic methods for tuberculosis are the tuberculin skin test, acid-fast stain, culture, and polymerase chain reaction.

<i>Mycobacterium</i> Genus of bacteria

Mycobacterium is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy in humans. The Greek prefix myco- means 'fungus', alluding to this genus' mold-like colony surfaces. Since this genus has cell walls with a waxy lipid-rich outer layer containing high concentrations of mycolic acid, acid-fast staining is used to emphasize their resistance to acids, compared to other cell types.

<i>Mycobacterium leprae</i> Bacterium that causes leprosy

Mycobacterium leprae is one of the two species of bacteria that cause Hansen's disease (leprosy), a chronic but curable infectious disease that damages the peripheral nerves and targets the skin, eyes, nose, and muscles.

<span class="mw-page-title-main">Phage therapy</span> Therapeutic use of bacteriophages to treat bacterial infections

Phage therapy, viral phage therapy, or phagotherapy is the therapeutic use of bacteriophages for the treatment of pathogenic bacterial infections. This therapeutic approach emerged at the beginning of the 20th century but was progressively replaced by the use of antibiotics in most parts of the world after the Second World War. Bacteriophages, known as phages, are a form of virus that attach to bacterial cells and inject their genome into the cell. The bacteria's production of the viral genome interferes with its ability to function, halting the bacterial infection. The bacterial cell causing the infection is unable to reproduce and instead produces additional phages. Phages are very selective in the strains of bacteria they are effective against.

<span class="mw-page-title-main">Transduction (genetics)</span> Transfer process in genetics

Transduction is the process by which foreign DNA is introduced into a cell by a virus or viral vector. An example is the viral transfer of DNA from one bacterium to another and hence an example of horizontal gene transfer. Transduction does not require physical contact between the cell donating the DNA and the cell receiving the DNA, and it is DNase resistant. Transduction is a common tool used by molecular biologists to stably introduce a foreign gene into a host cell's genome.

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<i>Escherichia virus T4</i> Species of bacteriophage

Escherichia virus T4 is a species of bacteriophages that infect Escherichia coli bacteria. It is a double-stranded DNA virus in the subfamily Tevenvirinae of the family Straboviridae. T4 is capable of undergoing only a lytic life cycle and not the lysogenic life cycle. The species was formerly named T-even bacteriophage, a name which also encompasses, among other strains, Enterobacteria phage T2, Enterobacteria phage T4 and Enterobacteria phage T6.

<i>Mycobacterium smegmatis</i> Species of bacterium

Mycobacterium smegmatis is an acid-fast bacterial species in the phylum Actinomycetota and the genus Mycobacterium. It is 3.0 to 5.0 μm long with a bacillus shape and can be stained by Ziehl–Neelsen method and the auramine-rhodamine fluorescent method. It was first reported in November 1884, who found a bacillus with the staining appearance of tubercle bacilli in syphilitic chancres. Subsequent to this, Alvarez and Tavel found organisms similar to that described by Lustgarten also in normal genital secretions (smegma). This organism was later named M. smegmatis.

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<i>Mycobacteroides abscessus</i> Species of bacterium

Mycobacteroides abscessus is a species of rapidly growing, multidrug-resistant, nontuberculous mycobacteria (NTM) that is a common soil and water contaminant. Although M. abscessus most commonly causes chronic lung infection and skin and soft tissue infection (SSTI), it can also cause infection in almost all human organs, mostly in patients with suppressed immune systems. Amongst NTM species responsible for disease, infection caused by M. abscessus complex are more difficult to treat due to antimicrobial drug resistance.

Giles is a bacteriophage that infects Mycobacterium smegmatis bacteria. The genome of this phage is very different from that of other mycobacteriophages and is highly mosaic. More than half of its predicted genes are novel and are not seen in other species.

Mycobacterium virus L5 is a bacteriophage known to infect bacterial species of the genus Mycobacterium, including Mycobacterium smegmatis and Mycobacterium tuberculosis. The viral effect on these species plays an important role in vaccine development and research on Mycobacteria pathogenic properties. Hatfull, Graham F.; Sarkis, Gary J.. "DNA sequence, structure and gene expression of mycobacteriophage L5: a phage system for mycobacterial genetics". Molecular Microbiology. 7 (3): 395–405. doi:10.1111/j.1365-2958.1993.tb01131.x. PMID 8459766. S2CID 10188307.</ref>

Gordonia is a genus of gram-positive, aerobic, catalase-positive bacterium in the Actinomycetota, closely related to the Rhodococcus, Mycobacterium, Skermania, and Nocardia genera. Gordonia bacteria are aerobic, non-motile, and non-sporulating. Gordonia is from the same lineage that includes Mycobacterium tuberculosis. The genus was discovered by Tsukamura in 1971 and named after American bacteriologist Ruth Gordon. Many species are often found in the soil, while other species have been isolated from aquatic environments. Some species have been associated with problems like sludge bulking and foaming in wastewater treatment plants. Gordonia species are rarely known to cause infections in humans.

Mycobacterium virus Patience, also called Patience, is a bacteriophage that infects Mycobacterium smegmatis bacteria. The large difference between the GC content of this virus's genome (50.3%) and that of its host (67.4%) indicate Patience likely evolved among bacteria of lower GC content but was able to infect M. smegmatis as well. It is the only species of the genus Patiencevirus.

The Mycobacterial 2 TMS Phage Holin Family is a group of transporters belonging to the Holin Superfamily VII. The Mycobactrerial 2 transmembrane segment (TMS) Holins have been identified and recognized by Catalao et al (2012). The Mycobacterium phage D29 gp11 protein is a holin that, upon expression, rapidly kills both E. coli and Mycobacterium smegmatis. Shortening gp11 from its C-terminus resulted in diminished cytotoxicity and smaller holes. The two TMSs at the N-terminus alone do not integrate into the cytoplasmic membrane and do not show toxicity. Fusion of the two TMSs and a small C-terminal coiled-coil region resulted in restoration of cell killing. The second TMS is dispensable for toxicity. The gp11 C-terminal region is therefore necessary but not sufficient for toxicity.

Mycobacterium virus Jeffabunny is a bacteriophage known to infect bacterial species of the genus Mycobacterium. It was discovered by Jeffrey Rubin in 2008 in a Howard Hughes Medical Institute funded lab as part of SEA-PHAGES. It was taken from surface soil in a planter, in the shade of a non-redwood tree at Merrill College found infecting, specifically, Mycobacterium smegmatis.

<span class="mw-page-title-main">PhagesDB</span>

The Actinobacteriophage database, more commonly known as PhagesDB, is an interactive, comprehensive, database-backed website that collects and shares information related to the discovery, characterization and genomics of viruses that typically infect Actinobacterial hosts. It is used to compare these phages and their genomic annotations, allowing the research community to post new findings for analysis. The database provides information on more than 8,000 bacteriophages, as well as over 1,600 fully sequenced phages.

Unicornvirus is a genus of bacteriophage viruses in the class Caudoviricetes. The genus was named for the first virus of this type, Unicornvirus unicorn, which was originally called "Mycobacterium phage Unicorn".

References

  1. ↑ Padilla Sanchez, V. (2024). Bacteriophage Bxb1 Structure. Zenodo. https://doi.org/10.5281/zenodo.14186241
  2. ↑ Mankiewicz E (September 1961). "Mycobacteriophages isolated from persons with tuberculous and non-tuberculous conditions". Nature. 191 (4796): 1416–1417. Bibcode:1961Natur.191.1416M. doi:10.1038/1911416b0. PMID   14469307. S2CID   4263411.
  3. 1 2 3 "Mycobacteriophage Database". Phagesdb.org. Retrieved 4 September 2017.
  4. ↑ Hatfull GF (13 October 2010). "Mycobacteriophages: genes and genomes". Annual Review of Microbiology. 64 (1): 331–356. doi:10.1146/annurev.micro.112408.134233. PMID   20528690.
  5. ↑ Pope WH, Jacobs-Sera D, Russell DA, Peebles CL, Al-Atrache Z, Alcoser TA, et al. (January 2011). "Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution". PLOS ONE. 6 (1): e16329. Bibcode:2011PLoSO...616329P. doi: 10.1371/journal.pone.0016329 . PMC   3029335 . PMID   21298013.
  6. ↑ Gardner GM, Weiser RS (October 1947). "A bacteriophage for Mycobacterium smegmatis". Proceedings of the Society for Experimental Biology and Medicine. 66 (1): 205–206. doi:10.3181/00379727-66-16037. PMID   20270730. S2CID   20772051.
  7. ↑ Froman S, Will DW, Bogen E (October 1954). "Bacteriophage active against virulent Mycobacterium tuberculosis. I. Isolation and activity". American Journal of Public Health and the Nation's Health. 44 (10): 1326–1333. doi:10.2105/AJPH.44.10.1326. PMC   1620761 . PMID   13197609.
  8. ↑ Cater JC, Redmond WB (May 1963). "Mycobacterial phages isolated from stool specimens of patients with pulmonary disease". The American Review of Respiratory Disease. 87: 726–729. doi:10.1164/arrd.1963.87.5.726 (inactive 1 November 2024). PMID   14019331.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
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  10. ↑ Dedrick RM, Marinelli LJ, Newton GL, Pogliano K, Pogliano J, Hatfull GF (May 2013). "Functional requirements for bacteriophage growth: gene essentiality and expression in mycobacteriophage Giles". Molecular Microbiology. 88 (3): 577–589. doi:10.1111/mmi.12210. PMC   3641587 . PMID   23560716.
  11. ↑ "By host genera: Mycobacterium". The Actinobacteriophage Database. Retrieved 10 May 2023.
  12. ↑ "Taxonomy browser (Mycobacterium phage L5)". www.ncbi.nlm.nih.gov.
  13. ↑ "Taxonomy browser (Timquatrovirus)". www.ncbi.nlm.nih.gov.
  14. ↑ "Taxonomy browser (Corndogvirus)". www.ncbi.nlm.nih.gov.
  15. 1 2 3 4 Jacobs-Sera D, Marinelli LJ, Bowman C, Broussard GW, Guerrero Bustamante C, Boyle MM, et al. (Science Education Alliance Phage Hunters Advancing Genomics And Evolutionary Science Sea-Phages Program) (December 2012). "On the nature of mycobacteriophage diversity and host preference". Virology. 434 (2): 187–201. doi:10.1016/j.virol.2012.09.026. PMC   3518647 . PMID   23084079.
  16. ↑ Hatfull GF, Sarkis GJ (February 1993). "DNA sequence, structure and gene expression of mycobacteriophage L5: a phage system for mycobacterial genetics". Molecular Microbiology. 7 (3): 395–405. doi:10.1111/j.1365-2958.1993.tb01131.x. PMID   8459766. S2CID   10188307.
  17. ↑ Pedulla ML, Ford ME, Houtz JM, Karthikeyan T, Wadsworth C, Lewis JA, et al. (April 2003). "Origins of highly mosaic mycobacteriophage genomes". Cell. 113 (2): 171–182. doi: 10.1016/S0092-8674(03)00233-2 . PMID   12705866. S2CID   14055875.
  18. 1 2 Hatfull GF, Jacobs-Sera D, Lawrence JG, Pope WH, Russell DA, Ko CC, et al. (March 2010). "Comparative genomic analysis of 60 Mycobacteriophage genomes: genome clustering, gene acquisition, and gene size". Journal of Molecular Biology. 397 (1): 119–143. doi:10.1016/j.jmb.2010.01.011. PMC   2830324 . PMID   20064525.
  19. ↑ Jones WD (1975). "Phage typing report of 125 strains of "Mycobacterium tuberculosis"". Annali Sclavo; Rivista di Microbiologia e di Immunologia. 17 (4): 599–604. PMID   820285.
  20. ↑ Jacobs WR Jr. 2000. Mycobacterium tuberculosis: a once genetically intractable organism. In Molecular Genetics of the Mycobacteria, ed. GF Hatfull, WR Jacobs Jr, pp. 1–16. Washington, DC: ASM Press
  21. ↑ Jacobs WR, Tuckman M, Bloom BR (1987). "Introduction of foreign DNA into mycobacteria using a shuttle phasmid". Nature. 327 (6122): 532–535. Bibcode:1987Natur.327..532J. doi:10.1038/327532a0. PMID   3473289. S2CID   9192407.
  22. ↑ Mulvey MC, Sacksteder KA, Einck L, Nacy CA (2012). "Generation of a novel nucleic acid-based reporter system to detect phenotypic susceptibility to antibiotics in Mycobacterium tuberculosis". mBio. 3 (2): e00312–11. doi:10.1128/mBio.00312-11. PMC   3312217 . PMID   22415006.
  23. ↑ Danelishvili L, Young LS, Bermudez LE (2006). "In vivo efficacy of phage therapy for Mycobacterium avium infection as delivered by a nonvirulent mycobacterium". Microbial Drug Resistance. 12 (1): 1–6. doi:10.1089/mdr.2006.12.1. PMID   16584300.
  24. ↑ McNerney R, Traoré H (2005). "Mycobacteriophage and their application to disease control". Journal of Applied Microbiology. 99 (2): 223–233. doi:10.1111/j.1365-2672.2005.02596.x. PMID   16033452. S2CID   43134099.
  25. ↑ Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, et al. (May 2019). "Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus". Nature Medicine. 25 (5): 730–733. doi:10.1038/s41591-019-0437-z. PMC   6557439 . PMID   31068712.
  26. ↑ Nick JA, Dedrick RM, Gray AL, Vladar EK, Smith BE, Freeman KG, et al. (May 2022). "Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection". Cell. 185 (11): 1860–1874.e12. doi:10.1016/j.cell.2022.04.024. PMC   9840467 . PMID   35568033. S2CID   248755782.

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