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, the causative agent of tuberculosis, more than 4,200 mycobacteriophage have since been isolated from various environmental and clinical sources. 2,042 have been completely sequenced. Mycobacteriophages have served as examples of viral lysogeny and of the divergent morphology and genetic arrangement characteristic of many phage types.
All mycobacteriophages found thus far have had double-stranded DNA genomes and have been classified by their structure and appearance into siphoviridae or myoviridae.
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. The first bacteriophage that infects M. tuberculosis was discovered in 1954.
Diversity
Thousands of mycobacteriophage have been isolated using a single host strain, Mycobacterium smegmatis mc2155, over 1400 of which have been completely sequenced. These are mostly from environmental samples, but mycobacteriophages have also been isolated from stool samples of tuberculosis patients, although these have yet to be sequenced. 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).
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.
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.
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.
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: Phage L5 and its relatives are classified as Fromanvirus. See Mycobacterium virus L5. ZoeJ and TM4 are classified as Timquatrovirus (named after TM4). Phage "Corndog" is classified as Corndogvirus.
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). However, mutants can be readily isolated from some phages that expand their host range to infect these other strains. 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.
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.