FEMS Microbiology Letters, 363, 2016, fnw047
doi: 10.1093/femsle/fnw047
Advance Access Publication Date: 29 February 2016
Minireview
M I N I R E V I E W – Virology
Diversity of phage infection types and associated
terminology: the problem with ‘Lytic or lysogenic’
Zack Hobbs1 and Stephen T. Abedon2,∗
1
EpiBiome, Inc., 329 Oyster Point Blvd, South San Francisco, CA 94080, USA and 2 Department of Microbiology,
The Ohio State University, 1680 University Dr., Mansfield, OH 44906, USA
∗
Corresponding author: Department of Microbiology, The Ohio State University, 1680 University Dr., Mansfield, OH 44906, USA. Tel: +419-755-4343;
Fax: +419-755-4327; E-mail: [email protected]
One sentence summary: The phrase ‘Lytic or lysogenic’ we suggest can be problematic as most phages that display lysogeny also are ‘Lytic’ while
bacteria are lysogenic, not phages.
Editor: Andrew Millard
ABSTRACT
Bacteriophages, or phages, are viruses of members of domain Bacteria. These viruses play numerous roles in shaping the
diversity of microbial communities, with impact differing depending on what infection strategies specific phages employ.
From an applied perspective, these especially are communities containing undesired or pathogenic bacteria that can be
modified through phage-mediated bacterial biocontrol, that is, through phage therapy. Here we seek to categorize phages in
terms of their infection strategies as well as review or suggest more descriptive, accurate or distinguishing terminology.
Categories can be differentiated in terms of (1) whether or not virion release occurs (productive infections versus lysogeny,
pseudolysogeny and/or the phage carrier state), (2) the means of virion release (lytic versus chronic release) and (3) the
degree to which phages are genetically equipped to display lysogenic cycles (temperate versus non-temperate phages). We
address in particular the use or overuse of what can be a somewhat equivocal phrase, ‘Lytic or lysogenic’, especially when
employed as a means of distinguishing among phages types. We suggest that the implied dichotomy is inconsistent with
both modern as well as historical understanding of phage biology. We consider, therefore, less ambiguous terminology for
distinguishing between ‘Lytic’ versus ‘Lysogenic’ phage types.
Keywords: lytic phage; obligately lytic; phage therapy; professionally lytic; strictly lytic; temperate phage
INTRODUCTION
In this minireview we consider the diversity of phage types as
based on potential infection strategies, particularly productive
or lysogenic along with lytic release versus chronic release, with
emphasis on what major variants should be called (see Table 1
for glossary of terms). In a few of these cases, efforts towards
naming do not appear to have been a priority within the community. In other cases, perhaps too many names exist, at least
some of which are less precise than may be desirable. We place
particular emphasis on addressing what we will argue is common misuse of the phrase, ‘Lytic or lysogenic’, as a means of dis-
tinguishing non-temperate from temperate phages. We begin,
however, with a scheme for classifying phages, in terms of infection strategies, into four distinct categories: (I) lytic and nontemperate, (II) chronic and non-temperate, (III) lytic and temperate or (IV) chronic and temperate.
Strategies of phage infection and release
Phages can be defined as semi-autonomous genetic elements
that at some point in their life cycles exist as encapsidated
genomes, particularly infectious capsids that are not found
within the bounds of host cells. Most viruses can be defined
Received: 31 January 2016; Accepted: 23 February 2016
C FEMS 2016. All rights reserved. For permissions, please e-mail: [email protected]
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FEMS Microbiology Letters, 2016, Vol. 363, No. 7
Table 1. Glossary of terms.
Term
Statesa
Clear mutant
Phagesb
Categoryc
Definition as employed here
λ mutant
I
Mutated temperate phage that as a consequence is unable to display
lysogenic cycles and thus forms clear rather than turbid plaques
Productive infections in which virions are released over long intervals
without substantial disruption of host cells
Phage whose productive infection is chronic (may or may not be a temperate
phage)
Chronic phage that is able to display lysogenic cycles, i.e. during which
virions are neither produced nor released
Referring to virion maturation during release, e.g. as seen with filamentous
phages
Referring to virion maturation prior to release, e.g. as seen with tailed phages
Mature virion that is extracellularly located
Intracellular transition of a lysogenic infection to a productive infection
For bacteriophages, these predominantly are lysogenic infections
Phage replication as a prophage that does not directly result in virion
production or release
Ongoing phage existence as a prophage
Bacterium that is latently infected with a temperate phage
Property of a bacterium indicating that it is hosting a prophage/lysogenic
cycle
Property of a bacterium indicating an ability to release factors that are able
to lyse other bacterial cultures
Ability to generate lysis in bacterial cultures
A prophage-containing latent phage infection
Productive infections in which phage virions are released over short
intervals with lethal disruption of host cells
Vegetative phage replication that ends with lysis
Productive infection in which virions are released via host-cell lysis
Phage whose productive infection is lytic (may nor may not be a temperate
phage)
Lytic phage that is able to display lysogenic cycles
Description of a phage that is unable to display lysogenic cycles
Phage that upon infection is inherently unable to display lysogenic cycles or
chronic release
Phage that upon infection is inherently unable to display lysogenic cycles
Vegetative phage replication associated with either chronic or lytic release
Product of either adsorption or induction involving vegetative state and
subsequent phage release
Phage that is both obligately lytic and not recently descended from a
temperate ancestor
Phage genome as it exists during lysogenic cycles
Latent infection during which neither phage genome replication nor
prophage formation occurs; other definitions exist and in some cases the
phrase ‘carrier state’ has been used synonymously
Used synonymously with obligately lytic
Description of a phage that is able to display lysogenic cycles
An intracellular phage genome that has not been packaged into a virion
particle
Replicating phage genome that is not a prophage (contrast both lysogenic
and pseudolysogenic)
Description of ability of phage populations to lyse cultures of bacterial hosts
Often used synonymously with obligately lytic
Clear temperate phage mutant that can form plaques even on lysogens
formed by the phage wild-type parent
Chronic
D
M13, CTX
II, IV
Chronic phage
D
M13, CTX
II, IV
Chronic temperate phage
P,V,D
CTX
IV
Encapsidated during release
D
M13, CTX
II, IV
Encapsidated intracellularly
Free phage
Induction
Latent infection
Lysogenic cycle
B
F
V
P
P
T4, λ
All
λ, CTX
λ, CTX
λ, CTX
I, III
All
III, IV
III, IV
III, IV
Lysogenic infection
Lysogen
Lysogenic (current def.)
P
P
P
λ, CTX
λ, CTX
λ, CTX
III, IV
III, IV
III, IV
λ
III
Lysogenic (historical def.)
Lysogenic (literal def.)
Lysogeny
Lytic
P
B
T4, λ
λ, CTX
T4, λ
I, III
III, IV
I, III
Lytic cycle
Lytic infection
Lytic phage
B
B
B
T4, λ
T4, λ
T4, λ
I, III
I, III
I, III
Lytic temperate phage
Non-temperate
Obligately lytic
P,V,B
V
B
λ
T4, M13
T4
III
I, II
I
Obligately productive
Productive cycle
Productive infection
B
V
V
T4, M13
All
All
I, II
All
All
Professionally lytic
B
T4
I
Prophage
Pseudolysogeny
P
λ, CTX
III, IV
Strictly lytic
Temperate
Unencapsidated
B
P,V
T4
λ, CTX
All
I
III, IV
All
Vegetative
V
All
All
Virulence
Virulent
Virulent mutant
B
B
B
T4
λ mutant
I
I
a
‘States’ refers to distinguishing characteristics as abbreviated throughout the manuscript: ‘B’ refers to phage genome packaging and virion maturation that occurs
Before virion release (property of lytic phages only), ‘D’ refers to phage genome packaging and virion maturation that occurs During virion release (property of chronic
phages only), ‘F’ refers to Free phages, ‘P’ refers to existence as a Prophage (a property only of temperate phages), ‘V’ refers to display of a Vegetative phase. Vegetative
phases are a property of all productive phage infections, though to avoid clutter this is mostly not explicitly indicated in the table. Either B or D states also are properties
of all productive phage infections as too, post infection, is the F state. The sequence ‘P,V’ indicates the existence of either Prophage or Vegetative states. P and V will
not occur simultaneously during the same infection though can occur sequentially, particularly P → V, which then will proceed through B or D states depending on
the phage, culminating in all cases, post successful productive infection, in an F state.
b
Example phages are as discussed in the main text.
c
Categories are ‘I’ meaning lytic and non-temperate, ‘II’ meaning chronic and non-temperate, ‘III’ meaning lytic and temperate and ‘IV’ meaning chronic and temperate.
Hobbs and Abedon
similarly, though especially fungal viruses (mycoviruses) do not
necessarily exist as host-unassociated virions or, in a few instances, even as encapsidated genomes (Hyman and Abedon
2012). Here, however, our emphasis primarily is on bacteriophages.
Phages, in terms of their encapsidation and location, can exist in three possible states: (1) intracellularly and unencapsidated, (2) intracellularly and packaged within mature virions or
(3) both encapsidated and extracellular. The first state (1) can
be further subdivided into what can be described as a “Vegetative phase” (Lwoff 1953), or productive cycle, versus existing as a prophage, that is, instead displaying a lysogenic cycle.
The second state (2) can be distinguished from phage genomes
that instead are not packaged until the virion release step. The
third state (3) consists of free phages, that is, assembled virions that are no longer found within their bacterial host. Abbreviations used henceforward to describe these different states
include V for Vegetative phase, P for Prophage, B for genome
packaging into mature virions Before release, D for genome
packaging into mature virions During release and F for Free
phages.
To distinguish among phages, but intentionally without using more standard terms as otherwise are under discussion,
we categorize phages into four distinct types using the ab-
3
breviations introduced at the end of the previous paragraph.
These are
I.
II.
III.
IV.
‘V → B → F’ phages
‘V → D → F’ phages
‘V or P → B → F’ phages
‘V or P → D → F’ phages
The phrase ‘V or P’ is intended to imply that these phages
can display either V- or, instead, P- and then V-type infection
states, i.e. Vegetative or Prophage states (Table 1). Productive infections, ones which produce Free phage virions (‘F’), can be contrasted with infections that instead may be described as ‘Reductive’ (Lwoff 1953), particularly lysogenic infections (‘P’) but also,
though not otherwise considered here, pseudolysogenic ones
(Miller and Day 2008; Abedon 2009; Abedon, Duffy and Turner
2009; Los and Wegrzyn 2012).
In more familiar terms, the phage types described above and
in Fig. 1 thus include the following: (I) lytic phages that do not
display lysogenic cycles (‘V → B → F’ phages), (II) chronically released phages that do not display lysogenic cycles (‘V → D →
F’), (III) lytic phages that can display lysogenic cycles (i.e. temperate phages; ‘V or P → B → F’) and (IV) chronically released
phages also that can display lysogenic cycles (which are temperate phages as well; ‘V or P → D → F’). In other words, we can
Figure 1. Distinguishing among phage states. Intracellularly and unencapsidated, phages can exist in Vegetative versus Prophage forms. Maturation of virion particles
can be completed either Before or During virion release (corresponding to lytic versus chronic release, respectively). Lytic phages here are indicated as tailed. Though
most tailless phages likely are lytic phages as well, members of phage families Inoviridae and Plasmaviridae are exceptions. Chronically released phages are indicated
as filamentous, i.e. members of phage family Inoviridae. The four categories of phage types, as indicated with I, II, III or IV to the left of the figure, are named to the
right, with the list found at the top and corresponding to ‘I’ consisting of multiple synonyms for ‘Lytic, non-temperate’.
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FEMS Microbiology Letters, 2016, Vol. 363, No. 7
Table 2. Distinguishing among different phage types in terms of basic phage infection properties.a
Phage types (below; characteristics to right)
Vb
Pc
V or P → Vd
Be
Df
Fg
All phages (I, II, III or IV)
Obligately Productive (I or II)h
Chronic (II or IV)
Obligately Chronic (II)i
Lytic (I or III)
Obligately or Strictly Lytic (I)
Professionally Lytic (I)
Virulent, meaning Obligately Lytic (I)
Virulent, meaning Highly Destructive of Cultures (I)j
Virulent, meaning Mutant of a Temperate Phage (I)
Temperate (III or IV)
+
+
+
+
+
+
+
+
+
+
+
±
−
±
−
±
−
−
−
−
−
+
±
±
±
±
±
±
−
±
±
+
×
±
±
−
−
+
+
+
+
+
+
±
±
±
+
+
−
−
−
−
−
−
±
+
+
+
+
+
+
+
+
+
+
+
a
‘+’ implies always a characteristic of, ‘−’ implies never a characteristic of and ‘±’ implies may or may not be a characteristic of.
Can exist in a Vegetative state, which is a reproductive, non-prophage, bacterium-infecting, phage genome.
c
Can exist as a prophage, at least for a given host and conditions; distinguishes temperate (+) from non-temperate (−) phages.
d
Mutant and/or descendant of temperate phage, one that no longer can display lysogenic cycles; distinguishes obligately productive descendants of temperate phages
(+) from either obligately productive phages that are not descendants of temperate phages (−) or that simply are temperate phages themselves and therefore not
obligately productive (×).
e
Exists as a mature virion prior to release from host bacteria; distinguishes chronic (−) from lytic (+) phages.
f
Does not exist as a mature virion prior to release from host bacteria; distinguishes chronic (+) from lytic (−) phages.
g
Exists as a free phage at some point in life cycle.
h
Not a commonly used descriptor.
i
Not a commonly used descriptor.
j
In this case the culture in question is assumed to consist exclusively of bacteria that do not support lysogenic infections by the phage in question, even if that phage
is capable of displaying lysogenic infections when infecting different bacterial strains.
b
contrast phage types into lytic versus chronic (‘B’ versus ‘D’
phages) as well as not-temperate versus temperate (‘V-only’ versus ‘V or P’ phages). See Table 1 and Table 2 for further consideration.
See Abedon (2008) and Abedon, Duffy and Turner (2009) for
additional discussion of phage types distinguished by infection
characteristics as well as Calendar and Abedon (2006) for numerous individual reviews of specific phage types. See Table 1 for association of these phage types with specific terms and concepts
as considered in this minireview.
Example phages
Examples of obligately lytic phages (category I) include Max
Delbrück’s well-studied tailed phages T1-T7 (Abedon 2000), with
phage T4 the most thoroughly studied (Karam 1994; Miller et al.
2003). While tailed phages are always lytic, they are not always obligately lytic (i.e. see category III, below). RNA-genomed
phages of families Leviviridae (van Duin and Tsareva 2006)
and Cystoviridae (Mindich 2006) we can speculate are consistently obligately lytic. The Microviridae (Fane et al. 2006),
however, may include members which are not obligately lytic
(Krupovic and Forterre 2011). Note that there exists as well
variation on how lysis is induced by various lytic phages
(Young 2014).
Phage M13 is one of the best studied category II phages
(non-temperate, chronic) (Russel and Model 2006). As with lysis, the mechanisms by which chronic release occurs varies
among phages, i.e. via extrusion as seen with phage family Inoviridae (Russel and Model 2006) versus via budding
as seen with phage family Plasmaviridae (Maniloff and
Dybvig 2006).
Phage λ is the most intensely studied of the tailed, temperate
phages (Hendrix et al. 1983; Ptashne 2004; Casjens and Hendrix
2015) and thereby is representative of category III.
Phage CTX (Mai-Prochnow et al. 2015), which encodes the
cholera toxin, is the most prominent example of category IV,
though with additional members of phage family Inoviridae also
thought to be temperate (Yamada et al. 2007). In addition, mycoplasma phage L2, a member of phage family Plasmaviridae
(Maniloff and Dybvig 2006), has been described as temperate
(Maniloff, Kampo and Dascher 1994).
Lytic or lysogenic
Use of the phrase ‘Lytic or lysogenic’ as a means of distinguishing among phage types may be becoming increasingly common
(e.g. see the following paragraph for its use in publications). This
we believe is of concern particularly during discussions of the
medical procedure known as a phage therapy (e.g. Kutter et al.
2010; Abedon et al. 2011; Abedon 2015), which as typically practiced tends to strive to avoid using phages that can be categorized into types II, III or IV, i.e. phages that are not obligately lytic.
In this section we therefore strive to illuminate the problems
associated with the dichotomy of ‘Lytic or lysogenic’, particularly as a means of distinguishing among phage types (‘phage’ or
‘phages’, etc. in the searches below), even if the intended meaning is not altogether lost.
Using Google Scholar, a search on ‘lytic or lysogenic phage’
OR ‘lytic or lysogenic phages’ OR ‘lytic or lysogenic bacteriophage’ OR ‘lytic or lysogenic bacteriophages’ (with quotation
marks) yielded 36 results. The dates of these results are 2015
(four results), 2014 (six), 2013 (six), 2012 (four), 2011 (four), 2010
(one), 2009 (two), 2007 (three), 2005 (two), 2002 (one), 1989 (one),
1984 (one) and 1967 (one), that is, most of this usage is fairly recent. At least one of these results, in 2015, refers, however, to a
‘lytic or lysogenic phage life cycle’ (emphasis added). By comparison, a Google Scholar search on ‘lytic or lysogenic cycle’ OR ‘lytic
or lysogenic cycles’ yields a total of 101 results. By decades, numbers are 2006–2015 (65 results), 1996–2005 (23), 1986–1995 (six),
and then two additional results from 1968. Both phrases thus
appear to be becoming increasingly part of the phage biology
vernacular.
Hobbs and Abedon
5
2005; Brüssow and Kutter 2005; Brüssow 2007; Letarov and
Kulikov 2009; Weiss et al. 2009; Letarov, Golomidova and
Tarasyan 2010; Sarker et al. 2012; Bourdin et al. 2014). All of these
terms are preferable to simply ‘Lytic’ when describing phages,
unless one is intentionally referring simultaneously to category
I phages (‘V → B → F’, i.e. strictly lytic) and category III phages
(‘V or P → B → F’, i.e. temperate phages that can display both lytic
and lysogenic cycles). That is, the phrase ‘Lytic phage’ (with 6080
Google Scholar results for a ‘lytic phage’ OR ‘lytic phages’ search)
distinguishes among phages particularly in terms of their mode
of virion release, lytic rather than chronic, rather than in terms
of their ability to display lysogenic cycles. These various phage
descriptors and others are summarized in Table 1. (For completeness, note that a ‘chronic phage’ OR ‘chronic phages’ search
yields 49 Google Scholar results.)
Figure 2. Comparison of per-year usage of ‘Lysogenic phage(s)’ (red filled, lower
curve) versus ‘Temperate phage(s)’ (green filled, upper curve). Though ‘Temperate phage(s)’ currently is used approximately twice as often as ‘Lysogenic
phage(s)’, in fact in modern times it was only in the late 1990s that this relative frequency was reached, suggesting a greater preference for ‘Temperate
phage(s)’ over ‘Lysogenic phage(s)’ over the roughly 40-year span from the mid1950s through to the mid-1990s. Similar trends were observed when ‘. . . phage. . . ’
and ‘. . . bacteriophage. . . ’ were simultaneously searched on. From 1920 through
1951, however, there are just 12 instances of ‘Lysogenic phage(s)’ or ‘Lysogenic
bacterophage(s)’ but only a single instance of ‘Temperate phage(s)’ or ‘Temperate bacterophage(s)’, the latter dating from 1948 and approximately coinciding
at least temporally with the discovery of prophage induction (Lwoff 1966).
Part of the problem with use of the phrase, ‘Lytic or lysogenic’,
is that bacteria can be lysogenic while phages instead can be
temperate, but not vice versa (see Fig. 2 for an exploration of
the history of the usage of ‘Lysogenic phage’ versus ‘Temperate
phage’). Thus, from Lwoff (1953), p. 271 (emphasis his): ‘Lysogeny
is the hereditary power to produce bacteriophage. A lysogenic
bacterium is a bacterium possessing and transmitting the power to
produce bacteriophage. Each bacterium of a lysogenic strain gives
rise to a lysogenic clone. . . ’ Also from Lwoff (1953), p. 273 (emphasis his): ‘The power to lysogenize is the property of temperate phages. . . ’ The vast majority of temperate phages in addition
display ‘Lytic’ cycles when productively infecting, that is, rather
than chronically releasing virion progeny, hence the term, ‘Lysogenic’, to describe them. What, then, is meant when contrasting
‘Lytic’ with ‘Lysogenic’?
Though most temperate phages during productive cycles release virions via lysis—that is, during lytic cycles—nonetheless
in all likelihood the intended use of ‘Lytic’ in ‘Lytic or lysogenic’
as descriptions of phage types is as shorthand for the ‘V → B
→ F’ (I) phages, that is, lytic, non-temperate phages. The term
‘Virulent’, however, is often employed preferentially to ‘Lytic,
non-temperate’ (Lwoff 1953), thus, ‘Virulent or lysogenic’ might
be employed rather than ‘Lytic or lysogenic’. Unfortunately, the
term virulent has had multiple meanings over the years with regard to phages (next section). To avoid this issue, it can be preferable, for example, to use the phrase ‘Obligately lytic’ instead of
‘Virulent’ to describe lytic, non-temperate phages. As an aside,
note that ‘obligatorily lytic’ (in quotation marks) yields 26 Google
Scholar results versus 142 for ‘obligately lytic’.
There exist additional terms that can be used equivalently to
‘Obligately lytic’. These include ‘Strictly lytic’ (which in a withinquotes Google Scholar search yields 223 results), ‘Obligate lytic’
(113 Google Scholar results), ‘Professionally lytic’ (10 results, e.g.
Brüssow and Kutter 2005; Kutter 2008; Henein 2013; Kutter et al.
2013; Miroshnikov et al. 2014), ‘Professionally virulent’ (Górski
et al. 2009) and ‘Professional virulent’ (nine results, e.g. Brüssow
Further arguments against ‘Virulent’
The term ‘Virulence’ can be used as a description of those
phages that are particularly adept at inflicting substantial destruction on their host (Smith, Huggins and Shaw 1987). Within
a historical context, this is as occurs primarily to bacterial
cultures rather than specifically to individual bacterial cells
(Summers 1991). Phages that are less adept at lysing bacterial cultures therefore can be described as being less ‘Virulent’.
These can include both temperate phages and also chronically
released phages, though the latter are not an emphasis of this
section. In the case of temperate phages, this lower virulence
occurs because a subset of individual phage infections display
lysogenic rather than lytic cycles. The resulting bacterial lysogens also tend to be insensitive to attempts at lytic infection by
the same phage types that are lysogenically infecting them—
due to display of superinfection immunity (Hershey and Dove
1983; Fogg et al. 2010; Hyman and Abedon 2010; Casjens and Hendrix 2015)—and therefore are inclined to resist phage-mediated
clearance.
A further complication on the term, ‘Virulent’, is that otherwise temperate phages that are genetically defective in their
ability to lysogenize are described as virulent mutants (Lwoff
1953) (2240 Google Scholar results for ‘virulent mutant’ OR ‘virulent mutants’; though refining the search to include the term
‘phage’, not in quotes, yields only 1140 results). Virulence, of
course, began as a term that was not specific to phage biology
and which, according to the Oxford Dictionary, dates back at
least to the 1800s in the English language. ‘Virulent’ was then legitimately coopted close to the beginning of the study of phage
biology to describe phages that in a traditional sense are indeed
more virulent, at least against bacterial cultures. The term then
came to be used to a large extent as a description of phages that
do not display lysogenic cycles and which otherwise are lytic, including as referring to virulent mutants of otherwise temperate
phages (Ptashne 2004).
The term ‘Obligately lytic’, or ‘Strictly lytic’, etc., contrasting
the ambiguity of ‘Virulent’, is meant to explicitly imply an unavoidable display of lytic, productive cycles upon successful infection (Abedon 2008). The term ‘Obligately productive’, though
almost never used (no PubMed hits and no Google Scholar hits
that are not associated with one of us), would imply a similarly
requisite display of either lytic or chronic infections, depending on the phage, rather than referring exclusively to lytic infections, as is implied by ‘Obligately lytic’. Consider also ‘Obligately chronic’ (Table 2). All of these terms can be viewed as
more-precise alternatives to the concept of ‘Virulent’ to describe
phages that are not temperate. In addition, note that obligately
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FEMS Microbiology Letters, 2016, Vol. 363, No. 7
Figure 3. Proposed usage. ‘Temperate phage’ is always preferable to ‘Lysogenic phage’. ‘Virulent mutant’ is not controversial. ‘Professionally lytic’ we support for
the usage as indicated. ‘Strictly lytic’ might be employed equivalently though is insufficiently robust, we feel, in conveying the latter’s meaning. ‘Obligately lytic’ or
‘Strictly lytic’ we suggest may be employed as the more general term for ‘Lytic and not temperate’, with ‘Virulent mutant’ or ‘Professionally lytic’ employed when
greater specificity is desired.
lytic phages may or may not be recent descendants of temperate
phages and thus may or may not represent virulent mutants.
Within this framework, what then is meant by ‘Lytic or lysogenic’? This question is particularly relevant within the context of phage therapy where ‘Lytic’ phages typically are considered to be preferable to ‘Lysogenic’ ones. One simple answer could be that ‘Lytic’ is being used equivalently to ‘Obligately lytic’ or ‘Strictly lytic’ as a substitute for ‘Virulent’. Such
usage can be problematic, however, since with phage therapy
a temperate phage ancestry can be of concern, even if lysogenic cycles themselves do not occur, since temperate phages
especially have been shown to carry bacterial virulence factor genes (Hyman and Abedon 2008; Kuhl, Hyman and Abedon
2012; Christie et al. 2012). In response to this concern, one
could replace ‘Lytic’—in ‘Lytic or lysogenic’—with the phrase,
‘Virulent meaning obligately lytic but nevertheless not a virulent
mutant of a temperate phage’. Obviously, however, such phrasing is too complex to become a part of everyday practice. Instead,
and perhaps ideally, one might, for example, use the otherwise
somewhat underutilized ‘Professionally lytic’ to specifically describe those phages that are both obligately lytic and not closely
related to temperate phages, that is, lytic phages that are both
not temperate and not virulent mutants of temperate phages
(Curtright and Abedon 2011). This perspective we summarize in
Fig. 3.
Lytic and Lysogenic
As alternatives to ‘Lytic or lysogenic’, we thus can have ‘Nontemperate or temperate’, ‘Virulent or temperate’, ‘Obligately
lytic or temperate’, ‘Strictly lytic or temperate’, ‘Virulent mutant
or temperate’ and/or ‘Professionally lytic or temperate’. ‘Lytic or
temperate’, by contrast, does not really work, despite the increasing popularity of ‘Lytic or lysogenic’ as a description of
phage types, since most temperate phages, as noted, are also
lytic phages. Nonetheless, what all of these alternative phrases
have in common is their use of the term, ‘Temperate’, and this
is rather than ‘Lysogenic’. What is the justification for this substitution?
‘Lysogenic’ literally means ‘Generating lysis’; see Lwoff (1953)
for discussion of the early history of the study of lysogeny. The
majority of phages, though, appear to be lysis generating. Indeed, that is precisely what should be meant by the term ‘Lytic
phage’—a lytic phage literally is a lysis-generating phage. As
a consequence, it logically can be preferable to state ‘Lytic and
lysogenic’ rather than ‘Lytic or lysogenic’. The apparent equivalence of these two terms—terms that in ‘Lytic or lysogenic’
seemingly are used to imply polar opposites—stems from an
error in usage. That is, rather than a description of a phage
property, the term ‘Lysogenic’ when correctly employed is a description of a bacterial property. Specifically, certain bacterial cultures exist that when added to cultures of certain other bacterial
strains can give rise to the lysis of these other cultures. The first
culture thus has the property of being able to generate lysis in
the second culture. This first culture therefore is lysis generating, that is, lysogenic (Lwoff 1953).
As scientific understanding has advanced, at least one of the
conditions associated with this lysogenic property, that it can be
a property of bacterial cultures, came to be associated with what
today we refer to as lysogens: bacteria that harbor prophages.
As part of this transition in meaning, note that Lwoff (1953), in
his classic review, does not appear to even use ‘Lysogen’ but instead refers to a ‘Lysogenic bacterium’, as too does Adams (1959),
though ‘Lysogen’ is found in Stent (1963). The term ‘Temperate
phage’, by contrast, does appear in Lwoff as does also ‘Temperate’ alone, as in, “The temperate or virulent character of a phage”
(p. 326).
Professionally Lytic or Temperate
With the phrase ‘Lytic or lysogenic’, as considered here, it is
probable that virulent, obligately lytic, or strictly lytic is what
generally is intended by ‘Lytic’, while ‘Temperate’ without question should replace ‘Lysogenic’. ‘Obligately lytic or temperate’
(four Google Scholar results), ‘Strictly lytic or temperate’ (two
Hobbs and Abedon
results), or instead ‘Virulent or temperate’ (136 results) therefore could be legitimate alternatives to ‘Lytic or lysogenic’. ‘Virulent’, though, and as noted, is burdened not only with historical ambiguity, but also may not be the most ideal of descriptors in terms of the marketing of virus-based medicinals. Indeed,
within a phage therapy context, ‘Professionally lytic or temperate’ (zero results in either Google Scholar or Google Books) would
seem to be the most meaningful alternative to the highly questionable, ‘Lytic or lysogenic’, that is, so long as ‘Professionally
lytic’ phages contrast not just with temperate phages but with
virulent derivatives of temperate phages as well (Table 2; Fig. 3).
We suggest therefore that an effort might be made to replace
even informal use of ‘Lytic or lysogenic’ with ‘Professionally lytic
or temperate’, assuming, of course, that this is the distinction
which is intended.
CONCLUSION
In this minireview, we have considered the diversity of phage
types from the perspective of productive versus lysogenic infections along with lytic versus chronic release. We have emphasized issues associated with use of the terms ‘Lytic’ and ‘Lysogenic’ as stand-alone descriptors of phages and their properties, which either can be ambiguous (as is the case for ‘Lytic’)
or etymologically inappropriate (for ‘Lysogenic’ as a descriptor of phages). In particular, we have criticized the phrasing,
‘Lytic or lysogenic’. We note as well that ‘Lysogenic’, logically,
should never be used in association with non-lytic viral release
from cells, that is, to describe phages that release their virions chronically or continuously from infected bacteria (category
II). ‘Lysogenic’, strictly speaking, also is not an accurate general descriptor of all phage latent infections since ‘Lysogens’ associated with non-lytic viruses (category IV), such as the filamentous phage, CTX (Mai-Prochnow et al. 2015), are not lysis
generating.
Despite our numerous concerns with use of the phrase, ‘Lytic
or lysogenic’, there nonetheless exist circumstances in which
the phrase unquestionably is valid. This is seen when describing
the initial infection of a bacterium by a lytic, temperate phage
(category III), such as phage λ, where the choice is between a
lytic cycle or, instead, a lysogenic cycle, thus, ‘Lytic or lysogenic
[cycles]’. The suitability of ‘Lytic or lysogenic’ as shorthand for
distinguishing among phage ‘infection’ types—particularly lytic
versus lysogenic ‘Cycles’ as one sees with phage λ—does not,
however, imply an equivalent legitimacy of extension of this
phrasing to distinguish among ‘Phage’ types.
ACKNOWLEDGEMENTS
STA has consulted and served on advisory boards for companies with phage therapy interests and maintains the websites phage.org and phage-therapy.org. ZH is an employee of
EpiBiome Inc., a phage-based biotech company. Neither received
help or financial support in writing the manuscript.
Conflict of interest. None declared.
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