scholarly journals Convergent evolution of pathogenicity islands in helper cos phage interference

2016 ◽  
Vol 371 (1707) ◽  
pp. 20150505 ◽  
Author(s):  
Nuria Carpena ◽  
Keith A. Manning ◽  
Terje Dokland ◽  
Alberto Marina ◽  
José R. Penadés
Keyword(s):  
Staphylococcus Aureus ◽  
Life Cycle ◽  
Convergent Evolution ◽  
Pathogenicity Islands ◽  
Capsid Assembly ◽  
Helper Phage ◽  
Phage Capsid ◽  
Helper Phages

Staphylococcus aureus pathogenicity islands (SaPIs) are phage satellites that exploit the life cycle of their helper phages for their own benefit. Most SaPIs are packaged by their helper phages using a headful ( pac ) packaging mechanism. These SaPIs interfere with pac phage reproduction through a variety of strategies, including the redirection of phage capsid assembly to form small capsids, a process that depends on the expression of the SaPI-encoded cpm A and cpm B genes. Another SaPI subfamily is induced and packaged by cos -type phages, and although these cos SaPIs also block the life cycle of their inducing phages, the basis for this mechanism of interference remains to be deciphered. Here we have identified and characterized one mechanism by which the SaPIs interfere with cos phage reproduction. This mechanism depends on a SaPI-encoded gene, ccm , which encodes a protein involved in the production of small isometric capsids, compared with the prolate helper phage capsids. As the Ccm and CpmAB proteins are completely unrelated in sequence, this strategy represents a fascinating example of convergent evolution. Moreover, this result also indicates that the production of SaPI-sized particles is a widespread strategy of phage interference conserved during SaPI evolution. This article is part of the themed issue ‘The new bacteriology’.

scholarly journals How pirate phage interferes with helper phage: Comparison of the two distinct strategies

2019 ◽  
Author(s):  
Namiko Mitarai
Keyword(s):  
Staphylococcus Aureus ◽  
Structural Proteins ◽  
Phage Gene ◽  
Competing Interests ◽  
Helper Phage ◽  
System A ◽  
Phage Production ◽  
Competing Interest ◽  
Uninfected Host ◽  
Helper Phages

AbstractPirate phages use the structural proteins encoded by unrelated helper phages to propagate. The best-studied example is the pirate P4 and helper P2 of coliphages, and it has been known that theStaphylococcus aureuspathogenicity islands (SaPIs) that can encode virulence factors act as pirate phages, too. When alone in the host, the pirate phages act as a prophage, but when the helper phage gene is also in the same host cell, the pirate phage has ability to exploit the helper phages structural proteins to produce pirate phage particles and spread, interfering with the helper phage production. The known helper phages in these systems are temperate phages. Interestingly, the interference of the pirate phage to the helper phage occurs in a different manner between the SaPI-helper system and the P4-P2 system. SaPIs cannot lyse a helper lysogen upon infection, while when a helper phage lyse a SaPI lysogen, most of the phage particles produced are the SaPI particles. On the contrary, in the P4-P2 system, a pirate phage P4 can lyse a helper P2 lysogen to produce mostly the P4 particles, while when P2 phage lyses a P4 lysogen, most of the produced phages are the P2 particles. Here, the consequences of these different strategies in the pirate and helper phage spreading among uninfected host is analyzed by using mathematical models. It is found that SaPI’s strategy interferes with the helper phage spreading significantly more than the P4’s strategy, because SaPI interferes with the helper phage’s main reproduction step, while P4 interferes only by forcing the helper lysogens to lyse. However, the interference is found to be weaker in the spatially structured environment than in the well-mixed environment. This is because, in the spatial setting, the system tends to self-organize so that the helper phages take over the front of propagation due to the need of helper phage for the pirate phage spreading.Competing interestsThe author declares no competing interest.

scholarly journals Shape shifter: redirection of prolate phage capsid assembly by staphylococcal pathogenicity islands

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
N’Toia C. Hawkins ◽  
James L. Kizziah ◽  
José R. Penadés ◽  
Terje Dokland
Keyword(s):  
Electron Microscopy ◽  
Staphylococcus Aureus ◽  
Capsid Protein ◽  
Pathogenicity Islands ◽  
Size And Shape ◽  
Cryo Electron Microscopy ◽  
Phage Multiplication ◽  
End Caps ◽  
Phage Capsid ◽  
Preferential Incorporation

AbstractStaphylococcus aureus pathogenicity islands (SaPIs) are molecular parasites that hijack helper phages for their transfer. SaPIbov5, the prototypical member of a family of cos type SaPIs, redirects the assembly of ϕ12 helper capsids from prolate to isometric. This size and shape shift is dependent on the SaPIbov5-encoded protein Ccm, a homolog of the ϕ12 capsid protein (CP). Using cryo-electron microscopy, we have determined structures of prolate ϕ12 procapsids and isometric SaPIbov5 procapsids. ϕ12 procapsids have icosahedral end caps with Tend = 4 architecture and a Tmid = 14 cylindrical midsection, whereas SaPIbov5 procapsids have T = 4 icosahedral architecture. We built atomic models for CP and Ccm, and show that Ccm occupies the pentameric capsomers in the isometric SaPIbov5 procapsids, suggesting that preferential incorporation of Ccm pentamers prevents the cylindrical midsection from forming. Our results highlight that pirate elements have evolved diverse mechanisms to suppress phage multiplication, including the acquisition of phage capsid protein homologs.

scholarly journals Role of Staphylococcal Phage and SaPI Integrase in Intra- and Interspecies SaPI Transfer

2007 ◽  
Vol 189 (15) ◽  
pp. 5608-5616 ◽  
Author(s):  
Elisa Maiques ◽  
Carles Úbeda ◽  
María Ángeles Tormo ◽  
María Desamparados Ferrer ◽  
Íñigo Lasa ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Special Reference ◽  
Attachment Site ◽  
Pathogenicity Islands ◽  
Specific Attachment ◽  
Generalized Transduction

ABSTRACT SaPIbov2 is a member of the SaPI family of staphylococcal pathogenicity islands and is very closely related to SaPIbov1. Typically, certain temperate phages can induce excision and replication of one or more of these islands and can package them into special small phage-like particles commensurate with their genome sizes (referred to as the excision-replication-packaging [ERP] cycle). We have studied the phage-SaPI interaction in some depth using SaPIbov2, with special reference to the role of its integrase. We demonstrate here that SaPIbov2 can be induced to replicate by different staphylococcal phages. After replication, SaPIbov2 is efficiently encapsidated and transferred to recipient organisms, including different non-Staphylococcus aureus staphylococci, where it integrates at a SaPI-specific attachment site, attC , by means of a self-coded integrase (Int). Phages that cannot induce the SaPIbov2 ERP cycle can transfer the island by recA-dependent classical generalized transduction and can also transfer it by a novel mechanism that requires the expression of SaPIbov2 int in the recipient but not in the donor. It is suggested that this mechanism involves the encapsidation of standard transducing fragments containing the intact island followed by int-mediated excision, circularization, and integration in the recipient.

scholarly journals Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly.

2020 ◽  
Author(s):  
Jonathan C. Reed ◽  
Dennis Solas ◽  
Anatoliy Kitaygorodskyy ◽  
Beverly Freeman ◽  
Dylan T. B. Ressler ◽  
...  
Keyword(s):  
Life Cycle ◽  
Virus Production ◽  
Life Cycle Stage ◽  
Multidrug Resistant ◽  
Capsid Assembly ◽  
Resistance Mutations ◽  
Life Cycle Stages ◽  
Human T Cell ◽  
Gag Assembly ◽  
Hiv 1

Given the projected increase in multidrug resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life-cycle stages not targeted by drugs currently in use. Host-targeting compounds are of particular interest because they can offer a high barrier to resistance. Here we report identification of two related small molecules that inhibit HIV-1 late events, an HIV-1 life cycle stage for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and PBMCs and are effective against a primary isolate. They reduce virus production, likely by inhibiting a post-translational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gag in situ; however, unexpectedly, selection experiments failed to identify compound-specific resistance mutations in gag or pol, even though known resistance mutations developed upon parallel nelfinavir selection. Thus, we hypothesized that instead of binding to Gag directly, these compounds localize to assembly intermediates, the intracellular multiprotein complexes containing Gag and host factors that form during immature HIV-1 capsid assembly. Indeed, imaging of infected cells shows compound colocalized with two host enzymes found in assembly intermediates, ABCE1 and DDX6, but not two host proteins found in other complexes. While the exact target and mechanism of action of this chemotype remain to be determined, these findings suggest that these compounds represent first-in-class, host-targeting inhibitors of intracellular events in HIV-1 assembly. IMPORTANCE The success of antiretroviral treatment for HIV-1 is at risk of being undermined by the growing problem of drug resistance. Thus, there is a need to identify antiretrovirals that act on viral life cycle stages not targeted by drugs in use, such as the events of HIV-1 Gag assembly. To address this gap, we developed a compound screen that recapitulates the intracellular events of HIV-1 assembly, including viral-host interactions that promote assembly. This effort led to identification of a new chemotype that inhibits HIV-1 replication at nanomolar concentrations, likely by acting on assembly. This compound colocalized with Gag and two host enzymes that facilitate capsid assembly. However, resistance selection did not result in compound-specific mutations in gag, suggesting that the chemotype does not directly target Gag. We hypothesize that this chemotype represents a first-in-class inhibitor of virus production that acts by targeting a viral-host complex important for HIV-1 Gag assembly.

scholarly journals Sip, an integrase protein with excision, circularization and integration activities, defines a new family of mobile Staphylococcus aureus pathogenicity islands

2003 ◽  
Vol 49 (1) ◽  
pp. 193-210 ◽  
Author(s):  
Carles Úbeda ◽  
Ma. Ángeles Tormo ◽  
Carme Cucarella ◽  
Pilar Trotonda ◽  
Timothy J. Foster ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pathogenicity Islands ◽  
New Family ◽  
Integrase Protein

scholarly journals Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

2020 ◽  
Author(s):  
Jonathan C. Reed ◽  
Dennis Solas ◽  
Anatoliy Kitaygorodskyy ◽  
Beverly Freeman ◽  
Dylan T. B. Ressler ◽  
...  
Keyword(s):  
Life Cycle ◽  
Virus Production ◽  
Multidrug Resistant ◽  
Capsid Assembly ◽  
Resistance Mutations ◽  
Life Cycle Stages ◽  
Human T Cell ◽  
T Cell Lines ◽  
Gag Assembly ◽  
Hiv 1

ABSTRACTGiven the projected increase in multidrug resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life-cycle stages that are not targeted by antiretrovirals currently in use. Host-targeting drugs are of particular interest because they can offer a high barrier to resistance. Here we report identification of two related small molecules that inhibit HIV-1 late events, a stage of the HIV-1 life cycle for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and PBMCs and are effective against a primary isolate. They reduce virus production, likely by inhibiting a post-translational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gag in situ; however, unexpectedly, selection experiments failed to identify compound-specific resistance mutations in gag or pol, even though known resistance mutations developed in a parallel nelfinavir selection. Thus, we hypothesized that instead of binding to Gag directly, these compounds might localize to assembly intermediates, the intracellular multiprotein complexes containing Gag and host factors that are formed during immature HIV-1 capsid assembly. Indeed, imaging of infected cells showed colocalization of the compound with two host enzymes found in assembly intermediates, ABCE1 and DDX6. While the exact target and mechanism of action of this chemotype remain to be determined, these findings suggest that these compounds represent first-in-class, host-targeting inhibitors of intracellular events in HIV-1 assembly.IMPORTANCEThe success of antiretroviral treatment for HIV-1 is at risk of being undermined by the growing problem of drug resistance. Thus, there is a need to identify antiretrovirals that act on viral life cycle stages not targeted by drugs in use, such as the events of HIV-1 Gag assembly. To address this gap, we developed a compound screen that recapitulates the intracellular events of HIV-1 assembly, including viral-host interactions that promote assembly. This effort led to identification of a new chemotype that inhibits HIV-1 replication at nanomolar concentrations by inhibiting virus production. This compound colocalized with Gag and two host enzymes that facilitate capsid assembly but resistance selection did not result in compound-specific mutations in gag, suggesting that the chemotype does not directly target Gag. We hypothesize that this chemotype may represent a first-in-class inhibitor of virus production that acts by targeting a viral-host complex important for HIV-1 Gag assembly.

scholarly journals Melanin properties at the different stages towards life cycle of the fly Hermetia illucens

2017 ◽  
Vol 7 (4) ◽  
pp. 424-431 ◽  
Author(s):  
N. A. Ushakova ◽  
A. E. Dontsov ◽  
N. L. Sakina ◽  
E. S. Brodsky ◽  
I. A. Ratnikova ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Candida Albicans ◽  
Life Cycle ◽  
Aspergillus Niger ◽  
Lauric Acid ◽  
Hermetia Illucens ◽  
Wide Range ◽  
And Staphylococcus Aureus ◽  
Test Cultures

<p>Eumelanin type pigments are synthesized at all the stages of the life cycle of the fly Hermetia illucens: in the larvae, pre-pupae,<br />pupae and adult flies (dead flies). The greatest content of melanin was recorded in the cuticles. Melanin was present not only<br />in the cuticle, hence it remained in the cuticle after the emergence of the adult fly. It was also found in the insect body in a<br />complex with lipids. In pupae, it is mostly lauric acid that was associated with melanin. Its proportion in the melanin-chitosan<br />complex was 80%. The isolated melanin-chitosan complex of adult flies showed a wide range of antibacterial activity, inhibiting<br />the growth of 21 out of the 25 of the test cultures. The melanin-chitosan complex of empty pupal membranes and alcohol<br />suspension of pupal melanin inhibited twice as smaller number of test cultures and the above activity was absolutely in the<br />pupal chitosan. The largest zone of growth inhibition was recorded with respect to Aspergillus niger, Candida albicans,<br />salmonella, and Staphylococcus aureus. An alcohol suspension of pupal melanin inhibited the growth of 10 test cultures. In this<br />case the greatest activity was shown in relation to Mycobacterium B5 and Acinetobacter sp. 1182.</p>

scholarly journals Antiviral Properties and Mechanism of Action Studies of the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Jan Martin Berke ◽  
Pascale Dehertogh ◽  
Karen Vergauwen ◽  
Wendy Mostmans ◽  
Koen Vandyck ◽  
...  
Keyword(s):  
Life Cycle ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Core Protein ◽  
Hbv Dna ◽  
Size Exclusion ◽  
Capsid Assembly ◽  
Phase Ii Trials ◽  
B Virus

ABSTRACT Capsid assembly is a critical step in the hepatitis B virus (HBV) life cycle, mediated by the core protein. Core is a potential target for new antiviral therapies, the capsid assembly modulators (CAMs). JNJ-56136379 (JNJ-6379) is a novel and potent CAM currently in phase II trials. We evaluated the mechanisms of action (MOAs) and antiviral properties of JNJ-6379 in vitro. Size exclusion chromatography and electron microscopy studies demonstrated that JNJ-6379 induced the formation of morphologically intact viral capsids devoid of genomic material (primary MOA). JNJ-6379 accelerated the rate and extent of HBV capsid assembly in vitro. JNJ-6379 specifically and potently inhibited HBV replication; its median 50% effective concentration (EC50) was 54 nM (HepG2.117 cells). In HBV-infected primary human hepatocytes (PHHs), JNJ-6379, when added with the viral inoculum, dose-dependently reduced extracellular HBV DNA levels (median EC50 of 93 nM) and prevented covalently closed circular DNA (cccDNA) formation, leading to a dose-dependent reduction of intracellular HBV RNA levels (median EC50 of 876 nM) and reduced antigen levels (secondary MOA). Adding JNJ-6379 to PHHs 4 or 5 days postinfection reduced extracellular HBV DNA and did not prevent cccDNA formation. Time-of-addition PHH studies revealed that JNJ-6379 most likely interfered with postentry processes. Collectively, these data demonstrate that JNJ-6379 has dual MOAs in the early and late steps of the HBV life cycle, which is different from the MOA of nucleos(t)ide analogues. JNJ-6379 is in development for chronic hepatitis B treatment and may translate into higher HBV functional cure rates.

scholarly journals Genome Sequence of Staphylococcus aureus Strain Newman and Comparative Analysis of Staphylococcal Genomes: Polymorphism and Evolution of Two Major Pathogenicity Islands

2007 ◽  
Vol 190 (1) ◽  
pp. 300-310 ◽  
Author(s):  
Tadashi Baba ◽  
Taeok Bae ◽  
Olaf Schneewind ◽  
Fumihiko Takeuchi ◽  
Keiichi Hiramatsu
Keyword(s):  
Staphylococcus Aureus ◽  
Genome Sequence ◽  
Virulent Strain ◽  
Phylogenetic Analyses ◽  
Human Infection ◽  
Aureus Strain ◽  
Pathogenicity Islands ◽  
Sequence Information ◽  
Polymorphism Analysis ◽  
Evolutionary Pathway

ABSTRACT Strains of Staphylococcus aureus, an important human pathogen, display up to 20% variability in their genome sequence, and most sequence information is available for human clinical isolates that have not been subjected to genetic analysis of virulence attributes. S. aureus strain Newman, which was also isolated from a human infection, displays robust virulence properties in animal models of disease and has already been extensively analyzed for its molecular traits of staphylococcal pathogenesis. We report here the complete genome sequence of S. aureus Newman, which carries four integrated prophages, as well as two large pathogenicity islands. In agreement with the view that S. aureus Newman prophages contribute important properties to pathogenesis, fewer virulence factors are found outside of the prophages than for the highly virulent strain MW2. The absence of drug resistance genes reflects the general antibiotic-susceptible phenotype of S. aureus Newman. Phylogenetic analyses reveal clonal relationships between the staphylococcal strains Newman, COL, NCTC8325, and USA300 and a greater evolutionary distance to strains MRSA252, MW2, MSSA476, N315, Mu50, JH1, JH9, and RF122. However, polymorphism analysis of two large pathogenicity islands distributed among these strains shows that the two islands were acquired independently from the evolutionary pathway of the chromosomal backbones of staphylococcal genomes. Prophages and pathogenicity islands play central roles in S. aureus virulence and evolution.

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