scholarly journals Competition between social cheater viruses is driven by mechanistically different cheating strategies

2020 ◽  
Vol 6 (34) ◽  
pp. eabb7990 ◽  
Author(s):  
Moran Meir ◽  
Noam Harel ◽  
Danielle Miller ◽  
Maoz Gelbart ◽  
Avigdor Eldar ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Experimental Evolution ◽  
Rna Structure ◽  
Deletion Mutant ◽  
Polymerase Activity ◽  
Wild Type ◽  
Viral Packaging ◽  
Antagonistic Interactions

Cheater viruses, also known as defective interfering viruses, cannot replicate on their own yet replicate faster than the wild type upon coinfection. While there is growing interest in using cheaters as antiviral therapeutics, the mechanisms underlying cheating have been rarely explored. During experimental evolution of MS2 phage, we observed the parallel emergence of two independent cheater mutants. The first, a point deletion mutant, lacked polymerase activity but was advantageous in viral packaging. The second synonymous mutant cheater displayed a completely different cheating mechanism, involving an altered RNA structure. Continued evolution revealed the demise of the deletion cheater and rise of the synonymous cheater. A mathematical model inferred that while a single cheater is expected to reach an equilibrium with the wild type, cheater demise arises from antagonistic interactions between coinfecting cheaters. These findings highlight layers of parasitism: viruses parasitizing cells, cheaters parasitizing intact viruses, and cheaters may parasitize other cheaters.

scholarly journals Structural and Thermodynamic Analysis of the Resistance Development to Pimodivir (VX-787), the Clinical Inhibitor of Cap Binding to PB2 Subunit of Influenza A Polymerase

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1007
Author(s):  
Jiří Gregor ◽  
Kateřina Radilová ◽  
Jiří Brynda ◽  
Jindřich Fanfrlík ◽  
Jan Konvalinka ◽  
...  
Keyword(s):  
Thermodynamic Analysis ◽  
Influenza A ◽  
Polymerase Activity ◽  
Second Phase ◽  
Missense Mutations ◽  
Wild Type ◽  
Resistance Development ◽  
Third Phase ◽  
Major Mutation ◽  
Control And Prevention

Influenza A virus (IAV) encodes a polymerase composed of three subunits: PA, with endonuclease activity, PB1 with polymerase activity and PB2 with host RNA five-prime cap binding site. Their cooperation and stepwise activation include a process called cap-snatching, which is a crucial step in the IAV life cycle. Reproduction of IAV can be blocked by disrupting the interaction between the PB2 domain and the five-prime cap. An inhibitor of this interaction called pimodivir (VX-787) recently entered the third phase of clinical trial; however, several mutations in PB2 that cause resistance to pimodivir were observed. First major mutation, F404Y, causing resistance was identified during preclinical testing, next the mutation M431I was identified in patients during the second phase of clinical trials. The mutation H357N was identified during testing of IAV strains at Centers for Disease Control and Prevention. We set out to provide a structural and thermodynamic analysis of the interactions between cap-binding domain of PB2 wild-type and PB2 variants bearing these mutations and pimodivir. Here we present four crystal structures of PB2-WT, PB2-F404Y, PB2-M431I and PB2-H357N in complex with pimodivir. We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors.

scholarly journals N-3-Hydroxy Dodecanoyl-DL-homoserine Lactone (OH-dDHL) Triggers Apoptosis of Bone Marrow-Derived Macrophages through the ER- and Mitochondria-Mediated Pathways

2021 ◽  
Vol 22 (14) ◽  
pp. 7565
Author(s):  
Kyungho Woo ◽  
Dong Ho Kim ◽  
Man Hwan Oh ◽  
Ho Sung Park ◽  
Chul Hee Choi
Keyword(s):  
Bone Marrow ◽  
Quorum Sensing ◽  
Deletion Mutant ◽  
Transmembrane Protein ◽  
Cell Communication ◽  
Homoserine Lactone ◽  
Host Responses ◽  
Wild Type ◽  
Mutant Strains

Quorum sensing of Acinetobacter nosocomialis for cell-to-cell communication produces N-3-hydroxy dodecanoyl-DL-homoserine lactone (OH-dDHL) by an AnoR/I two-component system. However, OH-dDHL-driven apoptotic mechanisms in hosts have not been clearly defined. Here, we investigated the induction of apoptosis signaling pathways in bone marrow-derived macrophages treated with synthetic OH-dDHL. Moreover, the quorum-sensing system for virulence regulation was evaluated in vivo using wild-type and anoI-deletion mutant strains. OH-dDHL decreased the viability of macrophage and epithelial cells in dose- and time-dependent manners. OH-dDHL induced Ca2+ efflux and caspase-12 activation by ER stress transmembrane protein (IRE1 and ATF6a p50) aggregation and induced mitochondrial dysfunction through reactive oxygen species (ROS) production, which caused cytochrome c to leak. Pretreatment with a pan-caspase inhibitor reduced caspase-3, -8, and -9, which were activated by OH-dDHL. Pro-inflammatory cytokine and paraoxonase-2 (PON2) gene expression were increased by OH-dDHL. We showed that the anoI-deletion mutant strains have less intracellular invasion compared to the wild-type strain, and their virulence, such as colonization and dissemination, was decreased in vivo. Consequently, these findings revealed that OH-dDHL, as a virulence factor, contributes to bacterial infection and survival as well as the modification of host responses in the early stages of infection.

scholarly journals Borrelia burgdorferi Lacking BBK32, a Fibronectin-Binding Protein, Retains Full Pathogenicity

2006 ◽  
Vol 74 (6) ◽  
pp. 3305-3313 ◽  
Author(s):  
Xin Li ◽  
Xianzhong Liu ◽  
Deborah S. Beck ◽  
Fred S. Kantor ◽  
Erol Fikrig
Keyword(s):  
Life Cycle ◽  
Borrelia Burgdorferi ◽  
Deletion Mutant ◽  
Binding Protein ◽  
Kanamycin Resistance ◽  
Binding Activity ◽  
Mammalian Host ◽  
Wild Type ◽  
Fibronectin Binding Protein ◽  
Fibronectin Binding

ABSTRACT BBK32, a fibronectin-binding protein of Borrelia burgdorferi, is one of many surface lipoproteins that are differentially expressed by the Lyme disease spirochete at various stages of its life cycle. The level of BBK32 expression in B. burgdorferi is highest during infection of the mammalian host and lowest in flat ticks. This temporal expression profile, along with its fibronectin-binding activity, strongly suggests that BBK32 may play an important role in Lyme pathogenesis in the host. To test this hypothesis, we constructed an isogenic BBK32 deletion mutant from wild-type B. burgdorferi B31 by replacing the BBK32 gene with a kanamycin resistance cassette through homologous recombination. We examined both the wild-type strain and the BBK32 deletion mutant extensively in the experimental mouse-tick model of the Borrelia life cycle. Our data indicated that B. burgdorferi lacking BBK32 retained full pathogenicity in mice, regardless of whether mice were infected artificially by syringe inoculation or naturally by tick bite. The loss of BBK32 expression in the mutant had no adverse effect on spirochete acquisition (mouse-to-tick) and transmission (tick-to-mouse) processes. These results suggest that additional B. burgdorferi proteins can complement the function of BBK32, fibronectin binding or otherwise, during the natural spirochete life cycle.

scholarly journals Deletion of znuA Virulence Factor Attenuates Brucella abortus and Confers Protection against Wild-Type Challenge

2006 ◽  
Vol 74 (7) ◽  
pp. 3874-3879 ◽  
Author(s):  
Xinghong Yang ◽  
Todd Becker ◽  
Nancy Walters ◽  
David W. Pascual
Keyword(s):  
Brucella Abortus ◽  
Deletion Mutant ◽  
Pasteurella Multocida ◽  
Brucella Melitensis ◽  
Normal Growth ◽  
Wild Type ◽  
Minimal Growth ◽  
M Genome ◽  
S19 Vaccine ◽  
Knockout Mutation

ABSTRACT znuA is known to be an important factor for survival and normal growth under low Zn2+ concentrations for Escherichia coli, Haemophilus spp., Neisseria gonorrhoeae, and Pasteurella multocida. We hypothesized that the znuA gene present in Brucella melitensis 16 M would be similar to znuA in B. abortus and questioned whether it may also be an important factor for growth and virulence of Brucella abortus. Using the B. melitensis 16 M genome sequence, primers were designed to construct a B. abortus deletion mutant. A znuA knockout mutation in B. abortus 2308 (ΔznuA) was constructed and found to be lethal in low-Zn2+ medium. When used to infect macrophages, ΔznuA B. abortus showed minimal growth. Further study with ΔznuA B. abortus showed that its virulence in BALB/c mice was attenuated, and most of the bacteria were cleared from the spleen within 8 weeks. Protection studies confirmed the ΔznuA mutant as a potential live vaccine, since protection against wild-type B. abortus 2308 challenge was as effective as that obtained with the RB51 or S19 vaccine strain.

A proteomics approach to study synergistic and antagonistic interactions of the fungal-bacterial consortium Fusarium oxysporum wild-type MSA 35

PROTEOMICS ◽  
2010 ◽  
Vol 10 (18) ◽  
pp. 3292-3320 ◽  
Author(s):  
Marino Moretti ◽  
Alexander Grunau ◽  
Daniela Minerdi ◽  
Peter Gehrig ◽  
Bernd Roschitzki ◽  
...  
Keyword(s):  
Fusarium Oxysporum ◽  
Bacterial Consortium ◽  
Wild Type ◽  
Proteomics Approach ◽  
Antagonistic Interactions

scholarly journals Somatic deficiency causes reproductive parasitism in a fungus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexey A. Grum-Grzhimaylo ◽  
Eric Bastiaans ◽  
Joost van den Heuvel ◽  
Cristina Berenguer Millanes ◽  
Alfons J. M. Debets ◽  
...  
Keyword(s):  
Neurospora Crassa ◽  
Experimental Evolution ◽  
Evolutionary Dynamics ◽  
Genetic Load ◽  
Wild Type ◽  
Fusion Frequency ◽  
Somatic Fusion ◽  
Extensive Variation ◽  
Reproductive Parasitism ◽  
Multicellular Organisms

AbstractSome multicellular organisms can fuse because mergers potentially provide mutual benefits. However, experimental evolution in the fungus Neurospora crassa has demonstrated that free fusion of mycelia favours cheater lineages, but the mechanism and evolutionary dynamics of this exploitation are unknown. Here we show, paradoxically, that all convergently evolved cheater lineages have similar fusion deficiencies. These mutants are unable to initiate fusion but retain access to wild-type mycelia that fuse with them. This asymmetry reduces cheater-mutant contributions to somatic substrate-bound hyphal networks, but increases representation of their nuclei in the aerial reproductive hyphae. Cheaters only benefit when relatively rare and likely impose genetic load reminiscent of germline senescence. We show that the consequences of somatic fusion can be unequally distributed among fusion partners, with the passive non-fusing partner profiting more. We discuss how our findings may relate to the extensive variation in fusion frequency of fungi found in nature.

scholarly journals The ham-2 Locus, Encoding a Putative Transmembrane Protein, Is Required for Hyphal Fusion in Neurospora crassa

Genetics ◽  
2002 ◽  
Vol 160 (1) ◽  
pp. 169-180
Author(s):  
Qijun Xiang ◽  
Carolyn Rasmussen ◽  
N Louise Glass
Keyword(s):  
Neurospora Crassa ◽  
Somatic Cell ◽  
Molecular Mechanism ◽  
Cell Fusion ◽  
Deletion Mutant ◽  
Transmembrane Protein ◽  
Wild Type ◽  
Vegetative Incompatibility ◽  
Hyphal Fusion ◽  
Aerial Hyphae

Abstract Somatic cell fusion is common during organogenesis in multicellular eukaryotes, although the molecular mechanism of cell fusion is poorly understood. In filamentous fungi, somatic cell fusion occurs during vegetative growth. Filamentous fungi grow as multinucleate hyphal tubes that undergo frequent hyphal fusion (anastomosis) during colony expansion, resulting in the formation of a hyphal network. The molecular mechanism of the hyphal fusion process and the role of networked hyphae in the growth and development of these organisms are unexplored questions. We use the filamentous fungus Neurospora crassa as a model to study the molecular mechanism of hyphal fusion. In this study, we identified a deletion mutant that was restricted in its ability to undergo both self-hyphal fusion and fusion with a different individual to form a heterokaryon. This deletion mutant displayed pleiotropic defects, including shortened aerial hyphae, altered conidiation pattern, female sterility, slow growth rate, lack of hyphal fusion, and suppression of vegetative incompatibility. Complementation with a single open reading frame (ORF) within the deletion region in this mutant restored near wild-type growth rates, female fertility, aerial hyphae formation, and hyphal fusion, but not vegetative incompatibility and wild-type conidiation pattern. This ORF, which we named ham-2 (for hyphal anastomosis), encodes a putative transmembrane protein that is highly conserved, but of unknown function among eukaryotes.

scholarly journals E22Δ Mutation in Amyloidβ-Protein Promotesβ-Sheet Transformation, Radical Production, and Synaptotoxicity, But Not Neurotoxicity

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Takayuki Suzuki ◽  
Kazuma Murakami ◽  
Naotaka Izuo ◽  
Toshiaki Kume ◽  
Akinori Akaike ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Conformational Change ◽  
Deletion Mutant ◽  
Protein A ◽  
Type A ◽  
Synaptic Dysfunction ◽  
Wild Type ◽  
Radical Production

Oligomers of 40- or 42-mer amyloidβ-protein (Aβ40, Aβ42) cause cognitive decline and synaptic dysfunction in Alzheimer's disease. We proposed the importance of a turn at Glu22 and Asp23 of Aβ42 to induce its neurotoxicity through the formation of radicals. Recently, a novel deletion mutant at Glu22 (E22Δ) of Aβ42 was reported to accelerate oligomerization and synaptotoxicity. To investigate this mechanism, the effects of the E22Δ mutation in Aβ42 and Aβ40 on the transformation ofβ-sheets, radical production, and neurotoxicity were examined. Both mutants promotedβ-sheet transformation and the formation of radicals, while their neurotoxicity was negative. In contrast, E22P-Aβ42 with a turn at Glu22 and Asp23 exhibited potent neurotoxicity along with the ability to form radicals and potent synaptotoxicity. These data suggest that conformational change in E22Δ-Aβis similar to that in E22P-Aβ42 but not the same, since E22Δ-Aβ42 exhibited no cytotoxicity, unlike E22P-Aβ42 and wild-type Aβ42.

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