Imperial College London

Dr Sophie Helaine

Faculty of MedicineDepartment of Infectious Disease

Honorary Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3976s.helaine

 
 
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Location

 

2.20Flowers buildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

49 results found

Thurston TLM, Helaine S, 2023, Editorial overview: Two to tango: The intricate communications between host and bacteria, CURRENT OPINION IN MICROBIOLOGY, Vol: 74, ISSN: 1369-5274

Journal article

Ronneau S, Michaux C, Helaine S, 2023, Decline in nitrosative stress drives antibiotic persister regrowth during infection, CELL HOST & MICROBE, Vol: 31, Pages: 993-+, ISSN: 1931-3128

Journal article

Rizvanovic A, Michaux C, Panza M, Iloglu Z, Helaine S, Wagner EGH, Holmqvist Eet al., 2022, The RNA-Binding Protein ProQ Promotes Antibiotic Persistence in Salmonella, MBIO, Vol: 13, ISSN: 2150-7511

Journal article

Michaux C, Ronneae S, Giorgio RT, Helaine Set al., 2022, Antibiotic tolerance and persistence have distinct fitness trade-offs, PLOS PATHOGENS, Vol: 18, ISSN: 1553-7366

Journal article

Paulini S, Fabiani FD, Weiss AS, Moldoveanu AL, Helaine S, Stecher B, Jung Ket al., 2022, The Biological Significance of Pyruvate Sensing and Uptake in <i>Salmonella enterica</i> Serovar Typhimurium, MICROORGANISMS, Vol: 10

Journal article

Vieira de Castro G, Worm D, Grabe G, Rowan F, Haggerty L, Losada De La Lastra A, Popescu O, Helaine S, Barnard Aet al., 2022, Characterisation of the key determinants of Phd antitoxin mediated Doc toxin inactivation in Salmonella, ACS Chemical Biology, Vol: 17, Pages: 1598-1606, ISSN: 1554-8929

In the search for novel antimicrobial therapeutics, toxin-antitoxin (TA) modules are promising yet underexplored targets for overcoming antibiotic failure. The bacterial toxin Doc has been associated with the persistence of Salmonella in macrophages, enabling its survival upon antibiotic exposure. After developing a novel method to produce the recombinant toxin, we have used antitoxin-mimicking peptides to thoroughly investigate the mechanism by which its cognate antitoxin Phd neutralizes the activity of Doc. We reveal insights into the molecular detail of the Phd–Doc relationship and discriminate antitoxin residues that stabilize the TA complex from those essential for inhibiting the activity of the toxin. Coexpression of Doc and antitoxin peptides in Salmonella was able to counteract the activity of the toxin, confirming our in vitro results with equivalent sequences. Our findings provide key principles for the development of chemical tools to study and therapeutically interrogate this important class of protein–protein interactions.

Journal article

Bikmetov D, Hall AMJ, Livenskyi A, Gollan B, Ovchinnikov S, Gilep K, Kim JY, Larrouy-Maumus G, Zgoda V, Borukhov S, Severinov K, Helaine S, Dubiley Set al., 2022, GNAT toxins evolve toward narrow tRNA target specificities, NUCLEIC ACIDS RESEARCH, Vol: 50, Pages: 5807-5817, ISSN: 0305-1048

Journal article

Paulini S, Fabiani FD, Weiß AS, Moldoveanu AL, Helaine S, Stecher B, Jung Ket al., 2022, Identification of two pyruvate transporters in<i>Salmonella enterica</i>serovar Typhimurium and their biological relevance

<jats:title>SUMMARY</jats:title><jats:p>Pyruvate (CH<jats:sub>3</jats:sub>COCOOH) is the simplest of the alpha-keto acids and is at the interface of several metabolic pathways both in prokaryotes and eukaryotes. In an amino acid-rich environment, fast-growing bacteria excrete pyruvate instead of completely metabolizing it. The role of pyruvate uptake in pathological conditions is still unclear. In this study, we identified two pyruvate-specific transporters, BtsT and CstA, in<jats:italic>Salmonella enterica</jats:italic>serovar Typhimurium (<jats:italic>S</jats:italic>. Typhimurium). Expression of<jats:italic>btsT</jats:italic>is induced by the histidine kinase/response regulator system BtsS/BtsR upon sensing extracellular pyruvate (threshold 200 μM), whereas expression of<jats:italic>cstA</jats:italic>is maximal in the stationary phase. Both pyruvate transporters were found to be important for the uptake of this compound, but also for chemotaxis to pyruvate, survival under oxidative and nitrosative stress, and persistence of<jats:italic>S</jats:italic>. Typhimurium in response to gentamicin. Compared with the wild-type, the Δ<jats:italic>btsT</jats:italic>Δ<jats:italic>cstA</jats:italic>mutant has disadvantages in antibiotic persistence in macrophages, as well as in colonization and systemic infection in gnotobiotic mice. These data demonstrate the surprising complexity of the two pyruvate uptake systems in<jats:italic>S</jats:italic>. Typhimurium.</jats:p>

Journal article

Hill PWS, Moldoveanu AL, Sargen M, Ronneau S, Glegola-Madejska I, Beetham C, Fisher RA, Helaine Set al., 2021, The vulnerable versatility of<i> Salmonella</i> antibiotic persisters during infection, CELL HOST & MICROBE, Vol: 29, Pages: 1757-+, ISSN: 1931-3128

Journal article

Grabe GJ, Giorgio RT, Hall AMJ, Morgan RML, Dubois L, Sisley TA, Rycroft JA, Hare SA, Helaine Set al., 2021, Auxiliary interfaces support the evolution of specific toxin-antitoxin pairing, NATURE CHEMICAL BIOLOGY, Vol: 17, Pages: 1296-1304, ISSN: 1552-4450

Journal article

Ronneau S, Hill PWS, Helaine S, 2021, Antibiotic persistence and tolerance: not just one and the same, CURRENT OPINION IN MICROBIOLOGY, Vol: 64, Pages: 76-81, ISSN: 1369-5274

Journal article

Moldoveanu AL, Rycroft JA, Helaine S, 2021, Impact of bacterial persisters on their host, CURRENT OPINION IN MICROBIOLOGY, Vol: 59, Pages: 65-71, ISSN: 1369-5274

Journal article

Michaux C, Ronneau S, Helaine S, 2021, Studying Antibiotic Persistence During Infection, BACTERIAL PERSISTENCE, 2 EDITION, Pages: 273-289, ISSN: 1064-3745

Journal article

Michaux C, Ronneau S, Helaine S, 2021, Correction to: Studying Antibiotic Persistence During Infection.

Book chapter

Michaux C, Ronneau S, Helaine S, 2021, Studying Antibiotic Persistence During Infection (vol 2357, pg 273, 2021), BACTERIAL PERSISTENCE, 2 EDITION, Editors: Verstraeten, Michiels, Publisher: HUMANA PRESS INC, Pages: C1-C1, ISBN: 978-1-0716-1620-8

Book chapter

Pham THM, Brewer SM, Thurston T, Massis LM, Honeycutt J, Lugo K, Jacobson AR, Vilches-Moure JG, Hamblin M, Helaine S, Monack DMet al., 2020, Salmonella-driven polarization of granuloma macrophages antagonizes TNF-mediated pathogen restriction during persistent infection, Cell Host and Microbe, Vol: 27, Pages: 54-67.E5, ISSN: 1931-3128

Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas composed of macrophages. Granuloma macrophages exhibit heterogeneous polarization states, or phenotypes, that may be functionally distinct. Here, we elucidate a host-pathogen interaction that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella Typhimurium ( STm) infection. We show that STm persists within splenic granulomas that are densely populated by CD11b +CD11c +Ly6C + macrophages. STm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the effector SteE, which contributes to the establishment of persistent infection. We demonstrate that tumor necrosis factor (TNF) signaling limits M2 granuloma macrophage polarization, thereby restricting STm persistence. TNF neutralization shifts granuloma macrophages toward an M2 state and increases bacterial persistence, and these effects are partially dependent on SteE activity. Thus, manipulating granuloma macrophage polarization represents a strategy for intracellular bacteria to overcome host restriction during persistent infection.

Journal article

Panagi I, Jennings E, Zeng J, Günster RA, Stones CD, Mak H, Jin E, Stapels DAC, Subari NZ, Pham THM, Brewer SM, Ong SYQ, Monack DM, Helaine S, Thurston TLMet al., 2020, Salmonella effector SteE converts the mammalian serine/threonine kinase GSK3 into a tyrosine kinase to direct macrophage polarization., Cell Host and Microbe, Vol: 27, Pages: 41-53.e6, ISSN: 1931-3128

Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Rα (IL-4Rα). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment.

Journal article

Hill P, Helaine S, 2019, Antibiotic Persisters and Relapsing Salmonella enterica Infections., Persister Cells and Infectious Disease, Editors: Lewis, Publisher: Springer Nature, ISBN: 9783030252410

Antibiotic persistence is defined as the ability of a subpopulation of bacteria within a clonal antibiotic-susceptible population to survive antibiotic treatment. Studies on antibiotic persistence have traditionally been carried out on bacteria cultured in laboratory media. However, over recent years, there has been a push to study antibiotic persisters in more physiologically relevant systems. Thus, the concept of antibiotic persistence during infection, which refers to the ability of a subpopulation of bacteria to survive combined host and antibiotic challenges, has emerged as a major new frontier of research. Here, we discuss the relevance and principles of this concept using relapsing Salmonella enterica infections as an example. We critically evaluate the clinical and experimental evidence for the existence and importance of antibiotic persisters in relapsing Salmonella infections; we outline our current understanding of the molecular mechanisms that enable successful antibiotic persistence during infection; and, finally, we discuss the challenges for this nascent field going forward.

Book chapter

Ronneau S, Helaine S, 2019, Clarifying the Link between Toxin-Antitoxin Modules and Bacterial Persistence, JOURNAL OF MOLECULAR BIOLOGY, Vol: 431, Pages: 3462-3471, ISSN: 0022-2836

Journal article

Panagi I, Jennings E, Zeng J, Günster RA, Stones CD, Mak H, Jin E, Stapels DAC, Subari NZ, Pham THM, Brewer SM, Ong SYQ, Monack D, Helaine S, Thurston Tet al., 2019, The Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase, Publisher: Elsevier BV

Working paper

Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B, Andersson DI, Brynildsen MP, Bumann D, Camilli A, Collins JJ, Dehio C, Fortune S, Ghigo J-M, Hardt W-D, Harms A, Heinemann M, Hung DT, Jenal U, Levin BR, Michiels J, Storz G, Tan M-W, Tenson T, Van Melderen L, Zinkernagel Aet al., 2019, Definitions and guidelines for research on antibiotic persistence, Nature Reviews Microbiology, Vol: 17, Pages: 441-448, ISSN: 1740-1526

Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.

Journal article

Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B, Andersson DI, Brynildsen MP, Bumann D, Camilli A, Collins JJ, Dehio C, Fortune S, Ghigo J-M, Hardt W-D, Harms A, Heinemann M, Hung DT, Jenal U, Levin BR, Michiels J, Storz G, Tan M-W, Tenson T, Van Melderen L, Zinkernagel Aet al., 2019, Definitions and guidelines for research on antibiotic persistence (vol 17, pg 441, 2019), NATURE REVIEWS MICROBIOLOGY, Vol: 17, Pages: 460-460, ISSN: 1740-1526

Journal article

Gollan B, Grabe G, Michaux C, Helaine Set al., 2019, Bacterial Persisters and Infection: Past, Present, and Progressing, ANNUAL REVIEW OF MICROBIOLOGY, VOL 73, Vol: 73, Pages: 359-385, ISSN: 0066-4227

Journal article

Stapels DAC, Hill PWS, Westermann AJ, Fisher RA, Thurston TL, Saliba A-E, Blommestein I, Vogel J, Helaine Set al., 2018, Salmonella persisters undermine host immune defenses during antibiotic treatment, Science, Vol: 362, Pages: 1156-1160, ISSN: 0036-8075

Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of Salmonella species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that Salmonella persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the Salmonella pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing Salmonella cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.

Journal article

Wilcox B, Osterman I, Serebryakova M, Lukyanov D, Komarova E, Gollan B, Morozova N, Wolf Y, Makarova KS, Helaine S, Sergiev P, Dubiley S, Borukhov S, Severinov Ket al., 2018, Escherichia coli ItaT is a type II toxin that inhibits translation by acetylating isoleucyl-tRNA(Ile), Nucleic Acids Research, Vol: 46, Pages: 7873-7885, ISSN: 0305-1048

Prokaryotic toxin–antitoxin (TA) modules are highly abundant and are involved in stress response and drug tolerance. The most common type II TA modules consist of two interacting proteins. The type II toxins are diverse enzymes targeting various essential intracellular targets. The antitoxin binds to cognate toxin and inhibits its function. Recently, TA modules whose toxins are GNAT-family acetyltransferases were described. For two such systems, the target of acetylation was shown to be aminoacyl-tRNA: the TacT toxin targets aminoacylated elongator tRNAs, while AtaT targets the amino acid moiety of initiating tRNAMet. We show that the itaRT gene pair from Escherichia coli encodes a TA module with acetyltransferase toxin ItaT that specifically and exclusively acetylates Ile-tRNAIle thereby blocking translation and inhibiting cell growth. ItaT forms a tight complex with the ItaR antitoxin, which represses the transcription of itaRT operon. A comprehensive bioinformatics survey of GNAT acetyltransferases reveals that enzymes encoded by validated or putative TA modules are common and form a distinct branch of the GNAT family tree. We speculate that further functional analysis of such TA modules will result in identification of enzymes capable of specifically targeting many, perhaps all, aminoacyl tRNAs.

Journal article

Rycroft J, Gollan B, Grabe G, hall A, Cheverton A, Larrouy-Maumus G, Hare S, Helaine Set al., 2018, Activity of acetyltransferase toxins involved in Salmonella persister formation during macrophage infection, Nature Communications, Vol: 9, ISSN: 2041-1723

Non-typhoidal Salmonella strains are responsible for invasive infections associated withhigh mortality and recurrence in sub-Saharan Africa and there is strong evidence for clonalrelapse following antibiotic treatment. Persisters are non-growing bacteria that are thought tobe responsible for the recalcitrance of many infections to antibiotics. Toxin-antitoxin systemsare stress-responsive elements that are important for Salmonella persister formation,specifically during infection. Here we report analysis of persister formation of clinical invasive strains of S. Typhimurium and Enteritidis in human primary macrophages. We show that allthe invasive clinical isolates of both serovars that we tested produce high levels of persisters following internalization by human macrophages. Our genome comparison reveals that S.Enteritidis and S. Typhimurium strains contain three acetyltransferase toxins that we characterize structurally and functionally. We show that all induce the persister state byinhibiting translation through acetylation of aminoacyl-tRNAs. However, they differ in theirpotency and target partially different subsets of aminoacyl-tRNAs, potentially accounting fortheir non-redundant effect.

Journal article

Fisher RA, Gollan B, Helaine S, 2017, Persistent bacterial infections and persister cells, Nature Reviews Microbiology, Vol: 15, Pages: 453-464, ISSN: 1740-1526

Many bacteria can infect and persist inside their hosts for long periods of time. This can be due to immunosuppression of the host, immune evasion by the pathogen and/or ineffective killing by antibiotics. Bacteria can survive antibiotic treatment if they are resistant or tolerant to a drug. Persisters are a subpopulation of transiently antibiotic-tolerant bacterial cells that are often slow-growing or growth-arrested, and are able to resume growth after a lethal stress. The formation of persister cells establishes phenotypic heterogeneity within a bacterial population and has been hypothesized to be important for increasing the chances of successfully adapting to environmental change. The presence of persister cells can result in the recalcitrance and relapse of persistent bacterial infections, and it has been linked to an increase in the risk of the emergence of antibiotic resistance during treatment. If the mechanisms of the formation and regrowth of these antibiotic-tolerant cells were better understood, it could lead to the development of new approaches for the eradication of persistent bacterial infections. In this Review, we discuss recent developments in our understanding of bacterial persisters and their potential implications for the treatment of persistent infections.

Journal article

Hall A, Gollan B, Helaine S, 2017, Toxin-antitoxin systems: reversible toxicity, Current Opinion in Microbiology, Vol: 36, Pages: 102-110, ISSN: 1879-0364

Toxin–antitoxin (TA) systems encoded on the plasmids and chromosomes of bacteria are emerging as key players in stress adaptation. In particular, they have been implicated in the induction of persisters non-growing cells that can evade antibiotic exposure. TA toxins operate by a diverse range of mechanisms, either destructive or conservative, leading to the reversible growth arrest of bacterial cells. Whilst the molecular mechanisms of intoxication are now well understood, we still have very little information on how corrupted cells reawaken. Alongside the phenomenon of conditional cooperativity, new evidence suggests that the effects of some TA toxins can be reversed, allowing non-growing cells to be detoxified and growth to resume.

Journal article

Saliba A-E, Li L, Westermann AJ, Appenzeller S, Stapels DAC, Schulte LN, Helaine S, Vogel Jet al., 2016, Single-cell RNA-seq ties macrophage polarization to growth rate of intracellular Salmonella, Nature Microbiology, Vol: 2, Pages: 1-8, ISSN: 2058-5276

Intracellular bacterial pathogens can exhibit large heterogeneity in growth rate inside host cells, with major consequences for the infection outcome. If and how the host responds to this heterogeneity remains poorly understood. Here, we combined a fluorescent reporter of bacterial cell division with single-cell RNA-sequencing analysis to study the macrophage response to different intracellular states of the model pathogen Salmonella enterica serovar Typhimurium. The transcriptomes of individual infected macrophages revealed a spectrum of functional host response states to growing and non-growing bacteria. Intriguingly, macrophages harbouring non-growing Salmonella display hallmarks of the proinflammatory M1 polarization state and differ little from bystander cells, suggesting that non-growing bacteria evade recognition by intracellular immune receptors. By contrast, macrophages containing growing bacteria have turned into an anti-inflammatory, M2-like state, as if fast-growing intracellular Salmonella overcome host defence by reprogramming macrophage polarization. Additionally, our clustering approach reveals intermediate host functional states between these extremes. Altogether, our data suggest that gene expression variability in infected host cells shapes different cellular environments, some of which may favour a growth arrest of Salmonella facilitating immune evasion and the establishment of a long-term niche, while others allow Salmonella to escape intracellular antimicrobial activity and proliferate.

Journal article

Cheverton AM, Gollan B, Przydacz M, Wong CT, Mylona A, Hare SA, Helaine Set al., 2016, A Salmonella Toxin Promotes Persister Formation through Acetylation of tRNA., Molecular cell, Vol: 63, Pages: 86-96, ISSN: 1097-2765

The recalcitrance of many bacterial infections to antibiotic treatment is thought to be due to the presence of persisters that are non-growing, antibiotic-insensitive cells. Eventually, persisters resume growth, accounting for relapses of infection. Salmonella is an important pathogen that causes disease through its ability to survive inside macrophages. After macrophage phagocytosis, a significant proportion of the Salmonella population forms non-growing persisters through the action of toxin-antitoxin modules. Here we reveal that one such toxin, TacT, is an acetyltransferase that blocks the primary amine group of amino acids on charged tRNA molecules, thereby inhibiting translation and promoting persister formation. Furthermore, we report the crystal structure of TacT and note unique structural features, including two positively charged surface patches that are essential for toxicity. Finally, we identify a detoxifying mechanism in Salmonella wherein peptidyl-tRNA hydrolase counteracts TacT-dependent growth arrest, explaining how bacterial persisters can resume growth.

Journal article

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