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Prof. Teresa Frisan
Dept Molecular Biology, Umeå University

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0 Cancer Cell Biology
0 senescence
0 DNA damage response
0 immunobiology of infections
0 Infection Desease

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senescence
DNA damage response
bacterial genotoxin

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Review
Published: 17 June 2021 in Toxins
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The idea that bacterial toxins are not only killers but also execute more sophisticated roles during bacteria–host interactions by acting as negotiators has been highlighted in the past decades. Depending on the toxin, its cellular target and mode of action, the final regulatory outcome can be different. In this review, we have focused on two families of bacterial toxins: genotoxins and pore-forming toxins, which have different modes of action but share the ability to modulate the host’s immune responses, independently of their capacity to directly kill immune cells. We have addressed their immuno-suppressive effects with the perspective that these may help bacteria to avoid clearance by the host’s immune response and, concomitantly, limit detrimental immunopathology. These are optimal conditions for the establishment of a persistent infection, eventually promoting asymptomatic carriers. This immunomodulatory effect can be achieved with different strategies such as suppression of pro-inflammatory cytokines, re-polarization of the immune response from a pro-inflammatory to a tolerogenic state, and bacterial fitness modulation to favour tissue colonization while preventing bacteraemia. An imbalance in each of those effects can lead to disease due to either uncontrolled bacterial proliferation/invasion, immunopathology, or both.

ACS Style

Maria Lopez Chiloeches; Anna Bergonzini; Teresa Frisan. Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators. Toxins 2021, 13, 426 .

AMA Style

Maria Lopez Chiloeches, Anna Bergonzini, Teresa Frisan. Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators. Toxins. 2021; 13 (6):426.

Chicago/Turabian Style

Maria Lopez Chiloeches; Anna Bergonzini; Teresa Frisan. 2021. "Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators." Toxins 13, no. 6: 426.

Dataset
Published: 27 May 2021 in Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
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A recent genetic association study1 identified a gene cluster on chromosome 3 as a risk locus for respiratory failure after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A separate study (COVID-19 Host Genetics Initiative)2 comprising 3,199 hospitalized patients with coronavirus disease 2019 (COVID-19) and control individuals showed that this cluster is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. Here we show that the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50% of people in south Asia and around 16% of people in Europe.

ACS Style

Teresa Frisan; Zeberg H; Pääbo S. Faculty Opinions recommendation of The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2021, 587, 1 .

AMA Style

Teresa Frisan, Zeberg H, Pääbo S. Faculty Opinions recommendation of The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2021; 587 (7835):1.

Chicago/Turabian Style

Teresa Frisan; Zeberg H; Pääbo S. 2021. "Faculty Opinions recommendation of The major genetic risk factor for severe COVID-19 is inherited from Neanderthals." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 587, no. 7835: 1.

Conference paper
Published: 27 May 2021 in Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
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It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is inherited from Neandertals. New, larger genetic association studies now allow additional genetic risk factors to be discovered. Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region on chromosome 12 associated with requiring intensive care when infected with the virus is inherited from Neandertals. This region encodes proteins that activate enzymes that are important during infections with RNA viruses. In contrast to the previously described Neandertal haplotype that increases the risk for severe COVID-19, this Neandertal haplotype is protective against severe disease. It also differs from the risk haplotype in that it has a more moderate effect and occurs at substantial frequencies in all regions of the world outside Africa. Among ancient human genomes in western Eurasia, the frequency of the protective Neandertal haplotype may have increased between 20,000 and 10,000 y ago and again during the past 1,000 y.Copyright © 2021 the Author(s). Published by PNAS.

ACS Style

Teresa Frisan; Zeberg H; Pääbo S. Faculty Opinions recommendation of A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2021, 118, 1 .

AMA Style

Teresa Frisan, Zeberg H, Pääbo S. Faculty Opinions recommendation of A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2021; 118 (9):1.

Chicago/Turabian Style

Teresa Frisan; Zeberg H; Pääbo S. 2021. "Faculty Opinions recommendation of A genomic region associated with protection against severe COVID-19 is inherited from Neandertals." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 118, no. 9: 1.

Journal article
Published: 01 April 2021 in Cell Reports
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Summary Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram-negative bacteria, enriched in the microbiota of inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We address the role of typhoid toxin in modulation of the host-microbial interaction in health and disease. Infection with a genotoxigenic Salmonella protects mice from intestinal inflammation. We show that the presence of an active genotoxin promotes DNA fragmentation and senescence in vivo, which is uncoupled from an inflammatory response and unexpectedly associated with induction of an anti-inflammatory environment. The anti-inflammatory response is lost when infection occurs in mice with acute colitis. These data highlight a complex context-dependent crosstalk between bacterial-genotoxin-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.

ACS Style

Océane C.B. Martin; Anna Bergonzini; Maria Lopez Chiloeches; Eleni Paparouna; Deborah Butter; Sofia D.P. Theodorou; Maria M. Haykal; Elisa Boutet-Robinet; Toma Tebaldi; Andrew Wakeham; Mikael Rhen; Vassilis G. Gorgoulis; Tak Mak; Ioannis S. Pateras; Teresa Frisan. Influence of the microenvironment on modulation of the host response by typhoid toxin. Cell Reports 2021, 35, 108931 .

AMA Style

Océane C.B. Martin, Anna Bergonzini, Maria Lopez Chiloeches, Eleni Paparouna, Deborah Butter, Sofia D.P. Theodorou, Maria M. Haykal, Elisa Boutet-Robinet, Toma Tebaldi, Andrew Wakeham, Mikael Rhen, Vassilis G. Gorgoulis, Tak Mak, Ioannis S. Pateras, Teresa Frisan. Influence of the microenvironment on modulation of the host response by typhoid toxin. Cell Reports. 2021; 35 (1):108931.

Chicago/Turabian Style

Océane C.B. Martin; Anna Bergonzini; Maria Lopez Chiloeches; Eleni Paparouna; Deborah Butter; Sofia D.P. Theodorou; Maria M. Haykal; Elisa Boutet-Robinet; Toma Tebaldi; Andrew Wakeham; Mikael Rhen; Vassilis G. Gorgoulis; Tak Mak; Ioannis S. Pateras; Teresa Frisan. 2021. "Influence of the microenvironment on modulation of the host response by typhoid toxin." Cell Reports 35, no. 1: 108931.

Dataset
Published: 02 December 2020 in Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
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Streptococcus pneumoniae is the main bacterial pathogen involved in pneumonia. Pneumococcal acquisition and colonization density is probably affected by viral co-infections, the local microbiome composition and mucosal immunity. Here, we report the interactions between live-attenuated influenza vaccine (LAIV), successive pneumococcal challenge, and the healthy adult nasal microbiota and mucosal immunity using an experimental human challenge model. Nasal microbiota profiles at baseline are associated with consecutive pneumococcal carriage outcome (non-carrier, low-dense and high-dense pneumococcal carriage), independent of LAIV co-administration. Corynebacterium/Dolosigranulum-dominated profiles are associated with low-density colonization. Lowest rates of natural viral co-infection at baseline and post-LAIV influenza replication are detected in the low-density carriers. Also, we detected the fewest microbiota perturbations and mucosal cytokine responses in the low-density carriers compared to non-carriers or high-density carriers. These results indicate that the complete respiratory ecosystem affects pneumococcal behaviour following challenge, with low-density carriage representing the most stable ecological state.

ACS Style

Teresa Frisan; De Steenhuijsen Piters Waa; Jochems Sp; Mitsi E; Rylance J; Pojar S; Nikolaou E; German El; Holloway M; Carniel Bf; Chu Mljn; Arp K; Sanders Eam; Ferreira Dm; Bogaert D. Faculty Opinions recommendation of Interaction between the nasal microbiota and S. pneumoniae in the context of live-attenuated influenza vaccine. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2020, 10, 1 .

AMA Style

Teresa Frisan, De Steenhuijsen Piters Waa, Jochems Sp, Mitsi E, Rylance J, Pojar S, Nikolaou E, German El, Holloway M, Carniel Bf, Chu Mljn, Arp K, Sanders Eam, Ferreira Dm, Bogaert D. Faculty Opinions recommendation of Interaction between the nasal microbiota and S. pneumoniae in the context of live-attenuated influenza vaccine. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2020; 10 (1):1.

Chicago/Turabian Style

Teresa Frisan; De Steenhuijsen Piters Waa; Jochems Sp; Mitsi E; Rylance J; Pojar S; Nikolaou E; German El; Holloway M; Carniel Bf; Chu Mljn; Arp K; Sanders Eam; Ferreira Dm; Bogaert D. 2020. "Faculty Opinions recommendation of Interaction between the nasal microbiota and S. pneumoniae in the context of live-attenuated influenza vaccine." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 10, no. 1: 1.

Microreview
Published: 11 October 2020 in Cellular Microbiology
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Infections in humans occur in the context of complex niches where the pathogen interacts with both the host microenvironment and immune response, and the symbiotic microbial community. The polymicrobial nature of many human infections add a further layer of complexity. The effect of co‐ or polymicrobial infections can result in enhanced severity due to pathogens cooperative interaction or reduced morbidity because one of the pathogens affects the fitness of the other(s). In this review, the concept of co‐infections and polymicrobial interactions in the context of the intestinal mucosa is discussed, focusing on the interplay between the host, the microbiota and the pathogenic organisms. Specifically, we will examine examples of pathogen‐cooperative versus ‐antagonistic behavior during co‐ and polymicrobial infections. We discuss: the infection‐induced modulation of the host microenvironment and immune responses; the direct modulation of the microorganism’s fitness; the potentiation of inflammatory/carcinogenic conditions by polymicrobial biofilms; and the promotion of co‐infections by microbial‐induced DNA damage. Open questions in this very exciting field are also highlighted. This article is protected by copyright. All rights reserved.

ACS Style

Teresa Frisan. Co‐ and polymicrobial infections in the gut mucosa: The host–microbiota–pathogen perspective. Cellular Microbiology 2020, 23, 1 .

AMA Style

Teresa Frisan. Co‐ and polymicrobial infections in the gut mucosa: The host–microbiota–pathogen perspective. Cellular Microbiology. 2020; 23 (2):1.

Chicago/Turabian Style

Teresa Frisan. 2020. "Co‐ and polymicrobial infections in the gut mucosa: The host–microbiota–pathogen perspective." Cellular Microbiology 23, no. 2: 1.

Dataset
Published: 14 August 2020 in Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
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Kaposi's Sarcoma Herpesvirus (KSHV) is present in the main tumor cells of Kaposi's Sarcoma (KS), the spindle cells, which are of endothelial origin. KSHV is also associated with two B-cell lymphomas, Primary Effusion Lymphoma (PEL) and Multicentric Castleman's Disease. In KS and PEL, KSHV is primarily latent in the infected cells, expressing only a few genes. Although KSHV infection is required for KS and PEL, it is unclear how latent gene expression contributes to their formation. Proliferation of cancer cells occurs despite multiple checkpoints intended to prevent dysregulated cell growth. The first of these checkpoints, caused by shortening of telomeres, results in replicative senescence, where cells are metabolically active, but no longer divide. We found that human dermal lymphatic endothelial cells (LECs) are more susceptible to KSHV infection than their blood-specific endothelial cell counterparts and maintain KSHV latency to higher levels during passage. Importantly, KSHV infection of human LECs but not human BECs promotes their continued proliferation beyond this first checkpoint of replicative senescence. The latently expressed viral cyclin homolog is essential for KSHV-induced bypass of senescence in LECs. These data suggest that LECs may be an important reservoir for KSHV infection and may play a role during KS tumor development and that the viral cyclin is a critical oncogene for this process.

ACS Style

Teresa Frisan; DiMaio Ta; Vogt Dt; Lagunoff M. Faculty Opinions recommendation of KSHV requires vCyclin to overcome replicative senescence in primary human lymphatic endothelial cells. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2020, 16, 1 .

AMA Style

Teresa Frisan, DiMaio Ta, Vogt Dt, Lagunoff M. Faculty Opinions recommendation of KSHV requires vCyclin to overcome replicative senescence in primary human lymphatic endothelial cells. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2020; 16 (6):1.

Chicago/Turabian Style

Teresa Frisan; DiMaio Ta; Vogt Dt; Lagunoff M. 2020. "Faculty Opinions recommendation of KSHV requires vCyclin to overcome replicative senescence in primary human lymphatic endothelial cells." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 16, no. 6: 1.

Review
Published: 21 July 2020 in Cells
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Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host–pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease.

ACS Style

Daniel Humphreys; Mohamed Elghazaly; Teresa Frisan. Senescence and Host–Pathogen Interactions. Cells 2020, 9, 1747 .

AMA Style

Daniel Humphreys, Mohamed Elghazaly, Teresa Frisan. Senescence and Host–Pathogen Interactions. Cells. 2020; 9 (7):1747.

Chicago/Turabian Style

Daniel Humphreys; Mohamed Elghazaly; Teresa Frisan. 2020. "Senescence and Host–Pathogen Interactions." Cells 9, no. 7: 1747.

Journal article
Published: 07 July 2020 in Cancers
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Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRPα axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.

ACS Style

Alexandros Papalampros; Michail Vailas; Konstantinos Ntostoglou; Maria Chiloeches; Stratigoula Sakellariou; Niki Chouliari; Menelaos Samaras; Paraskevi Veltsista; Sofia Theodorou; Aggelos Margetis; Anna Bergonzini; Lysandros Karydakis; Natasha Hasemaki; Sophia Havaki; Ioannis Moustakas; Antonios Chatzigeorgiou; Timokratis Karamitros; Eleni Patsea; Christos Kittas; Andreas Lazaris; Evangelos Felekouras; Vassilis Gorgoulis; Teresa Frisan; Ioannis Pateras. Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression. Cancers 2020, 12, 1825 .

AMA Style

Alexandros Papalampros, Michail Vailas, Konstantinos Ntostoglou, Maria Chiloeches, Stratigoula Sakellariou, Niki Chouliari, Menelaos Samaras, Paraskevi Veltsista, Sofia Theodorou, Aggelos Margetis, Anna Bergonzini, Lysandros Karydakis, Natasha Hasemaki, Sophia Havaki, Ioannis Moustakas, Antonios Chatzigeorgiou, Timokratis Karamitros, Eleni Patsea, Christos Kittas, Andreas Lazaris, Evangelos Felekouras, Vassilis Gorgoulis, Teresa Frisan, Ioannis Pateras. Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression. Cancers. 2020; 12 (7):1825.

Chicago/Turabian Style

Alexandros Papalampros; Michail Vailas; Konstantinos Ntostoglou; Maria Chiloeches; Stratigoula Sakellariou; Niki Chouliari; Menelaos Samaras; Paraskevi Veltsista; Sofia Theodorou; Aggelos Margetis; Anna Bergonzini; Lysandros Karydakis; Natasha Hasemaki; Sophia Havaki; Ioannis Moustakas; Antonios Chatzigeorgiou; Timokratis Karamitros; Eleni Patsea; Christos Kittas; Andreas Lazaris; Evangelos Felekouras; Vassilis Gorgoulis; Teresa Frisan; Ioannis Pateras. 2020. "Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression." Cancers 12, no. 7: 1825.

Dataset
Published: 22 June 2020 in Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
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Inherited prion diseases are caused by autosomal dominant coding mutations in the human prion protein (PrP) gene (PRNP) and account for about 15% of human prion disease cases worldwide. The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis, to-date spontaneous formation of disease-relevant, transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated. Here, we report findings from transgenic mice that express human PrP 117V on a mouse PrP null background (117VV Tg30 mice), which model the PRNP A117V mutation causing inherited prion disease (IPD) including Gerstmann-Sträussler-Scheinker (GSS) disease phenotypes in humans. By studying brain samples from uninoculated groups of mice, we discovered that some mice (≥475 days old) spontaneously generated abnormal PrP assemblies, which after inoculation into further groups of 117VV Tg30 mice, produced a molecular and neuropathological phenotype congruent with that seen after transmission of brain isolates from IPD A117V patients to the same mice. To the best of our knowledge, the 117VV Tg30 mouse line is the first transgenic model expressing only mutant human PrP to show spontaneous generation of transmissible PrP assemblies that directly mirror those generated in an inherited prion disease in humans.

ACS Style

Teresa Frisan; Asante Ea; Linehan Jm; Tomlinson A; Jakubcova T; Hamdan S; Grimshaw A; Smidak M; Jeelani A; Nihat A; Mead S; Brandner S; Wadsworth Jdf; Collinge J. Faculty Opinions recommendation of Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2020, 18, 1 .

AMA Style

Teresa Frisan, Asante Ea, Linehan Jm, Tomlinson A, Jakubcova T, Hamdan S, Grimshaw A, Smidak M, Jeelani A, Nihat A, Mead S, Brandner S, Wadsworth Jdf, Collinge J. Faculty Opinions recommendation of Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2020; 18 (6):1.

Chicago/Turabian Style

Teresa Frisan; Asante Ea; Linehan Jm; Tomlinson A; Jakubcova T; Hamdan S; Grimshaw A; Smidak M; Jeelani A; Nihat A; Mead S; Brandner S; Wadsworth Jdf; Collinge J. 2020. "Faculty Opinions recommendation of Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 18, no. 6: 1.

Dataset
Published: 30 March 2020 in Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
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Estimation of the prevalence and contagiousness of undocumented novel coronavirus (SARS-CoV2) infections is critical for understanding the overall prevalence and pandemic potential of this disease. Here we use observations of reported infection within China, in conjunction with mobility data, a networked dynamic metapopulation model and Bayesian inference, to infer critical epidemiological characteristics associated with SARS-CoV2, including the fraction of undocumented infections and their contagiousness. We estimate 86% of all infections were undocumented (95% CI: [82%-90%]) prior to 23 January 2020 travel restrictions. Per person, the transmission rate of undocumented infections was 55% of documented infections ([46%-62%]), yet, due to their greater numbers, undocumented infections were the infection source for 79% of documented cases. These findings explain the rapid geographic spread of SARS-CoV2 and indicate containment of this virus will be particularly challenging.Copyright © 2020, American Association for the Advancement of Science.

ACS Style

Teresa Frisan; Li R; Pei S; Chen B; Song Y; Zhang T; Yang W; Shaman J. Faculty Opinions recommendation of Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2020, 1 .

AMA Style

Teresa Frisan, Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, Shaman J. Faculty Opinions recommendation of Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2020; ():1.

Chicago/Turabian Style

Teresa Frisan; Li R; Pei S; Chen B; Song Y; Zhang T; Yang W; Shaman J. 2020. "Faculty Opinions recommendation of Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2)." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature , no. : 1.

Dataset
Published: 24 February 2020 in Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
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Recent genomic data have revealed multiple interactions between Neanderthals and modern humans, but there is currently little genetic evidence regarding Neanderthal behaviour, diet, or disease. Here we describe the shotgun-sequencing of ancient DNA from five specimens of Neanderthal calcified dental plaque (calculus) and the characterization of regional differences in Neanderthal ecology. At Spy cave, Belgium, Neanderthal diet was heavily meat based and included woolly rhinoceros and wild sheep (mouflon), characteristic of a steppe environment. In contrast, no meat was detected in the diet of Neanderthals from El Sidrón cave, Spain, and dietary components of mushrooms, pine nuts, and moss reflected forest gathering. Differences in diet were also linked to an overall shift in the oral bacterial community (microbiota) and suggested that meat consumption contributed to substantial variation within Neanderthal microbiota. Evidence for self-medication was detected in an El Sidrón Neanderthal with a dental abscess and a chronic gastrointestinal pathogen (Enterocytozoon bieneusi). Metagenomic data from this individual also contained a nearly complete genome of the archaeal commensal Methanobrevibacter oralis (10.2× depth of coverage)-the oldest draft microbial genome generated to date, at around 48,000 years old. DNA preserved within dental calculus represents a notable source of information about the behaviour and health of ancient hominin specimens, as well as a unique system that is useful for the study of long-term microbial evolution.

ACS Style

Teresa Frisan; Weyrich Ls; Duchene S; Soubrier J; Arriola L; Llamas B; Breen J; Morris Ag; Alt Kw; Caramelli D; Dresely V; Farrell M; Farrer Ag; Francken M; Gully N; Haak W; Hardy K; Harvati K; Held P; Holmes Ec; Kaidonis J; Lalueza-Fox C; De La Rasilla M; Rosas A; Semal P; Soltysiak A; Townsend G; Usai D; Wahl J; Huson Dh; Dobney K; Cooper A. Faculty Opinions recommendation of Neanderthal behaviour, diet, and disease inferred from ancient DNA in dental calculus. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2020, 544, 1 .

AMA Style

Teresa Frisan, Weyrich Ls, Duchene S, Soubrier J, Arriola L, Llamas B, Breen J, Morris Ag, Alt Kw, Caramelli D, Dresely V, Farrell M, Farrer Ag, Francken M, Gully N, Haak W, Hardy K, Harvati K, Held P, Holmes Ec, Kaidonis J, Lalueza-Fox C, De La Rasilla M, Rosas A, Semal P, Soltysiak A, Townsend G, Usai D, Wahl J, Huson Dh, Dobney K, Cooper A. Faculty Opinions recommendation of Neanderthal behaviour, diet, and disease inferred from ancient DNA in dental calculus. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2020; 544 (7650):1.

Chicago/Turabian Style

Teresa Frisan; Weyrich Ls; Duchene S; Soubrier J; Arriola L; Llamas B; Breen J; Morris Ag; Alt Kw; Caramelli D; Dresely V; Farrell M; Farrer Ag; Francken M; Gully N; Haak W; Hardy K; Harvati K; Held P; Holmes Ec; Kaidonis J; Lalueza-Fox C; De La Rasilla M; Rosas A; Semal P; Soltysiak A; Townsend G; Usai D; Wahl J; Huson Dh; Dobney K; Cooper A. 2020. "Faculty Opinions recommendation of Neanderthal behaviour, diet, and disease inferred from ancient DNA in dental calculus." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 544, no. 7650: 1.

Review
Published: 21 January 2020 in Toxins
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Bacterial genotoxins (BTGX) induce DNA damage, which results in senescence or apoptosis of the target cells if not properly repaired. Three BTGXs have been identified: the cytolethal distending toxin (CDT) family produced by several Gram-negative bacteria, the typhoid toxin produced by several Salmonella enterica serovars, and colibactin, a peptide-polyketide, produced mainly by the phylogenetic group B2 Escherichia coli. The cellular responses induced by BTGXs resemble those of well-characterized carcinogenic agents, and several lines of evidence indicate that bacteria carrying genotoxin genes can contribute to tumor development under specific circumstances. Given their unusual mode of action, it is still enigmatic why these effectors have been acquired by microbes and what is their role in the context of the biology of the producing bacterium, since it is unlikely that their primary purpose is to induce/promote cancer in the mammalian host. In this review, we will discuss the possibility that the DNA damage induced by BTGX modulates the host immune response, acting as immunomodulator, leading to the establishment of a suitable niche for the producing bacterium. We will further highlight open questions that remain to be solved regarding the biology of this unusual family of bacterial toxins.

ACS Style

Océane C. B. Martin; Teresa Frisan. Bacterial Genotoxin-Induced DNA Damage and Modulation of the Host Immune Microenvironment. Toxins 2020, 12, 63 .

AMA Style

Océane C. B. Martin, Teresa Frisan. Bacterial Genotoxin-Induced DNA Damage and Modulation of the Host Immune Microenvironment. Toxins. 2020; 12 (2):63.

Chicago/Turabian Style

Océane C. B. Martin; Teresa Frisan. 2020. "Bacterial Genotoxin-Induced DNA Damage and Modulation of the Host Immune Microenvironment." Toxins 12, no. 2: 63.

Journal article
Published: 26 August 2019 in Cellular Microbiology
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Several commensal and pathogenic Gram-negative bacteria produce DNA-damaging toxins that are considered bona fide carcinogenic agents. The microbiota of colorectal cancer (CRC) patients is enriched in genotoxin-producing bacteria, but their role in the pathogenesis of CRC is poorly understood. The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in the majority of sporadic CRCs. We investigated whether the loss of APC alters the response of colonic epithelial cells to infection by Salmonella enterica, the only genotoxin-producing bacterium associated with cancer in humans. Using 2D and organotypic 3D cultures, we found that APC deficiency was associated with sustained activation of the DNA damage response, reduced capacity to repair different types of damage, including DNA breaks and oxidative damage, and failure to induce cell cycle arrest. The reduced DNA repair capacity and inability to activate adequate checkpoint responses was associated with increased genomic instability in APC-deficient cells exposed to the genotoxic bacterium. Inhibition of the checkpoint response was dependent on activation of the phosphatidylinositol 3-kinase pathway. These findings highlight the synergistic effect of the loss of APC and infection with genotoxin-producing bacteria in promoting a microenvironment conducive to malignant transformation.

ACS Style

Océane C.B. Martin; Anna Bergonzini; Federica D'Amico; Puran Chen; Jerry W. Shay; Jacques Dupuy; Mattias Svensson; Maria G. Masucci; Teresa Frisan. Infection with genotoxin‐producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells. Cellular Microbiology 2019, 21, e13099 .

AMA Style

Océane C.B. Martin, Anna Bergonzini, Federica D'Amico, Puran Chen, Jerry W. Shay, Jacques Dupuy, Mattias Svensson, Maria G. Masucci, Teresa Frisan. Infection with genotoxin‐producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells. Cellular Microbiology. 2019; 21 (12):e13099.

Chicago/Turabian Style

Océane C.B. Martin; Anna Bergonzini; Federica D'Amico; Puran Chen; Jerry W. Shay; Jacques Dupuy; Mattias Svensson; Maria G. Masucci; Teresa Frisan. 2019. "Infection with genotoxin‐producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells." Cellular Microbiology 21, no. 12: e13099.

Research article
Published: 29 October 2018 in International Journal of Cancer
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We have addressed the role of bacterial co‐infection in viral oncogenesis using as model Epstein‐Barr virus (EBV), a human herpesvirus that causes lymphoid malignancies and epithelial cancers. Infection of EBV carrying epithelial cells with the common oral pathogenic Gram‐negative bacterium Aggregatibacter actinomycetemcomitans (Aa) triggered reactivation of the productive virus cycle. Using isogenic Aa strains that differ in the production of the cytolethal distending toxin (CDT) and purified catalytically active or inactive toxin, we found that the CDT acts via induction of DNA double strand breaks and activation of the Ataxia Telangectasia Mutated (ATM) kinase. Exposure of EBV‐negative epithelial cells to the virus in the presence of sub‐lethal doses of CDT was accompanied by the accumulation of latently infected cells exhibiting multiple signs of genomic instability. These findings illustrate a scenario where co‐infection with certain bacterial species may favor the establishment of a microenvironment conducive to the EBV‐induced malignant transformation of epithelial cells. This article is protected by copyright. All rights reserved.

ACS Style

Teresa Frisan; Noemi Nagy; Dimitrios Chioureas; Marie Terol; Francesca Grasso; Maria G. Masucci. A bacterial genotoxin causes virus reactivation and genomic instability in Epstein-Barr virus infected epithelial cells pointing to a role of co-infection in viral oncogenesis. International Journal of Cancer 2018, 144, 98 -109.

AMA Style

Teresa Frisan, Noemi Nagy, Dimitrios Chioureas, Marie Terol, Francesca Grasso, Maria G. Masucci. A bacterial genotoxin causes virus reactivation and genomic instability in Epstein-Barr virus infected epithelial cells pointing to a role of co-infection in viral oncogenesis. International Journal of Cancer. 2018; 144 (1):98-109.

Chicago/Turabian Style

Teresa Frisan; Noemi Nagy; Dimitrios Chioureas; Marie Terol; Francesca Grasso; Maria G. Masucci. 2018. "A bacterial genotoxin causes virus reactivation and genomic instability in Epstein-Barr virus infected epithelial cells pointing to a role of co-infection in viral oncogenesis." International Journal of Cancer 144, no. 1: 98-109.

Book chapter
Published: 05 January 2018 in Toxins and Drug Discovery
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Bacterial genotoxins are a class of molecules that have the ability to enter the nucleus of a host cell and cause DNA damage by introducing single- and double-strand DNA breaks, leading to various effects, including activation of DNA damage response, senescence, apoptosis, and genetic aberrations. There is emerging evidence for an intricate connection between the DNA damage response and immunity, and it is becoming increasingly clear that bacterial genotoxins can act as potent immunomodulatory factors, which bacteria use in order to tailor the host immune response. This chapter will review some of the basic structural and functional characteristics of bacterial genotoxins and the internalization pathway used to reach the host DNA within the nuclear compartment. Special focus will be given to the connection between the genotoxin-induced DNA damage response and modulation of the host immune responses. Since it is not entirely clear what is the evolutionary advantage for bacteria that express these effectors, the possibility that they might play a role in influencing host immune response in order to promote stealth invasion and establishment of persistent infections will be explored.

ACS Style

Océane C. B. Martin; Teresa Frisan; Boris Mihaljevic. Bacterial Genotoxins as the Interphase Between DNA Damage and Immune Response. Toxins and Drug Discovery 2018, 383 -402.

AMA Style

Océane C. B. Martin, Teresa Frisan, Boris Mihaljevic. Bacterial Genotoxins as the Interphase Between DNA Damage and Immune Response. Toxins and Drug Discovery. 2018; ():383-402.

Chicago/Turabian Style

Océane C. B. Martin; Teresa Frisan; Boris Mihaljevic. 2018. "Bacterial Genotoxins as the Interphase Between DNA Damage and Immune Response." Toxins and Drug Discovery , no. : 383-402.

Comment
Published: 01 August 2016 in Microbial Cell
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Bacterial genotoxins are effectors that cause DNA damage in target cells. Many aspects of the biology of these toxins have been characterised in vitro, such as structure, cellular internalisation pathways and effects on the target cells. However, little is known about their function in vivo. Salmonella enterica serovar Typhi (S. Typhi) is a Gram-negative, intracellular bacterium that causes typhoid fever, a debilitating disease infecting more than 20 million people every year. S. Typhiproduce a genotoxin named typhoid toxin (TT), but its role in the contest of host infection is poorly characterized. The major obstacle in addressing this issue is that S. Typhi is exclusively a human pathogen. To overcome this limitation, we have used as model bacterium S. Typhimurium, and engineered it to produce endogenous levels of an active and inactive typhoid toxin, hereby named as TT (or genotoxic) and cdtB (or control), respectively. To our surprise, infection with the genotoxin strain strongly suppressed intestinal inflammation, leading to a better survival of the host during the acute phase of infection, suggesting typhoid toxin may exert a protective role. The presence of a functional genotoxin was also associated with an increased frequency of asymptomatic carriers.

ACS Style

R Guidi; L Del Bell Belluz; T Frisan. Bacterial genotoxin functions as immune-modulator and promotes host survival. Microbial Cell 2016, 3, 355 -357.

AMA Style

R Guidi, L Del Bell Belluz, T Frisan. Bacterial genotoxin functions as immune-modulator and promotes host survival. Microbial Cell. 2016; 3 (8):355-357.

Chicago/Turabian Style

R Guidi; L Del Bell Belluz; T Frisan. 2016. "Bacterial genotoxin functions as immune-modulator and promotes host survival." Microbial Cell 3, no. 8: 355-357.

Book chapter
Published: 24 June 2016 in Toxins and Drug Discovery
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Bacterial genotoxins are a class of molecules that have the ability to enter the nucleus of a host cell and cause DNA damage by introducing single- and double-strand DNA breaks, leading to various effects, including activation of DNA damage response, senescence, apoptosis, and genetic aberrations. There is emerging evidence for an intricate connection between the DNA damage response and immunity, and it is becoming increasingly clear that bacterial genotoxins can act as potent immunomodulatory factors, which bacteria use in order to tailor the host immune response. This chapter will review some of the basic structural and functional characteristics of bacterial genotoxins and the internalization pathway used to reach the host DNA within the nuclear compartment. Special focus will be given to the connection between the genotoxin-induced DNA damage response and modulation of the host immune responses. Since it is not entirely clear what is the evolutionary advantage for bacteria that express these effectors, the possibility that they might play a role in influencing host immune response in order to promote stealth invasion and establishment of persistent infections will be explored.

ACS Style

Océane C. B. Martin; Teresa Frisan; Boris Mihaljevic. Bacterial Genotoxins as the Interphase Between DNA Damage and Immune Response. Toxins and Drug Discovery 2016, 1 -20.

AMA Style

Océane C. B. Martin, Teresa Frisan, Boris Mihaljevic. Bacterial Genotoxins as the Interphase Between DNA Damage and Immune Response. Toxins and Drug Discovery. 2016; ():1-20.

Chicago/Turabian Style

Océane C. B. Martin; Teresa Frisan; Boris Mihaljevic. 2016. "Bacterial Genotoxins as the Interphase Between DNA Damage and Immune Response." Toxins and Drug Discovery , no. : 1-20.

Research article
Published: 07 April 2016 in PLOS Pathogens
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Bacterial genotoxins, produced by several Gram-negative bacteria, induce DNA damage in the target cells. While the responses induced in the host cells have been extensively studied in vitro, the role of these effectors during the course of infection remains poorly characterized. To address this issue, we assessed the effects of the Salmonella enterica genotoxin, known as typhoid toxin, in in vivo models of murine infection. Immunocompetent mice were infected with isogenic S. enterica, serovar Typhimurium (S. Typhimurium) strains, encoding either a functional or an inactive typhoid toxin. The presence of the genotoxic subunit was detected 10 days post-infection in the liver of infected mice. Unexpectedly, its expression promoted the survival of the host, and was associated with a significant reduction of severe enteritis in the early phases of infection. Immunohistochemical and transcriptomic analysis confirmed the toxin-mediated suppression of the intestinal inflammatory response. The presence of a functional typhoid toxin further induced an increased frequency of asymptomatic carriers. Our data indicate that the typhoid toxin DNA damaging activity increases host survival and favours long-term colonization, highlighting a complex cross-talk between infection, DNA damage response and host immune response. These findings may contribute to understand why such effectors have been evolutionary conserved and horizontally transferred among Gram-negative bacteria.

ACS Style

Lisa Del Bel Belluz; Riccardo Guidi; Ioannis S. Pateras; Laura Levi; Boris Mihaljevic; Syed Fazle Rouf; Marie Wrande; Marco Candela; Silvia Turroni; Claudia Nastasi; Clarissa Consolandi; Clelia Peano; Toma Tebaldi; Gabriella Viero; Vassilis Gorgoulis; Thorbjørn Krejsgaard; Mikael Rhen; Teresa Frisan. The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection. PLOS Pathogens 2016, 12, e1005528 .

AMA Style

Lisa Del Bel Belluz, Riccardo Guidi, Ioannis S. Pateras, Laura Levi, Boris Mihaljevic, Syed Fazle Rouf, Marie Wrande, Marco Candela, Silvia Turroni, Claudia Nastasi, Clarissa Consolandi, Clelia Peano, Toma Tebaldi, Gabriella Viero, Vassilis Gorgoulis, Thorbjørn Krejsgaard, Mikael Rhen, Teresa Frisan. The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection. PLOS Pathogens. 2016; 12 (4):e1005528.

Chicago/Turabian Style

Lisa Del Bel Belluz; Riccardo Guidi; Ioannis S. Pateras; Laura Levi; Boris Mihaljevic; Syed Fazle Rouf; Marie Wrande; Marco Candela; Silvia Turroni; Claudia Nastasi; Clarissa Consolandi; Clelia Peano; Toma Tebaldi; Gabriella Viero; Vassilis Gorgoulis; Thorbjørn Krejsgaard; Mikael Rhen; Teresa Frisan. 2016. "The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection." PLOS Pathogens 12, no. 4: e1005528.

Review
Published: 01 March 2016 in Biochimica et Biophysica Acta (BBA) - Biomembranes
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Bacterial protein genotoxins target the DNA of eukaryotic cells, causing DNA single and double strand breaks. The final outcome of the intoxication is induction of DNA damage responses and activation of DNA repair pathways. When the damage is beyond repair, the target cell either undergoes apoptosis or enters a permanent quiescent stage, known as cellular senescence. In certain instances, intoxicated cells can survive and proliferate. This event leads to accumulation of genomic instability and acquisition of malignant traits, underlining the carcinogenic potential of these toxins. The toxicity is dependent on the toxins' internalization and trafficking from the extracellular environment to the nucleus, and requires a complex interaction with several cellular membrane compartments: the plasma membrane, the endosomes, the trans Golgi network and the endoplasmic reticulum, and finally the nucleus. This review will discuss the current knowledge of the bacterial genotoxins internalization pathways and will highlight the issues that still remain unanswered. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.

ACS Style

Teresa Frisan. Bacterial genotoxins: The long journey to the nucleus of mammalian cells. Biochimica et Biophysica Acta (BBA) - Biomembranes 2016, 1858, 567 -575.

AMA Style

Teresa Frisan. Bacterial genotoxins: The long journey to the nucleus of mammalian cells. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2016; 1858 (3):567-575.

Chicago/Turabian Style

Teresa Frisan. 2016. "Bacterial genotoxins: The long journey to the nucleus of mammalian cells." Biochimica et Biophysica Acta (BBA) - Biomembranes 1858, no. 3: 567-575.