Genetic studies of Staphylococcus haemolyticus

PI (Principal Investigator): Pauline Cavanagh

Team: Hermoine Venter, Runa Wolden, Martin Christensen

We have previously demonstrated that infections with S. haemolyticus most frequently occur in immunocompromised patient groups, such as cancer patients and highly premature infants. This bacteria can cause severe infections and is often characterized by a high degree of antibiotic resistance. Through a comparative analysis of S. haemolyticus whole genome sequences from clinical and commensal isolates, we have found that genes encoding surface proteins, capsule, and a large proportion of antibiotic resistance genes distinguish the two populations. We have developed molecular tools to examine the effect of individual genes through gene knock-out experiments.

We are currently working on projects where we are studying:

1. The significance of various surface proteins for S. haemolyticus virulence
2. The significance of different capsule versions for S. haemolyticus virulence
3. The significance of various methylation profiles for S. haemolyticus virulence

For selected references since 2012, please refer to the publications in CRISTIN for the relevant Principal Investigator (PI).

• Cavanagh JP, Wolden R, Heise P, Esaiassen E, Klingenberg C, Fredheim EGA. Antimicrobial susceptibility and body site distribution of community isolates of Coagulase Negative Staphylococci. APMIS. 2016; 124: 973-8.
• Pain M, Hjerde E, Klingenberg C, Cavanagh JP. Comparative Genomic Analysis of Staphylococcus haemolyticus Reveals Keys to Hospital Adaptation and pathogenicity. Front Microbiol. 2019 Sep 10; 10:2096. 
• Cavanagh P, Hjerde E, Holden M, Kalkhe T, Klingenberg C, Flægstad T, Bentley S, Parkhill J, Sollid J. Whole genome sequencing reveals clonal expansion of multi-resistant Staphylococcus haemolyticus in European hospitals. J Antimicrob Chemother. 2014; 69: 2920-7.
• Cavanagh JP, Klingenberg C, Hanssen AM, Fredheim EA, Francois P, Schrenzel J, Flægstad T, Sollid JE. Core genome conservation of S. haemolyticus limits sequence based population structure analysis. J Microbiol Methods, 2012; 89: 159-66.
• Cavanagh JP, Pain M, Askarian F, Bruun JA, Urbarova I, Wai SN, Schmidt F, Johannessen M. Comparative exoproteome profiling of an invasive and a commensal Staphylococcus haemolyticus isolate. J Proteomics. 2019;197:106-114.
• Wolden R, Pain M, Karlsson R, Karlsson A, Aarag Fredheim EG, Cavanagh JP.
  Identification of surface proteins in a clinical Staphylococcus haemolyticus isolate by bacterial surface shaving. BMC Microbiol. 2020;20:80.

Modulation of host immune response to Coagulase-Negative Staphylococci (KNS) and various species of streptococci

PIs (Principal Investigators): Hildegunn Granslo, Claus Klingenberg, Pauline Cavanagh

Team: Tom Eirik Mollnes, Aline Bjerkhaug, Oda Gundersen, Synnøve Holmbukt

In collaboration with Prof. Mollnes in Bodø, we have conducted studies for several years using a blood model (including umbilical cord blood and adult blood) to assess immune responses to different microbes and investigate whether excessive immune responses can be inhibited. In this blood model, we can evaluate the degree of bacterial virulence and potential new strategies to inhibit the innate immune system, including the inhibition of the complement system and Toll-like receptors.

New knowledge about the interaction between the microbe and the host is essential for developing methods for the prevention and treatment of infections.

For selected references since 2012, please refer to the publications in CRISTIN for the respective Principal Investigators.

• Granslo HN, Klingenberg C, Fredheim EA, Acharya G, Mollnes TE, Flægstad T. Staphylococcus epidermidis biofilms induce lower complement activation in neonates compared to adults. Pediatr Res. 2013; 73: 294-300.
• Granslo HN, Fredheim EGA, Esaiassen E, Østrup Jensen P, Mollnes TE, Moser C, Flægstad T, Klingenberg C, Cavanagh JP. The synthetic antimicrobial peptide LTX21 induces inflammatory responses in an in vivo mouse peritonitis model and an ex vivo human whole blood model. APMIS 2019; 127: 475-83

Characterization and clinical significance of Staphylococcus borealis

PI (Principal Investigator): Pauline Cavanagh

Team: Claus Klingenberg, Pia Littauer

In 2020, our research group published the discovery of the new Staphylococcus species, Staphylococcus borealis. We are currently collecting clinical isolates of S. borealis to investigate the clinical significance of this new bacterial species.

For selected references since 2012, please refer to the publications in CRISTIN for the relevant Principal Investigator.

• Pain M, Wolden R, Jaén-Luchoro D, Salvà-Serra F, Iglesias BP, Karlsson R,Klingenberg C, Cavanagh JP. Staphylococcus borealis sp. nov., isolated from human skin and blood. Int J Syst Evol Microbiol. 2020; 70(12):6067-78.

Antimicrobial effect of bacteriocin produced by S. haemolyticus

PI (Principal Investigator): Pauline Cavanagh

Team: Hermoine Venter, Runa Wolden

Antibiotic-resistant microbes pose a global threat to modern medicine as we know it. In this project, we are characterizing the antimicrobial effect of a bacteriocin produced by S. haemolyticus. We have previously demonstrated that biofilm-producing bacteria are much more resistant to antibiotics than non-biofilm-producing bacteria. Therefore, we are testing the effect of the bacteriocin against bacteria in both planktonic growth and biofilm. The project is conducted in collaboration with researchers at NMBU

Selected references since 2012, see otherwise publications in CRISTIN for the relevant PI (Principal Investigator).

• Kranjec C, Kristensen SS, Bartkiewicz KT, Brønner M, Cavanagh JP, Srikantam A, Mathiesen G, Diep DB. A bacteriocin-based treatment option for Staphylococcus haemolyticus biofilms. Sci Rep. 2021 Jul 6;11(1):13909. doi: 10.1038/s41598-021-93158-z.

Gut flora in children with HIV

PI (Principal Investigator): Trond Flægstad

Team: Pauline Cavanagh, Evgeniya Sovershaeva, Erik Hjerde, Trym Tune Flygel

The main objective of the study was to investigate if azithromycin improves lung function in children with HIV and chronic lung disease. In the study, 346 children aged 6-19 years with HIV and chronic lung disease in Zimbabwe and Malawi received weekly azithromycin or a placebo for 12 months. In this sub-study, we are examining the gut flora in children with HIV. Using 16S rRNA sequencing, we are investigating whether the gut flora changes after the use of azithromycin and if any changes are reversed six months after the completion of treatment. The research project is part of the individually randomized, double-blind, placebo-controlled study "Bronchopulmonary function in response to azithromycin treatment for chronic lung disease in HIV-infected children (BREATHE)" (1, 2). The study is funded by The Research Council of Norway and is an international collaborative project.

For selected references since 2012, please refer to the publications in CRISTIN for the relevant PI.

• Flygel TT, Sovershaeva E, Claassen-Weitz S, Hjerde E, Mwaikono KS, Odland JØ, Ferrand RA, Mchugh G, Gutteberg TJ, Nicol MP, Cavanagh JP, Flægstad T; BREATHE Study Team. Composition of Gut Microbiota of Children and Adolescents With Perinatal Human Immunodeficiency Virus Infection Taking Antiretroviral Therapy in Zimbabwe. J Infect Dis. 2020 Jan 14;221(3):483-492. 

Epidemiological studies on infections and antibiotic use in newborns.

PI (Principal Investigator): Claus Klingenberg

Team: Zuzana Huncikova, Anlaug Vatne

For several years, we have been involved in various projects using population-based data from the Norwegian Neonatal Network (NNK) to study infections in both full-term and preterm infants. We have contributed to publications and plan to publish more in the next 1-2 years, focusing on antibiotic use and how infections affect the prognosis of preterm infants. We also collaborate with both national and international researchers in this field.

For selected references since 2012, please refer to the publications in CRISTIN for the relevant PI.

• Mundal HS, Rønnestad A, Klingenberg C, Stensvold HJ, Størdal K. Sepsis and antibiotic use in term and near-term newborns - a nationwide population-based study. Pediatrics. 2021;148: e2021051339.
• Dretvik T, Solevåg AL, Finvåg A, Størdal EH, Størdal K, Klingenberg C. Active antibiotic discontinuation in suspected but not confirmed early-onset neonatal sepsis – a quality-improvement initiative. Acta Paediatr. 2020; 109: 1125-30
• Vatne A, Klingenberg C, Øymar K, Rønnestad A, Manzoni P, Rettedal S. Reduced antibiotic exposure by serial physical examinations in term neonates at risk of early-onset sepsis. Pediatr Infect Dis J. 2020; 39:438-43.
• Achten NB, Klingenberg C, Benitz WE, Stocker M, Schlapbach LJ, Giannoni E, Bokelaar R, Driessen GJA, Brodin P, Uthaya S, van Rossum AMC, Plötz FB. Association of use of the early-onset sepsis calculator with reduction in antibiotic therapy and safety: A systematic review and meta-analysis. JAMA Pediatr. 2019; 173:1032-1040. 
• Fjalstad JW, Stensvold HJ, Bergseng H, Simonsen GS, Rønnestad A, Klingenberg C. Early onset sepsis and antibiotic exposure in term infants: a nationwide population-based study in Norway. Pediatr Infect Dis J. 2016; 35:1-6.

Studies on the effectiveness, side effects, and monitoring of aminoglycosides in newborns and older children.

PI (Principal Investigator): Claus Klingenberg

Team: Dagny Hemmingsen, Kasper Øvsthus, Lene Nymo Trulsen

For many years, we have been conducting research on aminoglycosides, an antibiotic group that is environmentally favorable and minimally promotes the development of resistance. The challenges with this antibiotic group include uncertainties regarding dosing and potential side effects. We have evaluated a gentamicin dosing regimen in newborns, including a thorough assessment of hearing. We have several ongoing projects related to the evaluation of aminoglycosides in newborns and older children.

For selected references since 2012, please refer to the publications in CRISTIN for the relevant PI.

• Hemmingsen D, Mikalsen C, Hansen AR, Fjalstad JW, Stenklev NC, Klingenberg C. Hearing assessment in schoolchildren after neonatal exposure to a high-dose gentamicin regimen. Pediatrics. 2020 145:e20192373.
• Rypdal V, Jørandli S, Hemmingsen D, Solbu MD, Klingenberg C. Exposure to an Extended-interval High-Dose Gentamicin regimen in the Neonatal period is not associated with long-term Nephrotoxicity. Front Pediatr 30 November 2021, doi: 10.3389/fped.2021.779827
• Fjalstad JW, Laukli E, van den Anker JN, Klingenberg C. High dose gentamicin in newborn infants: is it safe? Eur J Pediatr. 2014; 173: 489-95.

Studier på effekt av probiotika til nyfødte

PI: Claus Klingenberg,

Team: Pauline Cavanagh, Veronika Pettersen, Ahmed Bargheet

Vi har gjennomført en nasjonal studie der vi har sett på effekter av probiotika gitt til for tidlig fødte barn. Vi deltar nå sammen med en gruppe norske og tanzanianske forskere i en stor studie der vi undersøker om probiotika kan påvirke helsen til spedbarn i en gunstig retning samt ha en positiv effekt på tarmmikrobiomet.

Utvalgte referanser siden 2012, se ellers publikasjoner i CRISTIN til aktuelle PI

• Kuwelker K, Langeland N, Löhr I, Gidion J, Manyahi J, Moyo S, Blomberg B, Klingenberg C. Use of Probiotics to Reduce Infections and Death and Prevent Colonization with Extended-spectrum beta-lactamase (ESBL) producing bacteria among newborn infants in Tanzania (ProRIDE Trial): study protocol for a randomized controlled clinical trial. Trials, 2021;22:312.
• Esaiassen E, Hjerde E, Cavanagh JP, Pedersen T, Andresen JH, Rettedal SI, Støen R, Nakstad B, Willassen NP, Klingenberg C. Effects of Probiotic Supplementation on the Gut Microbiota and Antibiotic Resistome Development in Preterm Infants. Front Pediatr. 2018 Nov 16;6:347. doi: 10.3389/fped.2018.00347. eCollection 2018

Metabolomikk ved infeksjoner og antibiotikabehandling av nyfødte

PI: Veronika Pettersen, Pauline Cavanagh, Claus Klingenberg

Team: Hildegunn Granslo, Aline Bjerkhaug, Gaute Hovde Bø, Oda Gundersen, Synnøve Holmbukt

Vi gjennomfører, og planlegger, ulike studier der vi gjør analyser på metabolomikk i urin, avføring og blod hos nyfødte og spedbarn barn som behandles med antibiotika eller spedbarn som behandles med probiotika. Metabolomikk i avføring gjøres med tanke på å se hvordan probiotika/antibiotika påvirker metabolske forhold i tarmen. Metabolomikk i urin og blod er med tanke på utvikling av biomarkører for infeksjon og alvorlighetsgrad.

Utvalgte referanser siden 2012, se ellers publikasjoner i CRISTIN til aktuelle PI

• Bjerkhaug AU, Granslo HN, Klingenberg C. Metabolic responses in neonatal sepsis - A systematic review of human metabolomic studies. Acta Paediatr. 2021; 110: 2316-25.

MRSA utbrudd Nyfødtavdeling

PIs: Hildegunn Granslo, Pauline Cavanagh

Team: Claus Klingenberg, Karina Olsen, Christina Gabrielsen, Kjersti Wiik Larsen

Tarmmikrobiomet til barn med kreft - Compositional and metabolic changes of the gut microbiome in childhood cancers 

PI: Veronika Pettersen,

Team: Hildegunn Granslo, Trond Flægstad

The project is a collaboration between the Paediatric Research group at UiT, Norwegian Childhood Cancer Biobank, and researchers from the Centre for Ecological and Evolutionary Synthesis at the University of Oslo.

The gut microbiome has been implicated as a possible driver and regulator of cancer pathogenesis. Producing small molecules and metabolites that act both locally and systemically, the gut microbiome may promote or suppress cancer generation and progression.

This project explores the gut microbiome in paediatric cancer patients. By using DNA sequencing methods and metabolite profiling, we will characterize features of the gut microbiome associated with cancer diagnoses in children. The goal is to describe microbiome-based markers that discriminate cancer cases from healthy controls and microbial metabolites that can serve as diagnostic biomarkers in therapeutic explorations.

Gut Microbiome-based Biomarkers to Prevent Infections by Antimicrobial Resistant Bacteria in Infancy 

PI: Veronika Pettersen

Team: Claus Klingenberg, Hildegunn Granslo, Pauline Cavanagh

The microbial community living in the human intestine provides first-line defense against enteric pathogens. Exploiting symbiotic bacteria for pathogen suppression is a viable alternative to the use of antibiotics in preventing infections.

This research project leverages two cohort studies of term infants to describe the impact of antibiotics and probiotics on the gut microbiome. The first is a randomized clinical trial co-led by the Paediatric Research group in Tromsø (UiT/UNN), which investigates the effects of probiotic therapy in Tanzanian children and its potential to prevent infections by ESBL-producing Enterobacterales (ProRIDE: Probiotics to Reduce Infections and Death and Prevent Colonization with ESBL- producing bacteria). The second study is a prospective, observational pilot study of infants with suspected symptoms of infection during the 1st week of life leading to antibiotic therapy (IMPALE: Impact of Antibiotics on the Neonatal Metabolome). The aim of both studies is to describe changes in faecal metabolites and microbial composition in association with antibiotic/probiotic use, drug-resistant strain colonization, and a risk of infection.