Prof Joakim Larsson

Summary of funded projects

INTERACT - The interaction of metals and biocides with the selection of antibiotic-resistant bacteria

Strong Research Environment funded by FORMAS 2012-2016 with 25 MSEK. INTERACT is led by Joakim Larsson in collaboration with professors Dan Andersson (UU), Hans Blanck (GU) and Mats Tysklind (UmU)

Multi-resistant bacteria cause tens of thousands of deaths every year in Europe, jeopardizing all kinds of medical procedures. According to the WHO, the rapid resistance development is one of the largest threats to public health, globally. Alarmingly, not only antibiotics select for resistance, but the combined exposure to biocides and metals can also contribute through co-selection and cross-resistance. Chemicals in the environment may thus make bacteria untreatable with antibiotics at a later stage. To enable mitigations, INTERACT will identify chemicals and environments associated with high risks for combination effects. Specifically, we will assess:

1. What biocides and concentrations that promote resistance development
2. In which environments high-risk mixtures can be found
3. The genetic basis for co- and cross-resistance
4. The potential for resistancefactors to spread from the environment to human pathogens
    

INTERACT is expected to provide crucial input to environmental regulatory agencies, as well as the health care, water and shipping sectors.
 

Pharmaceutical pollution – antibiotic resistance development and mode-of-action based test strategies

Senior scientist position for Joakim Larsson 2009-2015 within the field of Translational Pharmacology including a startup-grant from the Swedish Research Council (Medicine).
This grant covers research on several aspects on environmental effects of pharmaceuticals where there currently are major knowledge gaps. My group will focus on three areas:

1. assess risks (including resistance development) associated with the extaordinary large releases of antibiotics and other pharmaceuticals from bulk drug producers in India
2. identify drugs likely to cause environmental effects and contribute to a scientifically founded framework for mode-of-action based environmental risk assessments of human pharmaceuticals
3. evaluate effluent treatment technologies to reduce the environmental impact of pharmaceuticals

MistraPharma - Identification and reduction of environmental risks caused by human pharmaceuticals (phase II).

Research program supported by the Swedish Foundation for Strategic Environmental Research (MISTRA) 2012-2015 with 52 MSEK. The program involves partners at the Sahlgrenska Academy at University of Gothenburg, Chalmers University of Technology, the Royal Institute of Technology, Uppsala University, Stockholm University, Umeå University, Brunel University (UK) and Stella Futura. Program website: www.mistrapharma.se

The major aims of this interdisciplinary research program are to:

(1) Identify high risk APIs
By generating new data with high relevance in environmental risk management
(2) Understand promotion of antibiotic resistance in the environment
By determining antibiotic resistance factors in contaminated environments and assessing different selection pressures
(3) Evaluate removal of high risk APIs through wastewater treatment
By assessing the feasibility of ozonation and/or activated carbon in wastewater treatment
(4) Contribute to the development of improved risk management
By improving the scientific basis for environmental classification, risk assessment and substitution
(5) Provide state-of-the-art analyses of APIs of environmental concern
By developing and quality assuring analytical methods
(6) Provide decision support to stakeholders
By communicating generated knowledge to ensure that it can be put to practical use.
 

Dissemination of antibiotic resistance through international travelling

Funding for three months full time senior bioinformatic support during 2013 from Science for Life Laboratories to Joakim Larsson, funded by the Knut and Alice Wallenberg Foundation. This is part of a joint project between our lab (PhD Student Johan Bengtsson, Assoc. Prof Joakim Larsson) the University of Umeå (Dr Anders Johansson and PhD student Martin Angelin) as well as Chalmers University of Technology (Assoc. Prof Erik Kristiansson).

International travel is a central risk factor in the spread of antibiotic resistance. In fact, many of the resistant factors we are struggling with today in Europe appear to have come from other continents. Most published studies to date on the role of travel in this context have centred on resistance towards specific antibiotics and/or specific bacterial species and strains. In this project, we take a more holistic approach by investigating a multitude of resistance genes in parallel using next generation metagenomic DNA sequencing. To this end, we have sequenced faecal samples from medical students before and after they have engaged in long-range travelling, primarily to the Indian peninsula and central Africa.
 

Antibiotic resistance in marine bacteria - the role of biocides and metals in the marine environment for promoting and maintaining antibiotic resistance

Funding for two PhD student from the Gothenburg Centre for Marine Research 2012-2015 to Joakim Larsson and Hans Blanck

One of the primary goals for Gothenburg Centre for Marine Research is to coordinate marine environmental research in Gothenburg and to bring together scientists from different disciplines. This interdisciplinary project combines competence from the Health Faculty and the Natural Science Faculty to address potential drivers for the development of antibiotic resistance, one of the most urgent threats to human health globally. Bacteria often carry resistance elements to metals and biocides together with resistance elements to antibiotics. Thus, a selection pressure from metals and biocides may select also for antibiotic resistance. By combining our competences in large-scale DNA sequencing and bacterial biofilm ecology, this project will address the risks for the promotion of antibiotic resistant bacteria, through indirect selection pressures, in the marine environment.  

NICE – Novel Instruments for effect-based assessment of Chemical pollution in coastal Ecosystems

Strong Research Environment funded by the Swedish Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) 2012-2016 with 25 MSEK. The program, coordinated by Dr Thomas Backhaus, involves 12 partners from the Gothenburg region. The JL group is mainly involved in work on bacterial metagenomics.

Mixtures of toxic chemicals regularly occur in our coastal ecosystems. NICE develops instruments for monitoring their ecological effects, as required by the Water Framework Directive and needed for identification of the relevant pollutants in the field. The NICE tools will be evaluated in field studies. We will suggest options for environmental regulation of chemical mixtures, thus providing input to the water management in Västra Götaland. Reference and contaminated sites mainly on the Swedish coast will be selected in co-operation with stakeholder authorities and subjected to deeper ecotoxicological investigations. Chemical monitoring data will initially be used for pinpointing the pollutants at each site. These will be ranked according to their expected environmental impact and then further investigated by extended chemical analysis. Ecotoxicological effect profiles ("fingerprints") of the priority pollutants will be recorded for microbial communities, invertebrates and fish, using classic biomarkers, population level endpoints, ecological effect indicators (PICT) and advanced fingerprints based on (gen-)OMICs. The fingerprints will be used to detect effects in the environment, providing causal links between the mere presence of pollutants and their ecological impact of a site. The effect profiles will be aggregated into models for site-specific ecological impacts, which will be amended, if needed, to take into account the presence of unknown pollutants and interactions.
 

Characterization of antibiotic resistance in bacterial communities: novel methods using next generation
sequencing

Project grant from the Swedish Research Council (VR-NT) 2012-2015 to Erik Kristiansson (DGJ Larsson, ERB Moore and G Kemp are co-applicants).

The accelerated development of antibiotic resistance is one of the most urgent threats to human health. Bacteria become resistant to antibiotics by acquiring resistance genes through the process of horizontal gene transfer. Since antibiotics are naturally produced by many organisms, environmental bacterial communities contain a particular high diversity of resistance genes. Understanding the role of the environment as a reservoir for resistance genes and their routes of transfer is therefore vital. In this project we will develop novel tools for explorative analysis of resistance genes in bacterial communities. The tools are based on data generated by the next generation DNA sequencing and have therefore a high sensitivity and precision, even for less abundant genes. We will also develop tools for culture-independent characterization of resistance plasmids, which are the main vehicles for transmission of resistance genes between bacterial cells. The methods will be used to analyze data from environmental bacterial communities, both with and without antibiotic selection pressure, and the human microbiome. The project will generate novel insights into the development, promotion and spread of antibiotic resistance. The methods will have a great applicability in both basic and clinical microbiology as well as in metagenomics in general.
 

Novel methods for improved statistical inference in quantitative metagenomics

Project grant from the Swedish Research Council (VR-NT) 2012-2015 to Erik Kristiansson (DGJ Larsson, O Nerman, T Backhaus and H Blanck are co-applicants).

In metagenomics communities of microorganisms are studied by observing random fragments of their genomes. The potential of metagenomics have increased with the introduction of next generation DNA sequencing and it constitutes today an important measurement technique in ecology, ecotoxicology and medicine. Metagenomics is however limited by high levels of technical and biological noise, the low number of samples and the high dimensionality of the observed data. In this project we will develop novel statistical methods for analysis of gene count abundance in metagenomes. We will model the complex structure of metagenomics data and develop robust estimators for the biological variation between metagenomes. We will also develop new methods for normalization of metagenomes with varying taxonomic composition. The methods will be applied in three collaborative research projects where metagenomics is an essential measurement technique. The methods will also be implemented in a software package that will be freely available for the microbiology research community. The statistical methodology developed within this project will improve the performance of metagenomics and thus the study of uncultured microorganisms in general.
 

Multi-drug-resistant Gram-negative infectious bacteria: new genotypic and phenotypic developments for diagnostics and epidemiological control within the clinical environment

ALF-LUA grant to Ed Moore and several co-applicants (including DGJ Larsson) 2012-2013.

A primary focus of the project is the use of an unusually well-defined epidemiological out-break situation to establish the basis for how we should conduct continuous monitoring of ESBL-producing bacteria and other multi drug resistant gram negatives in an efficient and cost effective manner. A range of different typing strategies, including MALDI-TOF, will be assessed and evaluated. My group’s primary involvement and interest in this project involve evaluations with sequencing-based technologies.
 

Antibiotic resistance in the external environment - the role of antibiotic pollution in the selection of resistance and subsequent gene transfer to the human microbiome

Project grant from the Swedish Research Council (VR-MH) 2011-2013
 

Does a high level of antibiotic pollution increase risks for mobilization of resistance genes from the environment to the human microflora - exploratory studies including deep sequencing

Project grant funded by the Swedish Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) 2011-2013.

Increasing frequencies of multiresistant pathogens is a global problem accelerated by our heavy use of antibiotics. As bacteria and bacterial genes often are mobile, the external environmental may serve as a reservoir of resistance genes to human pathogens. We have recently demonstrated unprecedented pollution with broad-spectrum antibiotics in India with potential implications for resistance development. The main questions to answer within the VR and FORMAS projects are ¹⁾ How does a high and persistent environmental antibiotic selection pressure affect the abundance of resistance genes and genetic elements promoting their mobility? ²⁾ Can we find evidence for a role of environmental antibiotic pollution in the transfer of resistance genes to the human microflora? ³⁾ Can we explore the environmental microbiome to identify novel resistance genes that we may face in the clinic tomorrow? High-throughput DNA sequencing of isolates and complex bacterial communities, in parallel with traditional microbiology, will be used to genetically and functionally characterize resistance factors in bacteria from river sediment, soil, drinking water and human faeces from highly antibiotic-polluted Indian environments and reference sites. Science-based evidence of the consequences of antibiotic pollution, as those generated here, could provide strong incentives to reduce antibiotic selection pressure on environmental bacteria in order to protect public health. Click here for a 15 minute presentation (in Swedish) on the challenges with antibiotics in the environment.
 

Microbial diversity and development of antibiotic resistance associated with industrial wastewater treatment

Swedish Research Link programme funded 2009-2011 by SIDA.

The Swedish Research Links programme from SIDA aims to stimulate research cooperation between researchers in Sweden and researchers in Asia, the Middle East and North Africa (MENA) region and South Africa. One important focus is to stimulate the mobility for the involved scientists. Within this collaborative project between the University of Gothenburg and Indian scientists, we intend to analyze the impact of extraordinary high levels of antibiotic pollution from pharmaceutical manufacturing near Hyderabad, India, on bacterial diversity and the development of antibiotic resistance. We will also study the potential impact on the emergence of antibiotic-resistant bacterial pathogens as well as the genetic background to their resistance. This research will provide insights into the relationships between selection processes due to antibiotic pollution and subsequent development of resistance.
 

Consumption of inexpensive medicines – increased risks for resistance development and environmental effects?

PhD-student project (Carolin Rutgersson) funded by the Research School for Environment and Health in Göteborg 2008-2012.

Pharmaceuticals are thought to reach the aquatic environment primarily via sewage effluents, where for example estrogens can feminize fish. Antibiotics in normal treated sewage effluents are not believed to cause resistance or affect microbial diversity. However, we recently showed that treated effluent from 90 production sites in India contains extremely high, toxic levels of antibiotics, with ciprofloxacin up to 1 million times the levels normally found in sewage effluents. We will start to address the environmental impact of the release of pharmaceuticals at this centre for the global bulk-drug market. This will also include the impact on species diversity and resistance development of bacterial communities. The project will also address different possibilities of how the situation can be improved. We believe the project will provide new knowledge on antibiotic pollution and the subsequent development of resistance, of urgent importance for improving regulatory standards for production units world-wide. The project will be performed in collaboration with several other research groups, both in Sweden and India.
 

Endocrine disruption of non-genomic progesterone signalling – consequences for gamete transport and sex ratios

Research program funded by the Swedish Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) 2008-2010 to Joakim Larsson. Anna Bylander is a PhD student within this program.

The aim of this project is to investigate how progesterone and various endocrine disrupters affect membrane progesterone receptor expression, oviductal ciliary activity, gamete transport and male to female ratios among the offspring in a mouse model. Within the project, the development and application of ciliary activity analysis together with Dr Mattias Goksör (Physics, GU) is particularly important. We believe our research will contribute both to our understanding of the gamete transport and the physiological control of sex in mammals as well as to better understand the interference by pollutants in these processes. In the future, this research could potentially pave the way for drugs or other treatments to reduce the risks for ectopic pregnancies in women.