Projects

Here you can read more about the different projects which are ongoing in Infectious medicine.

Our research has a broad base and we are currently focusing on the projects described below.

Sepsis and Septic shock

The focus of the project is the interplay between antibacterial and antifungal treatment and innate and specific immunological responses in severe infections.

Researchers: Mia Furebring (project leader), Jan Sjölin, Elisabeth Löwdin, Markus Castegren, Jesper Sperber, Eva Tano, Helena Janols, Anna Hedberg, Paul Skorup, Anna-Karin Smekal, Siri Kurland, Axel Nyberg, Frida Wilske, Katja Hanslin

The overall aim is to study the interplay between treatment and innate and specific immunological responses in severe sepsis and septic shock as well as in bacterial infections in the central nervous system. Translational projects involving clinical studies, in vitro experiments and intensive care animal models as clinically relevant as possible with the use of sedation, mechanical ventilation, vasopressors all known to influence the inflammatory response. Animal experiments focus mainly on clinical issues that cannot be solved by randomized clinical trials.

In previous sepsis models we have demonstrated that the inflammatory response and bacterial killing in the blood may be reduced in secondary sepsis, in which inflammatory and anti-inflammatory activities have been activated by preceding infection or trauma. This was also seen in a clinical pilot study published in 2015. In a new study bacterial killing of the phagocytic cells in the liver and the spleen was investigated after a 24-h infusion of endotoxin in our intensive care large animal (porcine) model and compared to that in healthy animals. Surprisingly, an increased bacterial killing was noticed and thus the concern that bacterial killing is negatively affected if bacteria enter the bloodstream once the inflammatory systems have been activated seems not valid. In another study on ventilator associated pneumonia there was, in contrast, a reduced bacterial killing in the lung using the same model indicating different systemic and local capacities to kill bacteria. During 2016 we have continued our efforts to develop a tertiary sepsis model, in which the inflammatory response is blunted by an endotoxin-induced anti-inflammatory response in combination with high-dose steroid treatment. This model will primarily be used to test in vivo killing of bacteria and Candida. We have almost solved the problems with this model and, if so, it will be the first large animal model of candidemia. With these varying models established, the antibacterial activity of different treatments with antibiotics and immunomodulatory drugs will be the primary focus. The present models will increase our knowledge and ability to conduct future clinical trials.

The effect of neurosurgical trauma and the innate immune response on the specific immunity by vaccination of patients with a T-cell dependent vaccine was published in 2015. A reduced response was seen if vaccinated during the 10 first days after trauma. We have now extended that analysis to the response to a T-cell independent pneumococcal vaccine that is not affected and thus preferably should be used for an early protection against pneumococcal meningitis. In 2016 the effect of immunomodulation by corticosteroids given before antibiotic treatment has been assessed in a registry comprising 1500 patients with meningitis. This is up to now the largest study on corticosteroids and meningitis.

Clinical studies evaluating the effect of the systemic inflammatory response on pharmacokinetics of antibiotics and antifungals have continued during the year. Furthermore, the work with an ex vivo antifungal model has been initiated determining the antifungal activity of patient blood.

Antibiotic resistance

Improved antibiotic therapy for multidrug-resistant bacteria and studies on the impact of antibiotics on the intestinal microbiota.

Researchers: Thomas Tängdén, Otto Cars, Pernilla Lagerbäck, Hanna Montelin, Kari-Pekka Skarp, Ayda Shams, Pikkei Yuen, Christer Malmberg

Ongoing in vitro studies include experiments aiming to find antibiotic combinations effective against multidrug-resistant bacteria and the evaluation of rapid antibiotic susceptibility tests. During 2016, we have completed an evaluation on automated methods for potential use in high-throughput screening for combinations against multidrug-resistant strains. The oCelloScope, which is based on automated microscopy and image analysis, has been considered feasible and is being used for this purpose in a 3-year project (CO-ACTION) funded by the Swedish research council within the framework of JPIAMR. A microfluidic assay using a linear antibiotic gradient to determine antibiotic susceptibility with high accuracy, CellDirector 3D, has been evaluated in collaboration with Gradientech AB within a 2-year project funded by VINNOVA, with promising results and will be further improved for use with positive blood cultures.

Clinical studies include a multicenter study on optimal antibiotic therapy for urinary tract infections caused by ESBL-producing bacteria and a study addressing the impact of antibiotics on the intestinal microbiota in hematological patients. The inclusion of patients in these studies will be completed in Q1 2017. A study on patients treated at the intensive care unit for burn injuries is ongoing and will address not only the impact of antibiotic therapy on the intestinal microbiota but also the feasibility to restore the microbial diversity with fecal transplantation.

Tomas Tängden's research group. From left to right: Pernilla Lagerbäck, Tomas Tängden, Pikkei Yuen, Christer Malmberg, Kari-Pekka Skarp, Ayda Shams, Wanchana Ungphakorn och Otto Cars.
From left to right: Pernilla Lagerbäck, Tomas Tängden, Pikkei Yuen, Christer Malmberg, Kari-Pekka Skarp, Ayda Shams, Wanchana Ungphakorn och Otto Cars.

Infections in organ transplantation and infections of the brain

Researchers: Britt-Marie Eriksson, Camilla Lorant, Gabriel Westman, Jakob Sparby, Fredrik Sund

Cells infected with cytomegalovirus.
Cytomegalovirus infected cells

We have previously studied cytomegalovirus infections in organ transplantation, congenital infection, inflammatory bowel disease and in patients with Alzheimer´s disease. In collaboration with Department of Clinical Immunology, different aspects of T-cell immunity has been studied. Ongoing is a project of  BK-virus infection after renal transplantation, an infection with potential to destroy graft function.

Another part of research is concerning infections of the brain. During a ten-year period we have been part of an international multi-centre study of additional valaciclovir therapy to patients with herpes simplex encephalitis (HSE). In a follow-up study of the Swedish patients we have been able to show that 25 %, about  four months after  disease onset, develop synaptic antibodies which seems to affect the  recovery of neuro-cognitive function. These are new data that probably will change treatment policies of a sub-group of patients with HSE. In another study we have mapped the incidence and the handling of ventricle-drainage related infections after neurosurgery. The findings of that study show the need for better diagnostics and we are now planning new studies for the valuation of molecular biology methods. The purpose is to substantially reduce the need of empirical anibiotic treatment.

The research group. From left to right: Fredrik Sund, Camilla Lorant, Gabriel Westman, Britt-Marie Eriksson and Jakob Sparby.
From left to right: Fredrik Sund, Camilla Lorant, Gabriel Westman, Britt-Marie Eriksson, Jakob Sparby

Infections in and vaccination in immune suppressed patients

Karlis Pauksens och Amelie Kinch

Data on safety, immunogenicity, and efficacy of vaccines for immunocompromised populations are limited. We have studied response to vaccination in different immunocompromised individuals such as elderly patients, patients with rheumatoid arthritis, and patients with cancer. Furthermore, we study opportunistic infections with special focus on Epstein-Barr virus (EBV) and post-transplant lymphoproliferative disorder (PTLD) after allogeneic stem cell transplantation and solid organ transplantation.

Influenza

Researchers: Josef Järhult, Anna Gillman, Erik Karlsson, Per Eriksson, Patrik Ellström, Björn Olsen

Mallards, the primary carriers of Influenza A virus, in a research enclosure.
Mallards being handled in a research enclosure.

During the last century, Influenza A virus (IAV) caused three pandemics. In 1918-1920, the Spanish Flu killed at least 50 million people. All pandemic viruses contain avian genetic material achieved through a re-assortment process. There are two different strategies used in treatment and prophylaxis of IAV. First, vaccines are effective but the production of vaccines is slow, and second antiviral drugs like the neuramidase inhibitors oseltamivir (OC) (Tamiflu) and zanamivir (ZA) (Relenza). OC is stable in water and not removed or degraded in sewage treatment plants. In the downstream water, ducks, the natural reservoir of IAV, are exposed to OC resulting in resistance induction of viruses in their gastrointestinal tract. With mallards as an animal model and by virological, chemical and molecular techniques we have detected induction of resistance in IAV and retention of resistance mutations in repeated replications and transmission without drug pressure. Our results will be of value for organizations and authorities working with strategic pandemic preparedness planning, like the WHO.

A. Gillman 2016, review article

Tick borne infections

Researchers: Erik Salaneck, Tove Hoffman, Mats Lindeborg, Björn Olsen

Birds fly. This fact makes them extremely important as vehicle and transmitters of various parasites and potential carriers of pathogenic microorganisms. The new concept “ornithological-medicine” is a research area that will give new insights into the ecology, epidemiology and infection biology of vector borne infections in general and tick born infections in particular. A basic knowledge on the mechanisms of the spread of and occurrence of zoonoses will be very important for agriculture and veterinary medicine. Borrelia spp and Ehrlichia spp. can cause infections in animals and humans and therefore basic research on the biology, pathogenicity and virulence of tick borne zoonoses is important. We will study the importance of seabirds and terrestrial birds in the dispersal of the tick borne pathogens. Further, by developing infection models we can study the interaction, virulence, pathology, and infection biology between host, vector and microorganism.

Campylobacter and other gastrointesitinal pathogens

Campylobacter is our most common zoonotic infection and most human cases can be attributed to the broiler industry. Despite years of research efforts, we still know very little about how Campylobacter reach the food industry, how they survive in the environment or how they transmit between species and cause disease in humans.

In this projects, we study barriers for transmission of Campylobacter between species. We also study bacterial virulence factors associated with different outcome of infection as well as the role of the gut microbiota in Campylobacter infection.

In 1995 we discovered that Campylobacter can survive and replicate in free living amoebae and currently we focus on understanding the role of such protozoans as environmental reservoirs for these bacteria. Campylobacter are globally abundant and wild birds are important hosts. Anywhere there are birds, there seem to be Campylobacter. During a number of expeditions, we have isolated Campylobacter even in Antarctica. Currently, we study the ecology of Campylobacter in these remote areas.

Antibiotic resistance in natural bacterial flora

Researchers: Jonas Bonnedahl, Josef Järhult, Badrul Hasan, Johan Kaarme, Åsa Melhus, Eva Tano, Björn Olsen

The main force behind emergence of antibiotic resistance is the use of antimicrobial agents in human and veterinary medicine and domestic animal husbandry.

However, there is also evidence that epidemic spread of drug-resistant bacteria and horizontal transfer of resistance genes are contributing factors to resistance emergence. It is important to realize that there are no closed systems, the bacteria we select for in environments close to humans will find their way to bacterial communities in nature and vice versa. The knowledge of antibiotic resistance in the environment is limited and we need to explore this field and link it to consumption of antibiotics in our societies.

We have brought together experts in different fields to evaluate how bacterial resistance is transferred and maintained within all potential reservoirs, including humans, domestic animals, wildlife and the environment. Our strengths complement each other in terms of methodological and practical skills, and in our team we have physicians, veterinarians, ecologists, micro- and molecular biologists, and environmental chemists.

Spotted fever rickettsiosis; diagnostic procedures, prevalence in vector and mammal hosts and association to clinical disease

Researchers: Karin Elfving, Katarina Wallmenius, Anders Lindblom, Carl Påhlson, Kenneth Nilsson

Rickettsia in a Vero cell.
Rickettsia in a Vero cell.

The spotted fever group of rickettisae has a world-wide distribution and different species are established depending on the geographic area. Migrating birds may however contribute to a long-distance dispersion of bacteria, and also to an inflow of novel and potentially pathogenic rickettsia species into countries. Rickettsia felis is usually transmitted by fleas while R. helvetica is the only tick-transmitted rickettsia found free in nature where the tick Ixodes ricinus represents the most important potential vector. R. helvetica is the most prevalent and is found endemic in tick populations and there is a need to consider infections when investigating disease after a tick bite. We have shown that patients may present a flu-like self-limiting mild febrile disease sometimes with prolonged fever as well as subacute meningitis or peri myocarditis. Growth characteristics and morphology of R. helvetica were studied to better understand invasiveness and virulence. We found that invasiveness is comparable with other rickettsia, though R. helvetica seems to have a stable but slightly slower growth.