In 2018, the Foundation for prevention of antibiotics resistance awarded a total of four million SEK in research support to four researchers. During the spring we will present them and their projects.

Susanna Brighenti, Karolinska Institutet, is one of the researchers who received grants from the Foundation in 2018. The overall goal of her research is to study immune responses in tuberculosis infection in order to gain knowledge about how new treatment options can be developed.

Susanna Brighenti, Associate Professor,
Karolinska Institutet

Can you briefly describe your research project?

The overall objective of my research group is to study immune responses in tuberculosis (TB) infection to obtain knowledge of how we could enhance or inhibit certain immune responses, aiming to develop new treatment options that could support conventional antibiotic therapy in TB. In this proposal, we will explore the role of multidrug-resistant tuberculosis (MDR-TB) in the origination and development of chronic TB disease. We plan to study immune responses generated by different strains of Mycobacterium tuberculosis (Mtb) including MDR-TB strains, using blood samples and bacterial isolates obtained from patients before and after treatment with conventional antibiotics. In addition, we will relate peripheral immune responses to the composition of the normal bacterial flora in the lung or gut in the patients and how this changes with second-line drug treatment.

In a clinical trial, we recently demonstrated that nutritional supplementation with two dietary compounds, vitamin D and phenylbutyrate, could support conventional antibiotic treatment and reduce clinical TB symptoms in patients with TB in the lung. Now, we will study T cell responses in blood samples obtained from these patients, to determine the type of immune response generated by these compounds.

How will the funds from the Foundation contribute to your work?

The funding from The Fondation to prevent antibiotic resistance is a very welcomed contribution to my group´s research budget and it will enable us to continue this important line of research for another three years. It is difficult and competitive to receive sufficient research funding and therefore it is fantastic that this new foundation has been started with the aim to support research in the field of antibiotic resistance.

In Novembre 2018, I was awarded partial financial support from Karolinska Institutet for the recruitment of a new PhD student in this project, and the funds The Fondation to prevent antibiotic resistanc will cover the other half of this position. The remaining funds will be used for running costs in the project, such as transcriptional analysis, flow cytometry, Mtb genotyping methods and microbiome analysis.

In what way will your work help to decrease the development of antibiotic resistance?

I am confident that we need to find new means to prevent and treat TB infection and combat drug resistance, which is the longterm goal of our proposal. Instead of focusing only on development of new drugs with direct killing effects on the bacteria, immunomodulatory compounds could complement antibiotics by enhancing immune cell function(s) and thus increase the ability of the immune system to effectively eliminate mycobacteria and reduce pathological inflammation. To accomplish this, we must obtain enhanced knowledge about the immune response to the bacteria and how the main target host cells respond to infection.

This is similar to the development in the cancer field, where combination treatments with cytostatic drugs (direct killing effect on cancer cells) and immune checkpoint inhibitors (prevent immunosuppression) show very promising results. Compounds that target multiple host pathways in an attempt to treat chronic infections such as TB may reduce the risk for drug-resistance and shorten treatment considerably. These types of adjunct immunotherapies and development of individualized treatment options also in MDR-TB, is certainly required in the future.

How is it that you ended up in the field of antibiotic resistance?

Years ago, when I started as a postdoc at Karolinska Institutet, my first project aimed to develop new treatment for MDR-TB based on so called antimicrobial peptides, which has the capacity to interact with and kill Mtb bacteria inside infected cells. The project was successful, although we did not pursue clinical studies at the time. But the following years I spent studying the presence of antimicrobial peptides and similar toxic molecules in lung tissue biopsies obtained from patients with MDR-TB and also in patients with lymph node TB. Importantly, we have found immune response signatures that can be used as diagnostic and prognostic markers or to evaluate novel TB vaccine candidates. Therefore, the results from our previous research is not only applicable to develop novel treatment strategies but may also be used to monitor efficacy of antibiotic treatment, which is an important advancement to prevent drug resistance.

When can you hopefully see any results from your project?

Positive results from our clinical trial, testing the efficacy of nutritional supplementation with vitamin D and phenylbutyrate in pulmonary TB, was recently published. Now it will be very exciting to follow up the clinical findings with in-depth analyses of the immune response in these patients, which may unravel the phenotype and function of protective immunity induced by this adjunct immunotherapy. We know that vitamin D and phenylbutyrate induce antimicrobial peptides and autophagy in Mtb-infected cells in vitro, but we don´t know the effects of this treatment on adaptive immune responses in vivo. In parallel, we will recruit an MDR-TB cohort in Ethiopia where we have our main clinical collaborations, and from these patients we will collect the clinical material required for the project. New knowledge from our analyses could be used to design clinical trials that can result in new guidelines for treatment of MDR-TB. But altogether these studies would take a number of years to conduct and evaluate.

How does your research contribute to the public?

As the Foundation published in its Newsletter August 2018, a growing number of pharmaceutical companies are stopping their antibacterial research because of a lack of profit. This puts great responsibility on academia and other non-commercial funders and agencies, to find new treatment strategies that could cure, prevent or improve clinical outcome but also reduce the spread of serious infections including MDR-TB. Despite a growing global problem of drug-resistant superbugs such as MDR-TB, the pipeline of new antibiotics is thin. These facts underline the necessity to invest in research that can facilitate the discovery of protective immune mechanisms and pathways that could be exploited as novel targets in drug-resistant infections.

In this process, we can also learn form already existing immunotherapeutic concepts and compounds, understanding their mechanisms of action in the complex physiological environment of the human body and how we can fine-tune the capacity of these drugs to combat chronic infections.