Research

Despite improved prevention and treatment options, bacterial pathogens remain a major cause of life-threatening acute and chronic disease worldwide. The prevalence of multidrug resistant bacteria in hospitals now threatens the considerable advances of modern medicine. Moreover, infections as well as the intake of broad-spectrum antibiotics can cause dramatic changes in the microbiota, with ramifications for the development and manifestation of seemingly unrelated diseases.

The research area Bacterial Infections aims to develop new ways to rapidly diagnose and treat bacterial infections. A major goal is the comprehensive simultaneous RNA-based profiling of the pathogen and the infected host in real time and at high resolution; where applicable, this should also include co-colonizing microbiota. The scientists in this area then focus on the mode of action of RNA molecules that are crucial for the synthesis of virulence traits of the pathogen, differentially expressed upon exposure to the host, or that impact gene expression in interacting members of the microbiota. This knowledge is then exploited for therapeutic intervention with clinically relevant bacterial pathogens.

Viruses are responsible for millions of acute and chronic infections with devastating consequences including life-long disability, cancer or death. Many of these infections lack effective vaccines or treatments. Moreover, the majority of emerging infections likely to cause global epidemics are of viral origin. Therefore, research on viral pathogenesis, the identification of novel drug targets, and drug development are of major public interest.

In the research area viral infections, HIRI scientists aim to unravel the role of RNA in productive viral infections and persistence. This includes understanding viral noncoding RNAs (ncRNAs) and regulatory elements, as well as host cellular RNA targeted by the virus. Scientists in this area are establishing new in-vitro and in-vivo models for the development and pre-clinical evaluation of a new generation of antivirals interfering with ncRNA functions.

The host response to infections involves complex interactions between pathogens, host cells, and the host immune system. During an infection, cells of the innate and adaptive immune system undertake a coordinated effort to control the pathogen, requiring major changes in the expression of both coding and noncoding transcripts. These RNA expression changes are shaped by both the pathogen and the activation of intrinsic host defence mechanisms, including the secretion of chemo- and cytokines. Control of these mechanisms is needed to prevent either pathogen survival or immunopathology, and crucially depends on intricate RNA-based regulatory networks.

Scientists in the research area Host Response aim to dissect the complex intercellular and subcellular RNA networks involved in the control of infection. Key goals are the comprehensive RNA-based profiling of cell type-specific responses during infection and the identification of novel RNA markers and mechanisms. The area investigates the functions of ncRNAs and RNA elements regulated by and regulating the host response to bacterial and viral infections. The knowledge obtained is utilised for therapeutic interventions, with the goal of modulating the host response to infection and limiting pathogenesis.

The spread of antimicrobial resistance and emergence of new pathogens drive the need to expand the anti-infective arsenal. In this regard, RNA-based therapeutics and RNA-binding drugs such as RNA silencers, therapeutic ribozymes and aptamers, RNA-based genome editing tools and tailor-made  mRNAs provide exciting opportunities for intervention in pathogen activity and for host protection.

The research area RNA Delivery will develop delivery technologies acting in concert with chemically optimized RNA drugs to treat infectious diseases. This requires interdisciplinary research at the interface of clinical medicine, life sciences, (nano-) material sciences and pharmaceutical research. Analytical studies are essential for successful translation, including thermodynamic, mechanic, and structural characterization of complex RNA delivery systems. In addition, process analytical techniques (PAT), quality-by-design approaches and stringent stability studies require implementation during manufacture, as do validated analytical methods, importantly high-performance liquid chromatography. Advanced physico-chemical analytics generated by this research area are fundamental to the translation of nucleotide/RNA drug research into the clinics.