The early interactions between pathogens (eg. viruses or bacteria) and the immune system are of central importance for the eventual outcome – pathology and disease versus clearance and reestablishment of homeostasis. In our laboratory we are interested in understanding the early events that occur during immunological challenge, and to characterize the impact on the control of infections. The innate immune system utilizes pattern recognition receptors (PRRs) to sense infections and to induce antimicrobial responses. In the case of virus infections, the type I interferons are particularly well-described to have strong antiviral activity. However, type I interferon can also cause significant pathology, and there is increasing appreciation of antiviral activities, which are independent of type I interferon. We seek to understand the mechanisms involved in both interferon-dependent and -independent antiviral immunity, and the interactions between these activities. Our research projects fall into five different, but highly interacting, areas. These are:
Many infections are acquired at epithelial surfaces and can spread from there to different target organs. As we have particular interest in neurotropic herpesviruses, we focus on immunological mechanisms at epithelial surfaces and the central nervous system. In addition, we are interested in understanding how, for instance, influenza virus and SARS-CoV2 overcome immunological elimination in the lung epithelium and induce pathological immune responses. Projects conducted in our laboratory take a broad methodological approach and aim to both uncover novel mechanisms and demonstrate physiological importance. To achieve this, we combine reductionist cellular/molecular systems with analysis of mouse models and patient material.
Several classes of PRRs have been described. They detect microbial infections on the cell surface, in endosomes, and in the cytoplasm. The Toll-like receptors (TLR)s sense viruses on the cell surface as well as viral nucleotides in endosomes, the RIG-I-like receptors (RLRs) detect viral RNA structures in the cytoplasm, and the DNA sensors detect viral DNA in the cytoplasm.
We are interested in knowing which PRRs are responsible for detection of viruses in different cell types and to identify and characterize the viral pathogen-associated molecular patterns (PAMPs). Moreover, our work aims at deciphering the virus-activated intracellular signaling and gene expression programs, and also to learn how viruses evade and exploit these responses. Finally, the intracellular dynamics of virus detection and signaling processes are emerging as an important parameter in the innate immune response, and we are studying this phenomenon during viral infection.
Infections activate not only “classical” receptor-driven host reactions but also lead to stimulation of a range of stress signals, including production of reactive oxygen species, autophagy, DNA damage responses, metabolic reprogramming, ER stress, proteasome activation, etc. Moreover, restriction factors contribute to immediate control of viral infections. Recently, it has emerged that many of these mechanisms contribute to the antiviral response in a non-inflammatory manner, hence providing a layer of homeostasis-guarding host defense. We are interested in the identification and characterization of novel homeostasis-guarding defense mechanisms, and to decipher their impact on protection against infection and prevention of disease.
The immune response to infections can have both protective and deleterious effects. Therefore, the mechanisms that determine whether the immune response promotes or prevents disease are complex processes, which can best be approached experimentally in animal model systems. With a focus on mouse models for herpes simplex virus (HSV) and SARS-CoV2 infections, we are studying the role and mechanism of action of the innate immune system in the host response to infection.
Key questions under investigation include:
(i) Role and mechanism of specific PRRs and innate recognition systems in control of viruses at epithelial surfaces and in the central nervous system,
(ii) immune mechanisms responsible for prevention/restriction of neuroentry and spread during HSV infection, and
(iii) cellular effector mechanisms of antiviral activities and inflammation during infection.
Our group is also closely linked to CellX (The Danish Single-Cell Examination Platform). You can learn more about their work here.