The early interactions between a pathogen (e.g. virus or bacteria) and the immune system are of central importance for the eventual outcome – pathology and disease versus clearance and reestablishment of homeostasis. In my 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 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:
· - Immune sensing and signaling during infections
· - Interferon-independent antiviral activities
· - Orchestration of antiviral defense in vivo
· - Viral immune evasion
· - Immune mechanisms in non-viral infections, cancer, and inflammatory diseases
Many infections are acquired at epithelial surfaces and can spread from there to different target organs. Since we have particular interest in the neurotropic herpesviruses, we have 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 my laboratory take a broad methodological approach and aim to both uncover novel mechanisms and to demonstrate physiological importance. To achieve this, we combine reductionist cellular/molecular systems with analysis of mouse models and patient material.
A. Detection of viruses by pattern recognition receptors of the innate immune system
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 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 is emerging as an important parameter in the innate immune response, and we are studying this phenomenon during viral infection.
B. Innate antiviral mechanisms exerted by constitutive and latent immune mechanisms
It has long been known that infections activate not only “classical” receptor-driven host reactions but also lead to stimulation of e.g. production of reactive oxygen species, autophagy, DNA damage responses, metabolic reprogramming, ER stress, and proteasome activation. Moreover, a panel of constitutively acting restriction mechanisms contribute to immediate control of virus infections. Recently, it has emerged that many of these mechanisms contribute to antiviral defense in a manner not associated with strong inflammatory activity, hence providing a “silent” layer of the immune system. We are interested in identification and characterization of constitutive and latent antiviral immune mechanisms, and to decipher their impact on host defense and prevention of disease.
C. In vivo models of viral infections
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 focus on mouse models for herpes simplex virus infections and SARS-CoV2, 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, (iii) cellular effector mechanisms of antiviral activities and inflammation during infection.