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The importance of immunity in the defence against viruses and microorganisms is exemplified by the current severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) pandemic. Prophylactic vaccines that boost immunity against components of the viral envelope are the central pillar of virus containment.
Virus-neutralising antibodies are predictive markers of an efficient immune response, and the efficiency of manufactured monoclonal antibodies in counteracting the receptor-binding domain of the SARS-CoV-2 spike protein have been proven in treating COVID-19, the disease caused by SARS-CoV-2. However, monoclonal antibodies are too expensive to be applied generally, and there is an urgent need to find predictive markers capable of determining in which individuals SARS-CoV-2 will progress towards severe pulmonary disease.
Recent association studies indicate that the innate immunity system can identify the general structural patterns of pathogens (Rig-I, MDA-5 virus sensors) and mount a robust interferon response. Immunity mediated by T cells and natural killer cells is less understood in SARS-CoV-2 infection. Still, it undoubtedly contributes to the immunological memory and enables an accelerated and enhanced immune response upon re-infection. SARS-CoV-2 variants that escape immunity induced by vaccines or past infections are of central concern in pandemic development. Finally, inflammatory cytokine storm is a characteristic feature of SARS-CoV-2 infection and is also associated with higher mortality among COVID-19 patients.
Although the involvement of different components of the immune response varies among pathogens, the outcome of viral or bacterial infection always depends on the interplay between the virulence of the virus and the immune defence of the host. Thus, in-depth knowledge of pathogen-host interactions (Research Programme 1) and immunity against pathogens (Research Programme 2) are prerequisites for the treatment of infectious diseases (Research Programme 3).
The human organism is colonized by a large number of different viruses. However, very little data are available on the role of viral communities in immunosuppressed patients who undergo transplantation of solid organs or hematopoietic stem cells. In this project, we will characterize the virome of these patients who are at high risk of reactivation of many latent infections and at risk of newly acquired viral infections. The project will focus on anelloviruses and their possible role in the prediction of transplant rejection and graft versus host disease. An understanding the variability and interaction of the anelloviruses with the human immune system can help reveal their role in the immune response after transplantation. The principal investigator Ruth Tachezy and her team have experience in the characterization of clinical samples by next-generation sequencing and virome analysis.
Virus-induced tumours represent almost one tenth of human tumours. Human papillomaviruses are responsible for most of these carcinomas. Some approaches to cancer immunotherapy markedly improved treatment efficacy, but immunotherapy still failed in most patients. Therefore, mouse models of immune escape mechanisms will be developed and utilized to overcome immune evasion. In these models, cancer immunotherapy will be optimized for the induction of both innate and adaptive immune reactions that will be investigated in the tumour microenvironment. Furthermore, immunotherapy will also address immunosuppression in tumours induced with human papillomaviruses. The proposed combined cancer immunotherapy, in association with the immunoprofiling of tumour samples, could improve the individualization of cancer treatment, resulting in its enhancement. The principal investigator Ruth Tachezy and her team focus on the development of mouse tumour models with immune escape mechanisms and the characterization of immune cells in tumour microenvironment.
The molecular mechanisms how DNA viruses modulate IFN responses to their genomes are still poorly understood. Our lab recently revealed that murine polyomavirus (MPyV) induces the activation of IFN pathways via DNA sensors, p204 (human IFI16) and cGAS. The IFN response to MPyV was moderate, suggesting a strong modulation of IFN pathways by the virus. We aim to extend our studies of IFN induction pathways to the human BK Polyomavirus (BKPyV) and to uncover the mechanisms of modulation of the pathways in MPyV and BKPyV infected cells. The research will be beneficial for the treatment of human polyomaviruses and will contribute to revealing connection of IFN induction pathway with and their modulation during carcinogenesis and virus persistence. Principal investigator Sandra Huerfano’s expertise includes molecular and cellular biology of polyomaviruses and antiviral innate immunity.
Human A-to-I RNA editing enzyme ADAR1 is inducible by interferon and constitutes part of the cellular innate immunity and antiviral defence machinery. ADAR1 detailed function in viral infection can differ from virus to virus and is poorly understood. Furthermore, reduced ADAR1 activity can cause onset of type I interferonopathies such as Aicardi–Goutières Syndrome that is characterized by childhood severe encephalopathy and high mortality. We will investigate into the ADAR1 regulon with the aim to better understand its role during viral infection and to either establish ADAR1 as an emerging target for new broad-range antivirals or to identify novel cellular and viral-specific targets. Principal investigator Martin Pospíšek’s expertise includes analysis of transcriptome, translatome and RNA editome, generation and characterization of ADAR1 knock-out cell lines and analysis their response to viral infection.
This research objective will focus on the immune memory and definition of fundamental principles how the memory T cells work. Differences in memory T cells induced by different types of pathogens and vaccination will be studied. This research activity is built up around the hypothesis that memory T cells are qualitatively different from naïve T cells. Moreover, individual pathogen types induce different subsets of memory, regulatory, and pathogenic cytotoxic T cells, which manifest as differences in the immune memory and inflammation-induced pathologies. This research objective will resolve the functional heterogeneity of memory T cells induced by different classes of pathogens. This research will advance the field of vaccines based on T-cell memory, which target pathogens not efficiently eliminated by antibodies. Principal investigator Ondřej Štěpánek focuses on cellular and molecular mechanisms in T cells, which result in protective immune responses to infection and cancer, and those, which help to establish the immune self-tolerance.
Vaccines and immunotherapies target the immune system to clear the pathogens and/or to avoid collateral damage to the host. The activation and co-stimulation immune pathways will be studied using the tools of in vivo reverse genetics. The specific hypotheses are that LCK kinase has differential importance in the major subsets of peripheral T cells and that ABIN1 represents a common negative regulatory node in T-cell activation pathways. This research objective will focus on the role of LCK, FYN, and ABIN1 in the orchestration of the immune system during acute and chronic infections. The final goal is to find novel candidate targets for the manipulation of the immune signalling, particularly T-cell activation via the antigenic signalling and co-stimulation in vivo. Principal investigator Ondřej Štěpánek has a strong background in combining the animal disease models with genetically engineered mice and with techniques of molecular biology, and bioinformatics.
B. pertussis is the least-controlled vaccine-preventable infectious disease, which has recently re-emerged and massively circulates in countries that use the acellular pertussis vaccines. A better understanding of B. pertussis virulence factors is necessary to combat the disease. We will characterize the synergic contributions of the protein toxins, adhesins and virulence factors in the immune evasion of B. pertussis. We will investigate its capacity to cause infectious rhinitis and transmit through enforced aerosolization by sneezing and coughing. Using omics, biochemistry, cellular and systems biology/immunology approaches on tissues, and in animal models, we shall decipher the molecular, cellular and mucosal immunology and physiological mechanisms underlying nasopharynx colonization and transmission of B. pertussis. Principal investigator Peter Šebo is well established in the study of microbial virulence factors and in the application of laboratory animals for modelling the virulence of human pathogens.
Emerging and re-emerging viruses constitute a significant threat to human health. The discovery of human monoclonal antibodies that are potent, public and broadly neutralizing will pave the way to the ongoing development of universal preventive and/or therapeutic strategies against a broad range of viruses. The study’s overall objective is the molecular characterization of the antibodies against selected viruses (tick-borne encephalitis virus, SARS-CoV-2 and others) that develop in individuals with exceptional serum neutralizing responses. We will discover, characterize and compare the antibodies from the memory B cells of naturally infected and vaccinated individuals. We aim to find potent and broadly neutralizing antibodies that could help develop medical countermeasures against viruses, for which specific treatments are lacking. Principal investigator Daniel Růžek is well experienced in developing human monoclonal antibodies and their testing under in vitro and in vivo conditions.
At present, very little is known about what determines the CNS pathology during flavivirus encephalitis. Here, we will address several crucial questions related to the role of immunopathology during the development of flavivirus encephalitis. We will monitor the effect of the direct infection of the flaviviruses of monocytes and dendritic cells by the expression of key chemokine receptors in infected cells, which have been shown to regulate immune cell recruitment through the blood-brain barrier. We will assay monocytes and dendritic cells chemoattraction and transcytosis using the in vitro blood-brain barrier model established in the lab. The effect of virus-infected monocytes and dendritic cells on blood-brain barrier integrity and homeostasis, and neuronal integrity will be characterized. Principal investigator Daniel Růžek is an expert in the research of pathogenesis of viral neuroinfections, with a special focus on flavivirus encephalitis.