Pathophysiology: Immunomodulation and Immune Control

Key area 4

Coordination: University of Veterinary Medicine Hannover (TiHo)

The already collected data on SARS-CoV pathogenesis in humans suggest that, in addition to the direct damage caused by the virus, the SARS-CoV-2 specific immune response plays an important role in COVID-19 disease. In this case, sustained innate and adaptive immune responses in the lung result in persistent inflammation, tissue damage, and also disruption of lung-specific repair mechanisms and, ultimately, multi-organ failure. For a better understanding of this complex infectious event, it is necessary to mimic a disease corresponding to COVID-19 in animal models and to identify the associated immunopathological and pathophysiological processes. This requires a close, interdisciplinary analysis of these processes under pathological, immunological and virological aspects. In the following step, it is then important to correlate the findings obtained with clinical data from humans. 

Studies on pathogenesis, immunopathogenesis and cell tropism

Not only the mechanisms of innate but also those of acquired immunity to pathogens and in particular to viruses as well as studies on pathogenesis, immunopathogenesis, and cell tropism are the main research focus at the TiHo. Several of the participating research groups at the TiHo have long-standing expertise in the field of viral molecular biology, infection-related changes in the lung, and virus-related humoral and cellular immunomodulation. In particular, the expertise regarding pathogenesis, cell tropism, and intervention strategies of several groups in the context of SARS-CoV-1 and MERS-coronavirus research ensures a focused implementation of the objectives of this key area in collaboration with the other participating partner institutions in Lower Saxony. 

A better understanding of the immunopathogenesis and pathophysiology of COVID-19 disease is the basis for the development of new therapeutic and preventive strategies as well as for the direct clinical care of COVID-19 patients.

Research aim

The focus of the research projects in this key area is to reveal the pathomechanisms associated with SARS-CoV-2 infection as well as the immunological processes. These will be correlated and directly related to human clinical data. This key area consists of the fields of immunology and pathology.

Immunology

In the field of immunology, the innate and adaptive immune responses following mild or severe SARS-CoV-2 infection are analysed in detail in animal models and also in humans. This includes the characterisation of inflammatory responses activated in response of the innate immune system to SARS-CoV-2 infection. Additionally, the adaptive immune components, i.e., SARS-CoV-2 specific antibodies and cellular T cell responses including NK cells are also investigated. In particular, the immune responses occurring locally in the lung is characterised and associated with the pathological changes identified in the lung. This also includes investigating these processes under different pathophysiological conditions, as for example, the content of oxygen in the lung and other tissues.

The causes for the highly diverse courses of SARS-CoV-2 infection seem to be manifold due to the clinical observations that severe courses do not only occur in older persons or persons with pre-existing diseases who need intensive care. In particular, the unusually dynamic courses during the comparatively long intensive care treatment of severely ill patients suggest, in addition to possible genetic differences, an individual interaction between the immune system and the infected lung tissue. This interaction seems to evolve from an initially helpful defense reaction, among others, by elimination of infected type I epithelial cells and induction of SARS-CoV-2-specific antibodies, into an exaggerated immune reaction called immunopathology.  This immunopathology may develop when the viral infection cannot be controlled locally in the throat or bronchial tract and spreads deeper into the lungs to the alveoli. There, direct cytopathic effects of the SARS-CoV-2 infected cells and their cytokine and chemokine release, the so-called cytokine storm, possibly accumulate with immune responses, i.e., specific T cells and antibodies, and lead to the severe impairment of lung function. Furthermore, this scenario could lead to destruction of the alveoli, so that SARS-CoV-2 could possibly spread further in the body via the capillaries. 

Pathology

The genesis and extent of lung pathology are determined more precisely in COVID-19 patients. In this context, the potentially harmful effects of SARS-CoV-2-specific immune responses is also evaluated. It is known from publications that patients often develop "collateral damage" such as thrombosis, microangiopathy, neuropathies, cardiovascular problems, and even diabetes. Thus, it is useful to study the different stages of the disease also in terms of immunopathology in the sense of interaction between immune cells and lung tissue, and to define the so-called “cytokine storm” not only in terms of the common cytokines, but to extend it to cover systemic signaling pathways of epithelial and endothelial function. There is even evidence that autoimmune-like collateral damage is induced in at least some of the patients, the basis of which should be explored to achieve better treatment and after-care.

The expertise available in the COFONI consortium enables an interdisciplinary approach to the above-mentioned questions by bundling the various fields. Additionally, the interaction of such immunopathological events with preventive strategies, such as vaccines, is investigated in this key area. On the one hand, different vaccine candidates are tested under different infection conditions and pathophysiological influences. Two important pathophysiological factors to be focused on in this key area are the influence of age and previous disease on the clinical manifestation of COVID-19 disease. Here, it is interesting to investigate how the immune response under such particular physiological conditions correlates with the expression of pathological changes and the associated clinic.

Our projects from key area 4 - Pathophysiology

Impact of SARS-CoV-2 infection on the molecular initiation of neurodegeneration

Sites: MHH, TWINCORE, UMG

Project leader: PD Dr. med. Franziska Hopfner

Role of the lung microbiome during SARS-CoV-2 infections

Sites: UMG, TiHo

Project leaders: Prof. Dr. Dr. Francesca Odoardi, Prof. Dr. Alexander Flügel

Contact

Prof. Dr. Maren von Köckritz-Blickwede
Leitung wiss. Administration und Biosicherheit, Research Center for Emerging Infections (RIZ)
Leitung AG Biochemie der Infektionen
Institut für Biochemie
Stiftung Tierärztliche Hochschule Hannover
Bünteweg 17
30559 Hannover
Maren.von.Koeckritz-Blickwede(at)tihohannover.de

Copyright: Prof. Dr. Maren von Köckritz-Blickwede

Prof. Dr. Asisa Volz
Institut für Virologie
Zentrum für Infektionsmedizin
Stiftung Tierärztliche Hochschule Hannover
Bünteweg 17
30559 Hannover
Asisa.Volz(at)tiho-hannover.de

Copyright: Prof. Dr. Asisa Volz

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