Pathophysiology: Immunomodulation and Immune Control

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. 

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.