Human immune responses to SARS-Cov-2 and influenza A virus infection : from myeloid-derived suppressor cells and T cell functions to antibody responses

Abstract

Acute respiratory viral infections are the most frequent reason for medical consultations in the world. They cause substantial illness and death every year, especially in young children, the immunocompromised and the elderly, with a large span of disease severity ranging from mild to fatal. This includes both seasonal and pandemic influenza viruses, as well as the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the ongoing corona virus disease 2019 (COVID-19) pandemic. Disease severity is likely influenced by immune responses directed against the virus, which are critical for clearance and protection but may also cause immunopathogenesis. Thus, understanding the dynamics and function of immune responses during respiratory viral infections is important to better understand and treat the disease.

In this thesis, we studied longitudinal innate and adaptive immune responses in SARS-CoV-2 and influenza A virus (IAV) infected patients to investigate how they associate with and possibly predict disease severity. We also investigated the effects of a genetically engineered anti-viral lectin on the functionality of human immune cells during IAV infection in vitro.

We found that innate monocytic myeloid-derived suppressor cells (M-MDSCs) were expanded in blood of both COVID-19 and influenza patients and strongly associated with disease severity. The MDSCs were functionally intact and potently suppressed T cell proliferation, suggesting a role for M-MDSCs in the dysregulated COVID-19 immune response (Paper I). Next, we observed that patients with moderate or severe COVID-19 disease generated higher levels of SARS-CoV-2-specific antibodies in both blood and airways compared to patients with mild symptoms (Paper II). Furthermore, we revealed the role of activated and virus-specific circulating T follicular helper (cTfh) cells in antibody production in response to SARS-CoV-2 infection.

Importantly, we found that the generation of activated virus-specific cTfh cells was delayed during early infection in patients who already displayed or later developed severe disease. In turn, this was associated with delayed production of virus-neutralizing antibodies needed to combat infection at an early stage and likely contributed to progression to severe COVID-19 disease (Paper III). An aberrant cTfh cell response was also observed in IAV infected patients where older patients displayed delayed appearance of activated cTfh cells compared to younger patients during acute infection. This was associated with lower levels of virus-specific antibodies, which may contribute to poorer clinical outcome in older individuals (Paper IV).

Finally, we found that the genetically engineered banana lectin (BanLec) H84T could inhibit IAV infection yet promote virus-specific CD8 T cell proliferation supported by dendritic cells, pointing to the potential benefit of H84T BanLec as an antiviral therapy (Paper V).

In conclusion, the findings in this thesis provide perspectives on dysregulated immune responses and novel avenues for treatment to combat influenza and COVID-19 more efficiently.