Innate immune determinants of human Coronavirus endemisation

• Applicants: Dr. Dorota Kmiec; Dr. Konstantin Sparrer
• Subject Area: Virology ; Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537692645

The innate immune system, including the interferon (IFN) system and autophagy, is a major barrier to cross-species transmission and spread of viruses. Thus, successful zoonotic viruses need to overcome this barrier to become endemic. All seven members of the human coronavirus family (hCoVs) have zoonotic origin and four of them, HKU1, 2293E, OC43 and NL63 (termed common cold Coronaviruses, ccCoVs) are endemic in humans and cause recurring seasonal respiratory infections. Most recently, SARS-CoV-2 was identified in 2019 and since then gave rise to several variants of concern (VoC) with increased fitness and/or immune evasion properties. Our central hypothesis is that efficient evasion and counteraction of human innate immune responses promote spread and endemisation of zoonotic viruses. Thus, comparative studies of endemic and recently emerged and still adapting, zoonotic Coronaviruses, provide an excellent model system to gain insight on determinants of viral endemisation. In support of this, our preliminary data shows that SARS-CoV-2 is more susceptible to IFN-mediated restriction than ccCoVs. Resistance towards targeting by autophagy appears to be a shared feature of all zoonotic CoVs, suggesting it may be a barrier against cross-species transmission. In addition, our data shows that a single specific mutation in E of the Omicron VoC enhances autophagy escape. This suggests that SARS-CoV-2 is in the process of enhancing innate immune antagonism, thus possibly paving the road to becoming endemic. To understand the underlying viral and cellular determinants of increased IFN resistance of endemic coronaviruses and elucidate common features and differences in autophagy escape mechanisms of both endemic and pandemic coronaviruses we will comparatively analyze the molecular mechanisms of IFN (Aim 1) and autophagy (Aim 2) evasion of ccCoVs and SARS-CoV-2. In addition, we aim to understand how enhanced autophagy antagonism may have contributed to the success of Omicron but also evaluate newly emerging alterations in the innate immune antagonism of SARS-CoV-2 VoCs (Aim 3) to reveal insights in the ongoing adaptation of SARS-CoV-2 to its new host. In summary, our results will delineate differences and similarities in innate defense antagonism of ccCoVs and SARS-CoV-2. Thus, we will be able to define innate immune determinants of coronavirus endemisation (=differences and VOC adaptations) and prerequisites of cross-species transmission (=similarities). Evaluation of emerging VOCs of SARS-CoV-2 will give valuable insights into current and future evolutionary trajectories of its adaption to humans. Altogether, these data will aid future risk assessment and endemic potential analyses of newly emerging zoonotic viruses.

• DFG Programme: Research Grants