Alternative viral receptors enabling SARS-CoV-2 infection

SARS-CoV-2 is a novel coronavirus, that has dramatically transformed our lives and social interactions as we knew it. Many aspects of its first transmission from animals to humans ("zoonosis") and spread among the human population, as well as the underlying infection mechanisms remain unknown. Therefore, there is an urgent need for a better understanding of the factors that enable emergence of novel human viral infectious agents hiding invisibly in animals. In their project, immunologists Anna Ohradanova-Repic and Hannes Stockinger are taking a closer look at the molecular mechanisms of viral transmission. Using SARS-CoV-2 as highly relevant model, the researchers will employ high-end proteomic approaches to identify alternative, previously uncharacterized, viral receptors that enable infection of cells of humans and various animal species. The alternative viral receptors are not anticipated to mediate a highly efficient infection immediately causing a severe disease. Instead, the immunologists postulate that they are critical for overcoming the initial host barrier, thereby facilitating the first jump from animals to humans, followed by an adaptation of a virus to a new human host. The results of the project will help to predict which animal species and their viruses might cause zoonotic disease outbreaks in the future. The second part of the project will provide insights into the interaction of SARS-CoV-2 with human immune cells and aims to contribute to better understanding of the still puzzling COVID-19 disease pathology seen in severely ill patients.

The project P34253-B aimed to elucidate alternative host factors involved in SARS-CoV-2 infection, beyond the canonical ACE2 receptor, with a particular focus on host cellular proteins hijacked by the virus to facilitate entry, dissemination, and immune evasion. Through a combination of molecular, cellular, and immunological approaches, the project provided new insights into how SARS-CoV-2 exploits host biology to expand its cellular tropism and modulate antiviral immune responses. A central outcome of the project was the identification of host cellular proteins that interact with viral components and act as alternative attachment or entry facilitators. We functionally characterised some of these host factors, namely cyclophilins. We showed that virus-hijacked cyclophilins influence viral uptake and subsequent infection of human innate immune cells called monocytes by engaging an alternative receptor CD147, thereby contributing to viral spread even under conditions where canonical receptor availability is limited. Importantly, several of these host proteins are regulators of the complement system, an innate immune defence against invading pathogens. We found that the virus can exploit these proteins to protect itself from complement-mediated attack, suggesting that this hijacking helps SARS-CoV-2 evade early antiviral responses. Together, these findings expand the current paradigm of SARS-CoV-2 host interactions and highlight the multifaceted role of host proteins in shaping infection outcomes. In parallel, the project systematically investigated host-derived inhibitors of SARS-CoV-2 infection. These studies demonstrated that naturally occurring antimicrobial proteins, such as lactoferrin, can interfere with viral attachment and entry by targeting host-virus interaction interfaces. Furthermore, comprehensive analyses of neutralizing antibodies induced by vaccination or natural infection revealed both qualitative and quantitative differences in their ability to block viral variants and prevent infection at the cellular level. These findings underscore the importance of host-mediated antiviral defences and provide mechanistic explanations for variability in protection against SARS-CoV-2. Overall, this project significantly advances the understanding of alternative viral receptors and host factors in SARS-CoV-2 infection. By integrating pro-viral host dependency factors with host-derived inhibitory mechanisms, it offers a more comprehensive view of the host-virus interface. The results open new avenues for future research aimed at targeting host factors for antiviral intervention, developing broad-spectrum therapeutics, and improving vaccine strategies that account for viral exploitation of host cellular pathways.