C-type Lectin CD209L/L-SIGN and CD209/DC-SIGN: Cell Adhesion Molecules Turned to Pathogen Recognition Receptors

SIMPLE SUMMARY: COVID-19 pandemic continues to pose a serious threat to global public health with overwhelming worldwide socio-economic disruption. SARS-CoV-2, the viral agent of COVID-19, uses its surface glycoprotein Spike (S) for host cell attachment and entry. The emerging picture of pathogenesis of SARS-CoV-2 demonstrates that S protein, in addition, to ACE2, interacts with the carbohydrate recognition domain (CRD) of C-type lectin receptors, CD209L and CD209. Recognition of CD209L and CD209 which are widely expressed in SARS-CoV-2 target organs can facilitate entry and transmission leading to dysregulation of the host immune response and other major organs including, cardiovascular system. Establishing a comprehensive map of the SARS-CoV-2 interaction with CD209 family proteins, and their roles in transmission and pathogenesis can provide new insights into host-pathogen interaction with implications in therapies and vaccine development. ABSTRACT: C-type lectin CD209/DC-SIGN and CD209L/L-SIGN proteins are distinct cell adhesion and pathogen recognition receptors that mediate cellular interactions and recognize a wide range of pathogens, including viruses such as SARS, SARS-CoV-2, bacteria, fungi and parasites. Pathogens exploit CD209 family proteins to promote infection and evade the immune recognition system. CD209L and CD209 are widely expressed in SARS-CoV-2 target organs and can contribute to infection and pathogenesis. CD209 family receptors are highly susceptible to alternative splicing and genomic polymorphism, which may influence virus tropism and transmission in vivo. The carbohydrate recognition domain (CRD) and the neck/repeat region represent the key features of CD209 family proteins that are also central to facilitating cellular ligand interactions and pathogen recognition. While the neck/repeat region is involved in oligomeric dimerization, the CRD recognizes the mannose-containing structures present on specific glycoproteins such as those found on the SARS-CoV-2 spike protein. Considering the role of CD209L and related proteins in diverse pathogen recognition, this review article discusses the recent advances in the cellular and biochemical characterization of CD209 and CD209L and their roles in viral uptake, which has important implications in understanding the host–pathogen interaction, the viral pathobiology and driving vaccine development of SARS-CoV-2.