Genetic deficiency and polymorphisms of cyclophilin A reveal its essential role for Human Coronavirus 229E replication

Abstract

Replication of coronaviruses is inhibited in vitro by cyclosporin A, a well-known immunosuppressive drug which binds to cellular cyclophilins thus inactivating their enzymatic cis-trans peptidyl-prolyl isomerase function. Latter is required for proper folding of cellular proteins and of proteins of several viruses. Here, we summarize present knowledge on the role of cyclophilin A during coronavirus replication. We present data on the effect of cyclophilin A single nucleotide polymorphism mutants on the replication of human CoV-229E demonstrating the requirement of proper cyclophilin A function for virus propagation. Results define cellular cyclophilin A as a host target for inhibition of coronaviruses ranging from relatively mild common cold to highly pathogenic SARS-CoV and MERS-CoV viruses with the perspective of disclosing non-immunosuppressive cyclosporin A analogs to broadly inactivate the coronavirus family.

Influences of cyclosporin A and non-immunosuppressive derivatives on cellular cyclophilins and viral nucleocapsid protein during human coronavirus 229E replication

“…For HCoV-NL63, we have recently shown that CypA expression is essential in CaCo-2 cells (Carbajo-Lozoya et al, 2014). Utilizing a Huh-7.5 CypA KD (knockdown) cell line, originally constructed for the study of the requirement of stable CypA for HCV replication (von Hahn et al, 2012) we found significantly reduced replication of a HCoV-229E-Renilla luciferase expressing virus (von Brunn et al, 2015). This indicates the involvement of CypA also in replication of HCoV-229E.…”

Cyclophilins and cyclophilin inhibitors in nidovirus replication

“…Subsequently, the importance of CypA as a host factor in CoV replication was further substantiated using knockdown or knockout of CypA expression, which was achieved using a variety of approaches. In Caco-2 and Huh7.5 cells, shRNA-mediated knockdown of CypA mRNA expression to below 3% of the normal levels was reported to nearly completely block HCoV-NL63 replication (Carbajo-Lozoya et al, 2014) and reduce HCoV-229E-driven luciferase expression by 10-to 20-fold (von Brunn et al, 2015). CypA-or CypB-knockout in feline fcwf-4 cells resulted in a near-complete block of FCoV replication.…”

Coronaviruses and arteriviruses display striking differences in their cyclophilin A-dependence during replication in cell culture

“…Previously, CypA and/or CypB were reported to play a role in the replication of a number of arteri-and coronaviruses (Carbajo-Lozoya et al, 2014;de Wilde et al, 2013a;Tanaka et al, 2017;von Brunn et al, 2015). The degree of sensitivity to Cyp depletion appeared to differ between these viruses, but was not compared directly.…”

“…Cyclophilins were initially implicated as host factors in nidovirus replication during studies with general Cyp inhibitors such as cyclosporine A (CsA). In cell culture, the replication of a variety of coronaviruses and arteriviruses was found to be strongly inhibited by lowmicromolar concentrations of CsA and the non-immunosuppressive CsA analogs Alisporivir (ALV) and NIM-811 (Carbajo-Lozoya et al, 2014de Wilde et al, 2017ade Wilde et al, , 2013bde Wilde et al, , 2011Kim and Lee, 2014;Tanaka et al, 2012;von Brunn, 2015;von Brunn et al, 2015). Subsequently, it was established that nidovirus replication can depend specifically on CypA and/or CypB.…”