Antibody-mediated enhancement aggravates chikungunya virus infection and disease severity

Lum, Fok-Moon; Couderc, Thérèse; Chia, Bing-Shao; Ong, Ruo-Yan; Her, Zhisheng; Chow, Angela; Leo, Yee-Sin; Kam, Yiu-Wing; Rénia, Laurent; Lecuit, Marc; Ng, Lisa F. P.

This study provides the first documentation of antibody-mediated enhancement in CHIKV infection in vitro and in relevant in vivo mouse models. Despite the increased detection of CHIKV antigen in primary human monocytes, B cells and MDMs when infection was performed in the presence of sub-neutralizing levels of CHIKV-specific antibodies, viral replication was not increased. Antibody-mediated enhancement in viral infections has been reported to mostly involve FcγRs 22 . The involvement of FcγRs in enhancing CHIKV infection may lead to two outcomes: the extrinsic and intrinsic pathways (Fig. 8 ). In the extrinsic pathway, virus attachment and possibly entry is facilitated without much significance to viral replication and manipulation of host immune responses 22, 50 . Results obtained with infection in the whole blood, primary human monocytes, B cells and MDMs supported that the extrinsic pathway is at play. The increase detection of Zs-Green signal in MDMs during the later time points is suggestive of viral entry and initiation of viral replication, as the Zs-Green is cloned under a duplicated sub-genomic promoter 42, 51 . However, no further increase in both Zs-Green signal and viral RNA load may suggest that enhanced CHIKV infection do not necessary augments viral replication. This quick shutdown of viral replication may actually indicate a putative mechanism employed by CHIKV for chronic persistence. While it is known that CHIKV could persist chronically using macrophages as possible cellular reservoirs 38, 39 , its exact mechanism is not known. As such, the restricted replication observed in monocytes and MDMs could be a form of immune subversion by the virus to achieve chronic persistency 52 .