Abstract
The arthropod-transmitted chikungunya virus (CHIKV) causes a flu-like disease that is characterized by incapacitating arthralgia. The re-emergence of CHIKV and the continual risk of new epidemics have reignited research in CHIKV pathogenesis. Virus-specific antibodies have been shown to control virus clearance, but antibodies present at sub-neutralizing concentrations can also augment virus infection that exacerbates disease severity. To explore this occurrence, CHIKV infection was investigated in the presence of CHIKV-specific antibodies in both primary human cells and a murine macrophage cell line, RAW264.7. Enhanced attachment of CHIKV to the primary human monocytes and B cells was observed while increased viral replication was detected in RAW264.7 cells. Blocking of specific Fc receptors (FcγRs) led to the abrogation of these observations. Furthermore, experimental infection in adult mice showed that animals had higher viral RNA loads and endured more severe joint inflammation in the presence of sub-neutralizing concentrations of CHIKV-specific antibodies. In addition, CHIKV infection in 11 days old mice under enhancing condition resulted in higher muscles viral RNA load detected and death. These observations provide the first evidence of antibody-mediated enhancement in CHIKV infection and pathogenesis and could also be relevant for other important arboviruses such as Zika virus.
Highlights
Chikungunya virus (CHIKV) is a member of the Alphavirus genus of the Togaviridae family[1,2]
The presence of chikungunya virus (CHIKV) antigen was detected by flow cytometry, where detection was increased by ~5 fold in monocytes (Fig. 1a) and by ~20 fold in B cells (Fig. 1b)
This study provides the first documentation of antibody-mediated enhancement in CHIKV infection in vitro and in relevant in vivo mouse models
Summary
Chikungunya virus (CHIKV) is a member of the Alphavirus genus of the Togaviridae family[1,2]. Enhancement of arbovirus infections via antibodies was first demonstrated in 196420 This is a paradoxical phenomenon of antibodies forming complexes by binding to viruses, which interact with cell surface receptors and promote entry into susceptible host cells, subsequently increasing virus replication[21,22]. We demonstrate antibody-mediated enhancement of CHIKV attachment and infection in primary human monocytes and B cells and a relevant murine cell line in the presence of sub-neutralizing levels of anti-CHIKV antibodies obtained from CHIKV-infected patients or animals. This enhancement was further demonstrated to mediate through the Fc receptors (FcγRs), with FcγRII being the key mediator. This study brings caution to the importance of such undesired effects in anti-CHIKV vaccine designs
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