Chikungunya virus mobilizes the apoptotic machinery to invade host cell defenses

Abstract

Chikungunya virus (CHIKV) surprised medical workers by a massive outbreak in the Indian Ocean region, reaching Europe in 2007, with exceptional pathologies in infants and elderly patients. Although CHIKV was recently shown to persist in myoblasts, monocytes, and macrophages, we argued that robust antiviral mechanisms, including apoptosis, are essential to ward off the virus. Herein, we tested the capacity of CHIKV to mobilize the apoptotic machinery in HeLa cells as well as primary fibroblasts, making use of several inhibitors of caspases, cell blebbing, and engulfment of the apoptotic blebs by neighboring cells. CHIKV triggered apoptosis through intrinsic and extrinsic pathways. Bystander apoptosis was also evidenced in neighboring cells in a caspase-8-dependent manner. Remarkably, by hiding in apoptotic blebs, CHIKV was able to infect neighboring cells. In HeLa cells, these events were inhibited specifically by zVAD-fmk and DEVD-cho (caspase inhibitors), blebbistatin, Y-27632 (ROCK inhibitor), and genistein, annexin V, and cytochalasin B (inhibitors of blebbing and engulfment). These CHIKV-apoptotic blebs were also capable of infecting macrophages (primary cultures, MM6- and THP1-PMA differentiated cells) otherwise refractory to infection by CHIKV alone. Remarkably, viral replication in macrophages did not yield a proinflammatory response. We describe a novel infectious mechanism by which CHIKV invades host cells and escapes the host response.

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

“…CHIKV infection is cytopathic and induces apoptosis, resulting in direct tissue injury (70,132,133). Numerous cell types, many of which are located at sites of disease, are susceptible to CHIKV, including chondrocytes, endothelial cells, fibroblasts, hepatocytes, macrophages, monocytes, muscle satellite cells, myocytes, and osteoblasts (8, 72, 75, 104-107, 113, 116, 134-139).…”

Multifaceted innate immune responses engaged by astrocytes, microglia and resident dendritic cells against Chikungunya neuroinfection

“…At 72 h p.i., neurons were shedding multiple membrane-bound microvesicles stained for CHIKV, which may correspond to apoptotic blebs (Krejbich-Trotot et al, 2011). The identity of the receptor for CHIKV is unknown and its expression may be differentially modulated on neurons.…”

A Virulent Bioluminescent and Fluorescent Dual-Reporter Marek's Disease Virus Unveils an Alternative Spreading Pathway in Addition to Cell-to-Cell Contact

“…Interestingly, by using live-cell fluorescence microscopy I was able to observe in both early and heavily infected cells a striking cell-blebbing phenomenon (27,28) (Fig. 4A).…”

“…Taken together, these results represent the first evidence that MDV does not rely exclusively on cell-to-cell contact for spreading. Indeed, the blebbing phenomenon was very reminiscent of the apoptotic mimicry "Trojan horse" scenario, where the correlation between virus-induced cell blebbing and the cellular apoptotic corps clearance mechanism has been shown to play a major role in virus dissemination (28)(29)(30).…”

“…For MDV, it was demonstrated previously that immunosuppressive treatments of chickens with cyclosporine or betamethasone resulted in widespread MDV infection in target organs and enhanced reactivation of the virus (26). As those drugs have been shown to be proapoptotic, further investigation of the direct role of apoptosis and apoptotic mimicry in MDV replication and spreading is needed (28)(29)(30).…”