Monocyte apoptotic bodies are vehicles for influenza A virus propagation

Abstract

The disassembly of apoptotic cells into small membrane-bound vesicles termed apoptotic bodies (ApoBDs) is a hallmark of apoptosis; however, the functional significance of this process is not well defined. We recently discovered a new membrane protrusion (termed beaded apoptopodia) generated by apoptotic monocytes which fragments to release an abundance of ApoBDs. To investigate the function of apoptotic monocyte disassembly, we used influenza A virus (IAV) infection as a proof-of-concept model, as IAV commonly infects monocytes in physiological settings. We show that ApoBDs generated from IAV-infected monocytes contained IAV mRNA, protein and virions and consequently, could facilitate viral propagation in vitro and in vivo, and induce a robust antiviral immune response. We also identified an antipsychotic, Haloperidol, as an unexpected inhibitor of monocyte cell disassembly which could impair ApoBD-mediated viral propagation under in vitro conditions. Together, this study reveals a previously unrecognised function of apoptotic monocyte disassembly in the pathogenesis of IAV infections.

Immunopeptidomic analysis of influenza A virus infected human tissues identifies internal proteins as a rich source of HLA ligands

“…Monolayer cultures of A549 cells were infected and sent into apoptosis essentially as previously described [48]. Briefly, 90% confluent monolayers of A549 cells were infected with A/Wisconsin/67/2005 influenza at an MOI of 1.0 in serum-free medium for 2 h, monolayers were rinsed twice with serum free medium to remove excess inoculum, and then cultured for a further 12 h in serum-free DMEM supplemented with penicillin-streptomycin and l-glutamine for a further 12 h. The infection rate of >80% was confirmed by flow cytometry (Fig S3) using detection of intracellular viral NP protein as previously described.…”

Unleashing the therapeutic potential of apoptotic bodies

“…In certain settings, active formation of ApoBD by infected or transformed cells can promote disease progression and worsen disease burden. For instance, ApoBDs derived from influenza A virus-infected monocytes can propagate viral infection in bystander cells through the transfer of accompanying virions [25]. Intriguingly, apoptosis of hepatitis C virus-infected hepatocytes induced by alcohol also accelerates viral spread via the similar ApoBD-assisted dissemination [26].…”

“…In contrast, inhibition of ApoBD formation may be beneficial in treating infection and cancer. Recently, haloperidol, an antipsychotic drug, has been reported to inhibit apoptotic monocyte disassembly, effectively reducing the propagation of influenza A virus in in vitro models and lessen disease severity in mouse models [25]. Speculatively, sertraline, a commonly prescribed antidepressant and recently demonstrated ApoBD formation blocker, may be repurposed to achieve similar antiviral dissemination effect.…”

“…In a recent histological study, celiac patients had markedly elevated level of ApoBDs in their duodenal biopsies [55]. Furthermore, coupled with cell surface markers, ApoBDs of different cell origins can be readily detected, quantified and isolated for cell-specific diagnosis [25,32], for example for graft-versus-host disease using crypt cell markers [56]. Since ApoBDs are abundantly circulating in bodily fluids [32,57], this cutting-edge technology would, therefore, allow for analyses of particular disease-associated apoptotic cells.…”

Stoking the Fire: How Dying Cells Propagate Inflammatory Signalling through Extracellular Vesicle Trafficking

“…ApoBDs can also propagate inflammatory signalling through the transfer of viral particles. For example, in an in-vivo model of Influenza A (IAV) infection, intranasal administration of THP1 monocyte-derived ApoBDs harbouring live IAV viral particles induced a robust proinflammatory cytokine and chemokine response in the lung tissue of mice [ 48 ].…”