Fc RECEPTOR-MEDIATED INFECTION OF MYELOID CELLS BY SARS-CoV-2

ABSTRACT

Background: The role of myeloid cells in the pathogenesis of SARS-CoV-2 is well established, in particular as drivers of cytokine production and systemic inflammation characteristic of severe COVID-19. However, the potential for myeloid cells to act as bona fide targets of productive SARS-CoV-2 infection remains unclear. Method(s) Using anti-SARS-CoV-2 mAbs with a range of neutralisation potencies and binding specificities, we performed a detailed assessment of mAb-mediated infection of monocytes/macrophages. THP-1 cells were used as a model system, with results confirmed in primary macrophages. Result(s) Infection of THP-1 cells was seen via mAbs targeting the spike RBD, but not with those targeting the NTD or S2 subunit. mAbs with the most consistent potential to mediate infection targeted a conserved region of the RBD (group 1/class IV). No infection was seen with the same quantity of virus but in the absence of antibody, and pre-treating the cells with FcgammaRI and -II blocking antibodies inhibited infection. Thus, antibody-FcR interactions are able to expand the tropism of SARS-CoV-2. Time-course studies demonstrated high-level and productive infection. Studies performed in human iPSC-derived macrophages and primary monocyte-derived macrophages paralleled results seen in THP-1 cells but with lower infection levels. Up to 2% of macrophages were infected, with infected cells appearing multinucleated and syncytial. Addition of ruxolitinib, an inhibitor of JAK1/2 signalling, increased infection up to 10-fold, indicating limitation of infection through innate immune mechanisms. Sera from primary infections (n=80) mediated rare infection events, with a minority of samples (n=3) promoting significant infection. Competition assays confirmed results seen in sera, with the addition of neutralising mAbs diminishing the infection seen with infection-mediating mAbs. Thus, the presence of antibodies with potential to mediate infection is not sufficient to predict myeloid cell infection, rather, the context in which the antibodies are produced is key. Conclusion(s) We hypothesise that a nascent antibody response during peak viral replication in primary infection presents a window of opportunity for myeloid cells to become infected, while establishment of a robust polyclonal response via vaccination or prior infection reduces the likelihood of this occurring. Infection via antibody-FcR interactions could contribute to pathogenesis in primary infection, systemic virus spread or persistent infection.