No evidence for human monocyte-derived macrophage infection and antibody-mediated enhancement of SARS-CoV-2 infection

Abstract

Vaccines are essential to control the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and to protect the vulnerable population. However, one safety concern of vaccination is the possible development of antibody-dependent enhancement (ADE) of SARS-CoV-2 infection. The potential infection of Fc receptor bearing cells such as macrophages, would support continued virus replication and inflammatory responses, and thereby potentially worsen the clinical outcome of COVID-19. Here we demonstrate that SARS-CoV-2 and SARS-CoV-1 neither infect human monocyte-derived macrophages nor induce inflammatory cytokines in these cells, in sharp contrast to Middle East respiratory syndrome (MERS) coronavirus and the common cold human coronavirus 229E. Furthermore, serum from convalescent COVID-19 patients neither induced enhancement of SARS-CoV-2 infection nor innate immune response in human macrophages. These results support the view that ADE may not be involved in the immunopathological processes associated with COVID-19, however, more studies are necessary to understand the potential contribution of antibodies-virus complexes with other cells expressing FcR receptors.

Highly restricted SARS-CoV-2 receptor expression and resistance to infection by primary human monocytes and monocyte-derived macrophages

“…TMPRSS2 is the principal protease that cleaves the S2’ Spike site required for fusion, but other proteases such as TMPRSS4 and TMPRSS11 may also function in that role 26,27 . Nevertheless, the lack of infection in our model argues against alternative entry pathways, and is consistent with findings reported by others using different macrophage cell models 21,25 . Finally, it has been reported that SARS‐CoV‐2 can cause abortive infection of macrophages 28,29 .…”

“…CD147 has been implicated as a pathway for SARS‐CoV‐2 entry, 23 but this is controversial 24 . Antibody‐dependent enhancement can lead to macrophage infection by some viruses in the absence of receptor expression, although evidence for this in SARS‐CoV‐2 is currently lacking 25 . TMPRSS2 is the principal protease that cleaves the S2’ Spike site required for fusion, but other proteases such as TMPRSS4 and TMPRSS11 may also function in that role 26,27 .…”

“…26,27 Nevertheless, the lack of infection in our model argues against alternative entry pathways, and is consistent with findings reported by others using different macrophage cell models. 21,25 Finally, it has been reported that SARS-CoV-2 can cause abortive infection of macrophages. 28,29 However, our findings that cellular receptor expression is lacking and SARS-CoV-2 Spike fails to mediate pseudovirus entry would argue against entry and abortive infection in these cells.…”

“…24 Antibody-dependent enhancement can lead to macrophage infection by some viruses in the absence of receptor expression, although evidence for this in SARS-CoV-2 is currently lacking. 25 TMPRSS2 is the principal protease that cleaves the S2' Spike site required for fusion, but other proteases such as TMPRSS4 and TMPRSS11 may also function in that role. 26,27 Nevertheless, the lack of infection in our model argues against alternative entry pathways, and is consistent with findings reported by others using different macrophage cell models.…”

Iron dysregulation in COVID‐19 and reciprocal evolution of SARS‐CoV‐2: Natura nihil frustra facit

“…69 It has been reported that there is no macrophage persistence from infection by SARS-CoV-2 and hence no ADE. 70,71 But if the variants are becoming more resistant to lysosomal proteases including Cathepsin G, then more severe infection observed in the variants could be attributed to ADE. As these mutations are present on different lineages, and we have seen many convergent mutations in past with SARS-CoV-2, these strains might be evolving in the same direction.…”