Sensing macrophages - a novel indirect pathway of plasmacytoid dendritic cells activation by viruses

Published in Microbiology
Sensing macrophages - a novel indirect pathway of plasmacytoid dendritic cells activation by viruses

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Obdulio García-Nicolás, Aurelie Godel, Gert Zimmer and Artur Summerfield

 For many years our laboratory has characterized the interplay of viruses with macrophages and dendritic cells (DC), in particular plasmacytoid DC (pDC). At the beginning of the COVID-19 global health emergency, when it became clear that vaccines will play an essential role in combating the pandemic, we decided to evaluate the potential of antibody-dependent enhancement of infection for SARS-CoV-2, an important aspect for the safety of vaccination. In the course of this work, we found that SARS-CoV-2 was unable to productively infect and activate human monocyte derived macrophages (MDM) (1). Nevertheless, these findings were apparently contradicting in vivo evidence for an important role of macrophages during COVID-19, in which macrophage signature cytokines such as TNF and IL-6 were found to correlate with disease severity (2). Indeed, SARS-CoV-2 proteins have been found in lymph node macrophages from fatal COVID-19 cases (3). Considering the essential function of macrophages to remove apoptotic and dead cells, the starting hypothesis of the present work was that antigen positivity may result from phagocytosis of infected cells, which could cause macrophage activation.

To test this hypothesis, we co-cultured SARS-CoV-2-infected Vero E6 cells with macrophages, demonstrating that the presence of viral nucleocapsid in macrophages was the result of phagocytosis of infected cells. In fact, only the phagocytosing macrophages were also positive for the viral antigen (Figure 1). Phagocytosis of virus-infected cells was associated with secretion of the pro-inflammatory cytokines IL-6 and TNF.

Figure 1. Three-dimensional modeling of a confocal microscopy image of a macrophage (red) that has phagocytosed a SARS-CoV-2-infected Vero E6 cell (blue). Viral nucleocapsid proteins are depicted in green.

A second line of our work was based on several previous studies from our and other laboratories, which demonstrated that pDC have the striking ability to recognize virus-infected cells, resulting in the production of extraordinary high levels of interferon type I. In many cases, sensing of infected cells greatly surpasses sensing of the virus itself. In all cases studied, sensing of infected cells requires cognate interactions involving adhesion molecules. After formation of synapse-like structures activation of pDC is mediated by transfer of stimulating elements such as nucleic acids from the infected cell to pDC (4-6). 

Based on this knowledge, we were wondering if pDC could go beyond sensing of infected cells and even react to macrophages that had phagocytosed infected cells. Indeed, after adding pDC to macrophages that had phagocytosed SARS-CoV-2-infected cells we detected very high levels of IFN-α in the cell culture supernatant. Strikingly, these IFN-α levels were up to ten times higher than pDC responses after stimulation with viral particles or with virus-infected Vero E6 cells. This is fascinating in light of the known protective effects of early strong IFN-α during COVID-19. On the other hand, such responses may also be involved in COVID-19 pathogenesis, considering that the levels of IL-6 and TNF were also higher when pDC were added to the culture system.

Like the stimulation of pDC by infected cells, IFN-α responses depended on tight interactions between both cell types. Interestingly, both TLR7 and STING pathways were involved in the observed immune responses in both macrophages and pDC, indicating that sensing is triggered by both viral (RNA) and host nucleic acids (DNA).

In conclusion, our work contributes to a better understanding of the induction pathways that lead to innate immune responses during COVID-19 (graphical summary in Figure 2). In a broader context, this novel pathway of pDC activation underlines the fascinating roles and cooperation of both macrophages and pDC in the induction in innate antiviral responses in a manner that bypasses virus-encoded inhibitors of the innate response.


Figure 2. Graphical representation of the main findings of our work.

  1. Garcia-Nicolas O, V'Kovski P, Zettl F, Zimmer G, Thiel V, Summerfield A. No Evidence for Human Monocyte-Derived Macrophage Infection and Antibody-Mediated Enhancement of SARS-CoV-2 Infection. Front Cell Infect Microbiol. 2021;11:644574.
  2. Lian Q, Zhang K, Zhang Z, Duan F, Guo L, Luo W, et al. Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model. Nat Commun. 2022;13(1):2028.
  3. Park MD. Macrophages: a Trojan horse in COVID-19? Nat Rev Immunol. 2020;20(6):351.
  4. Assil S, Coleon S, Dong C, Decembre E, Sherry L, Allatif O, et al. Plasmacytoid Dendritic Cells and Infected Cells Form an Interferogenic Synapse Required for Antiviral Responses. Cell Host Microbe. 2019;25(5):730-45 e6.
  5. Decembre E, Assil S, Hillaire ML, Dejnirattisai W, Mongkolsapaya J, Screaton GR, et al. Sensing of immature particles produced by dengue virus infected cells induces an antiviral response by plasmacytoid dendritic cells. PLoS Pathog. 2014;10(10):e1004434.
  6. Garcia-Nicolas O, Auray G, Sautter CA, Rappe JC, McCullough KC, Ruggli N, et al. Sensing of Porcine Reproductive and Respiratory Syndrome Virus-Infected Macrophages by Plasmacytoid Dendritic Cells. Front Microbiol. 2016;7:771.


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