Project 3 - Perturbations of the phagocytic and activation functions of macrophages by viral infections (HIV, respiratory virus)

Macrophages are a major initial target of the human immunodeficiency virus (HIV) and represent a productive reservoir for the virus because of their resistance to cytopathic effects. We contributed to show that targeting the CCR5 co-receptor trafficking inhibits HIV-1 infection of macrophages (Boncompain et al., 2019). Infection of macrophages by HIV-1 causes a severe impairment of the functions of these cells, which allows the development of opportunistic pathogens. We demonstrated that macrophages infected with HIV-1 exhibit defects in phagocytosis due to the virulence factor Nef (Mazzolini et al., 2010) and defects in phagosome maturation and bacterial clearance due to the Vpr viral protein interacting with microtubule-associated motors (Dumas et al., 2015). We continue to characterize the development of opportunistic bacteria, especially invasive Salmonella Typhimurium (iNTS) strains emerged in African HIV-1-infected patients (coll Dr Jay Hinton, Dr Melita Gordon, Liverpool and Malawi) (Le-Bury et al., 2020). The complex interplay between infected cells, HIV-1 and iNTS is further analyzed in collaboration with Emmanuel Saliba and Alexander Westermann (Würzburg) with the support of Sidaction.

Alveolar macrophages are the most abundant innate immune cells present in the airways that play a crucial role in airway homeostasis. They exhibit defective clearance capacities, often exacerbated by infection with human rhinoviruses (HRV) (Jubrail et al., 2017), in chronic inflammatory diseases such as asthma or chronic obstructive pulmonary disease (COPD). We are dissecting the mechanisms leading to this defective phagocytosis, in collaboration with Astra Zeneca and Prof. Pierre-Regis Burgel (Hôpital Cochin). We monitored the altered cytokine response of macrophages infected by HRV and then challenged with bacterial products (Jubrail et al., 2018) and revealed that Arpin is targeted by human rhinoviruses, explaining the defective bacterial uptake (Jubrail et al., 2020). The degradative capacity of macrophages as well as the virus-induced modifications of the phagocytic cells reprogramming are under investigation. A transcriptomic analysis of rhinovirus-treated macrophages allows further identification of new host targets, opening new avenues for potential therapeutic strategies.

Reference

  1. Boncompain G, Herit F, Tessier S, […], Brelot A, Niedergang F, Perez F (2019). Differential screening identifies molecules specifically inhibiting CCR5 transport to the cell surface and HIV infection. Science Advances Oct 16;5(10):eaax0821. doi: 10.1126/sciadv.aax0821. eCollection 2019 Oct.
  2. Mazzolini, J., Herit, F., Bouchet, J., Benmerah, A., Benichou, S., and Niedergang, F. (2010). Inhibition of phagocytosis in HIV-1-infected macrophages relies on Nef-dependent alteration of focal delivery of recycling compartments. Blood 115, 4226-4236.
  3. Dumas, A., Le-Bury, G., Marie-Anais, F., Herit, F., Mazzolini, J., Guilbert, T., Bourdoncle, P., Russell, D.G., Benichou, S., Zahraoui, A., et al. (2015). The HIV-1 protein Vpr impairs phagosome maturation by controlling microtubule-dependent trafficking. J Cell Biol 211, 359-372.
  4. Le-Bury, G., Deschamps, C., Kizilyaprak, C., Blanchard, W., Daraspe, J., Dumas, A., Gordon, M.A., Hinton, J.C.D., Humbel, B.M., and Niedergang, F. (2020). Increased intracellular survival of Salmonella Typhimurium ST313 in HIV-1-infected primary human macrophages is not associated with Salmonella hijacking the HIV compartment. Biol Cell 112, 92-101.
  5. Jubrail, J., Kurian, N., and Niedergang, F. (2017). Macrophage phagocytosis cracking the defect code in COPD. Biomed J 40, 305-312.
  6. Jubrail, J., Africano-Gomez, K., Herit, F., Baturcam, E., Mayer, G., Cunoosamy, D.M., Kurian, N., and Niedergang, F. (2018).  HRV16 impairs macrophages cytokine response to a secondary bacterial trigger. Front. Immunol. 9 :2908.
  7. Jubrail, J., Africano-Gomez, K., Herit, F., Mularski, A., Bourdoncle, P., Oberg, L., Israelsson, E., Burgel, P.R., Mayer, G., Cunoosamy, D.M., Kurian, N., and Niedergang, F. (2020). Arpin is critical for phagocytosis in macrophages and is targeted by human rhinovirus. EMBO Rep 21, e47963.