Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages

Abstract

While tuberculosis (TB) is a risk factor in HIV-1-infected individuals, the mechanisms by which Mycobacterium tuberculosis worsens HIV-1 pathogenesis remain poorly understood. Recently, we showed that HIV-1 infection and spread are exacerbated in macrophages exposed to TB-associated microenvironments due to tunneling nanotube (TNT) formation. To identify molecular factors associated with TNT function, we performed a transcriptomic analysis in these macrophages, and revealed the up-regulation of the lectin receptor Siglec-1. We demonstrate Siglec-1 expression depends on TB-mediated production of type I interferon.In co-infected non-human primates, Siglec-1 is highly expressed by alveolar macrophages, whose abundance correlates with pathology and activation of the type I interferon/STAT1 pathway. Intriguingly, Siglec-1 expression localizes exclusively on microtubule-containing TNT that are long and carry HIV-1 cargo. Siglec-1 depletion in macrophages decreases TNT length, diminishes HIV-1 capture and cell-to-cell transfer, and abrogates TB-driven exacerbation of HIV-1 infection. Altogether, we uncover a deleterious role for Siglec-1 in TB-HIV-1 co-infection, and its localization on TNT opens new avenues to understand cell-to-cell viral spread.

Peering into tunneling nanotubes—The path forward

“…These structures appear to be more resistant compared to thin TNTs, presumably from the rigidity provided by their thick architecture and microtubule cytoskeletal backbone and can reach up to 250 lm as described recently in macrophages (Dupont et al, 2020). They have been involved in the transfer of organelles (Eugenin et al, 2009;Hashimoto et al, 2016;Dupont et al, 2018) and HIV (Dupont et al, 2020); however, their specific structure and arrangement of their internal cytoskeleton, and whether they are open-ended has not been assessed yet.…”

“…This fact was demonstrated through two key findings: (I) microtubule‐disrupting and microtubule‐stabilizing agents (nocodazole and paclitaxel, respectively) did not alter induction of TNTs (Wang et al , 2011), and (II) F‐actin depolymerizing toxins, ( latrunculin , cytochalasin B , and cytochalasin D) blocked TNT formation (Bukoreshtliev et al , 2009; Schiller et al , 2013; Takahashi et al , 2013; Dupont et al , 2018). In addition to thin “canonical” TNTs fulfilling the characteristics outlined above, “thick” (> 0.7 μm in diameter), microtubule‐bearing TNTs have been found in macrophages (Onfelt et al , 2006; Souriant et al , 2019; Dupont et al , 2020), urothelial cells (Onfelt et al , 2006; Veranic et al , 2008; Resnik et al , 2018), B cells (Osteikoetxea‐Molnár et al , 2016); PC12 cells (Wang & Gerdes, 2015); astrocytes and cardiac myoblasts (Austefjord et al , 2014). These structures appear to be more resistant compared to thin TNTs, presumably from the rigidity provided by their thick architecture and microtubule cytoskeletal backbone and can reach up to 250 μm as described recently in macrophages (Dupont et al , 2020).…”

“…In addition to thin “canonical” TNTs fulfilling the characteristics outlined above, “thick” (> 0.7 μm in diameter), microtubule‐bearing TNTs have been found in macrophages (Onfelt et al , 2006; Souriant et al , 2019; Dupont et al , 2020), urothelial cells (Onfelt et al , 2006; Veranic et al , 2008; Resnik et al , 2018), B cells (Osteikoetxea‐Molnár et al , 2016); PC12 cells (Wang & Gerdes, 2015); astrocytes and cardiac myoblasts (Austefjord et al , 2014). These structures appear to be more resistant compared to thin TNTs, presumably from the rigidity provided by their thick architecture and microtubule cytoskeletal backbone and can reach up to 250 μm as described recently in macrophages (Dupont et al , 2020). They have been involved in the transfer of organelles (Eugenin et al , 2009; Hashimoto et al , 2016; Dupont et al , 2018) and HIV (Dupont et al , 2020); however, their specific structure and arrangement of their internal cytoskeleton, and whether they are open‐ended has not been assessed yet.…”