Biology subjects

Pinci, F.

Publications and source records attributed to Pinci, F..

3 recordsLinked to original sources

bioRxiv2023

Dissecting the neurotropism and neurovirulence of MPXV using human stem cell-based models

Mpox is a zoonotic illness of international concern that can lead to severe disease including neurological sequelae. However, the neurotropism of monkeypox virus (MPXV) and the mechanisms regulating cell-intrinsic antiviral immunity within the central nervous system (CNS) remain poorly understood. Here, we investigated the neurotropism of MPXV using astrocytes, cortical neurons, and microglia derived from human pluripotent stem cells (hPSCs) and ex vivo human brain tissue to demonstrate that MPXV infects and replicates more efficiently in astrocytes and microglia compared to cortical neurons. Upon MPXV exposure, glial cells, in contrast to cortical neurons, inhibit type I IFN antiviral programs potentially conferring differential susceptibility to MPXV. Furthermore, we demonstrate that treatment using either IFN-beta or tecovirimat inhibits MPXV infection. Together, our results suggest that MPXV has a broad tropism within the CNS and that differential type I IFN signaling underpins cell type-specific susceptibility to MPXV infection.

microbiology↗

bioRxiv2022

Tumor necrosis factor is a necroptosis-associated alarmin

Necroptosis is a form of regulated cell death that can occur downstream of several immune pathways. While previous studies have shown that dysregulated necroptosis leads to strong inflammatory responses, little is known about the identity of the endogenous molecules that trigger necroptosis-mediated inflammatory responses. Using a reductionist in vitro model, we found that soluble TNF is strongly released in the context of necroptosis. On the one hand, necroptosis promotes TNF translation by inhibiting negative regulatory mechanisms acting at the post-transcriptional level. On the other hand, necroptosis markedly enhances TNF release by activating ADAM proteases. In studying TNF release at single-cell resolution, we found that TNF release triggered by necroptosis is activated in a switch-like manner and exceeds steady-state TNF processing in magnitude and speed. Although this shedding response precedes massive membrane damage, it is closely associated with lytic cell death. In fact, we found that lytic cell death induction using a pore-forming toxin also triggers TNF shedding, indicating that the activation of ADAM proteases is not strictly related to the necroptotic pathway but associated with biophysical changes of the cell membrane upon lytic cell death. These results demonstrate that lytic cell death, particularly necroptosis, is a critical trigger for TNF release and thus qualify TNF as a necroptosis-associated alarmin.

immunology↗

bioRxiv2019

Priming enables a NEK7-independent route of NLRP3 activation

The NLRP3 inflammasome plays a central role in antimicrobial defense, as well as in sterile inflammatory conditions. NLRP3 activity is governed by two independent signals. The first signal primes NLRP3, allowing it to respond to its activation signal. In the murine system, the mitotic spindle kinase NEK7 has been identified as a crucial factor in relaying the activation signal to NLRP3. Here we show that the requirement for NEK7 can be bypassed by TAK1-dependent post-translational priming. Under pro-inflammatory conditions that activate TAK1, NEK7 was dispensable for NLRP3 inflammasome formation in human and murine cells. Intriguingly, dissecting the NEK7 requirement in iPSC-derived primary human macrophages revealed that this NEK7-independent mechanism constitutes the predominant NLRP3 priming pathway in these cells. In summary, our results suggest that NEK7 functions as an NLRP3 priming - rather than activation - factor that can work in synergy or redundancy with other priming pathways to accelerate inflammasome activation.

immunology↗