Human Innate Immunity

Nicolas Manel

Nicolas Manel Team Leader, DR2 INSERM

Innate immune responses are considered the first defensive line against harmful conditions, including cancer.

Figure 1: Capture of HIV-1 viral particles (green) by two human dendritic cells.
Figure 1: Capture of HIV-1 viral particles (green) by two human dendritic cells.

Human dendritic cells play a key role in the control of these responses and are a promising constituent of rational immune therapies. Indeed, dendritic cells possess a unique machinery to detect and sense injured tissues, cellular fragments and pathogens. Upon detection, dendritic cells become licensed to activate adaptive immunity and thus couple innate and adaptive responses. We use HIV, an important human pathogen that causes AIDS, as a model to understand the regulation of innate immunity in human dendritic cells (Figure 1).

 

We have discovered that an innate immune response to HIV-1 exists in dendritic cells. HIV-1 is normally unable to infect dendritic cells and we have used the Vpx protein found in other lentiviruses to render dendritic cells susceptible to HIV-1 infection. In these conditions, infection of dendritic cells results in induction of an innate immune response that can prime adaptive immunity and induce protective antiviral type I interferon. HIV-2, which is less pathogenic than HIV-1, encodes Vpx and naturally infects and induces an innate immune response in dendritic cells, pointing to an important role of this response in determining the ability of the immune system to control HIV replication.

We recently showed that innate immune sensing of HIV by dendritic cells is mediated by the cytosolic DNA sensor cGAS. In the virus, the viral DNA is required for cGAS activation. The viral DNA is embedded in a shell of viral capsid proteins, and we showed that the viral capsid determine the fate of the viral DNA towards viral replication or innate immune recognition. In addition, we showed that the binding of host protein Cyclophilin A to capsid is a key regulator of HIV sensing by dendritic cells.

Manel2
Figure 2: Human dendritic cells possess an intact innate machinery to sense and respond to HIV. This response requires cellular Cyclophilin A, leads the production of type I interferon and licenses dendritic cells for activation of naïve human T lymphocytes. It is normally avoided by HIV-1, but engaged by HIV-2, a less pathogenic virus.

 

Based on these findings, we now explore new avenues of research. Our first aim is to identify novel regulators of the innate immune response and the viral replication. Our second aim is to characterize the type of adaptive immune response that will be generated in T cells when the innate immune response to HIV-1 is active in dendritic cells. Lastly, we explore more general aspects of innate immune regulation. In particular, we focus on the regulation and functions of the important sensor cGAS in immune cells.  To achieve these aims, we utilize a number of molecular and cellular approaches, including RNAi in dendritic cells, functional screens and analysis of gene networks. Our results suggest new ways to generate adjuvants for immunotherapies and vaccines. A patent application has been filed accordingly.

 

Team MANEL

Key publications

Year of publication 2017

Cerboni S, Jeremiah N, Gentili M, Gehrmann U, Conrad C, Stolzenberg MC, Picard C, Neven B, Fischer A, Amigorena S, Rieux-Laucat F, Manel N (2017 May 8)

Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes

The Journal of Experimental Medicine : DOI : 10.1084/jem.20161674

Year of publication 2016

Xavier Lahaye, Takeshi Satoh, Matteo Gentili, Silvia Cerboni, Aymeric Silvin, Cécile Conrad, Abdelhakim Ahmed-Belkacem, Elisa C Rodriguez, Jean-François Guichou, Nathalie Bosquet, Matthieu Piel, Roger Le Grand, Megan C King, Jean-Michel Pawlotsky, Nicolas Manel (2016 May 7)

Nuclear Envelope Protein SUN2 Promotes Cyclophilin-A-Dependent Steps of HIV Replication.

Cell reports : DOI : S2211-1247(16)30363-1
M Raab, M Gentili, H de Belly, H R Thiam, P Vargas, A J Jimenez, F Lautenschlaeger, Raphaël Voituriez, A M Lennon-Duménil, N Manel, M Piel (2016 Apr 15)

ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death

Science (New York, N.Y.) : DOI : 10.1126/science.aad7611

Year of publication 2015

Gentili M, Kowal 1, Tkach M, Satoh T, Lahaye X, Conrad C, Boyron M, Lombard B, Durand S, Kroemer G, Loew D, Dalod M, Théry C, Manel N. (2015 Jul 30)

Transmission of innate immune signaling by packaging of cGAMP in viral particles.

Science : DOI : 10.1126/science.aab3628

Year of publication 2013

Xavier Lahaye, Takeshi Satoh, Matteo Gentili, Silvia Cerboni, Cécile Conrad, Ilse Hurbain, Ahmed El Marjou, Christine Lacabaratz, Jean-Daniel Lelièvre, Nicolas Manel (2013 Sep 6)

The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells.

Immunity : 1132-42 : DOI : 10.1016/j.immuni.2013.11.002

Year of publication 2011

Nicolas Manel, Dan R Littman (2011 Jul 14)

Hiding in plain sight: how HIV evades innate immune responses.

Cell : 271-4 : DOI : 10.1016/j.cell.2011.09.010
All publications