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In vivo functions of nuclear envelope rupture and antiviral specialization in dendritic cells

Periodic Reporting for period 1 - DCBIO (In vivo functions of nuclear envelope rupture and antiviral specialization in dendritic cells)

Reporting period: 2018-02-01 to 2020-01-31

Dendritic cells are rapidly activated when DNA is exposed to the cytosol, which can occur in viral infections. Recent in vitro work has revealed that DNA is also transiently accessible to the cytosol in migrating DCs due to rupture of the nuclear envelope, and is detected by the cytosolic DNA sensor cGAS. The immune consequences of nuclear envelope rupture in vivo are unknown and were investigated as the first objective of this project.
Viral infection of DCs impairs their immune functions. Unpublished data has revealed that in humans, the CD141+ DC subset is constitutively resistant to a broad range of enveloped viruses. Resistance was associated with the expression of the GTPase, RAB15. In the second objective of this project, the function of RAB15 in DC biology was investigated in vivo to study the division of antiviral labor among DC subsets.

Dissecting the mechanisms that regulate the immune system is critical for the development of novel therapeutic strategies including vaccines, anti-tumor therapies and other means of immunomodulation.
In the first objective, several genetic mouse lines were imported from collaborators or generated de novo to allow the perturbation of factors that regulate the structure and integrity of the nuclear envelope. We used these models to conduct a candidate approach genetic screen to investigate the impact of nuclear envelope modulation on the immune system by analysing a range of immune cell populations in a number of immune organs within naïve, unchallenged animals. We identified a nuclear envelope mutant with a striking loss of an important immune population residing within the lung. This phenotype was associated with DNA damage and lung pathology. Single cell RNA sequencing of revealed parallels between the transcriptional changes occurring due to nuclear envelope modulation and those that occur naturally with age.

In the second objective, despite some initial technical difficulties in generating a colony of mutant mice with Rab15 deficiency we obtained encouraging preliminary data suggesting that Rab15 deficiency within dendritic cells accelerates disease progression following influenza A (PR1) infection. This finding will be further pursued once a larger colony is at our disposal.
Through this work we therefore identified a specific in vivo context in which the nuclear envelope plays a critical role in preserving the homeostasis of a cellular population within the lung. Interestingly, we believe this phenotype also mimics some aspects of natural aging resulting in an aged immune population residing within the body of a young mouse. This work has implications for understanding natural aging mechanisms within the immune system.
Immunosenescence and aging of the immune system are important medical problems that are not well understood. An improved understanding of the mechanisms underpinning these processes is expected to reveal opportunities for therapeutic intervention. We believe our study may also reveal important markers of immunosenescence that could have clinical applications for monitoring aging within the immune system.
Overview of the project aims