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Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production

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Standard

Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production. / Reinert, Line S; Rashidi, Ahmad S; Tran, Diana N; Katzilieris-Petras, Georgios; Hvidt, Astrid K; Gohr, Mette; Fruhwürth, Stefanie; Bodda, Chiranjeevi; Thomsen, Martin K; Vendelbo, Mikkel H; Khan, Ahmad R; Hansen, Brian; Bergström, Petra; Agholme, Lotta; Mogensen, Trine H; Christensen, Maria H; Nyengaard, Jens R; Sen, Ganes C; Zetterberg, Henrik; Verjans, Georges Mgm; Paludan, Søren R.

In: Journal of Clinical Investigation, Vol. 131, No. 1, e136824, 01.2021.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Reinert, LS, Rashidi, AS, Tran, DN, Katzilieris-Petras, G, Hvidt, AK, Gohr, M, Fruhwürth, S, Bodda, C, Thomsen, MK, Vendelbo, MH, Khan, AR, Hansen, B, Bergström, P, Agholme, L, Mogensen, TH, Christensen, MH, Nyengaard, JR, Sen, GC, Zetterberg, H, Verjans, GM & Paludan, SR 2021, 'Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production', Journal of Clinical Investigation, vol. 131, no. 1, e136824. https://doi.org/10.1172/JCI136824

APA

Reinert, L. S., Rashidi, A. S., Tran, D. N., Katzilieris-Petras, G., Hvidt, A. K., Gohr, M., Fruhwürth, S., Bodda, C., Thomsen, M. K., Vendelbo, M. H., Khan, A. R., Hansen, B., Bergström, P., Agholme, L., Mogensen, T. H., Christensen, M. H., Nyengaard, J. R., Sen, G. C., Zetterberg, H., ... Paludan, S. R. (2021). Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production. Journal of Clinical Investigation, 131(1), [e136824]. https://doi.org/10.1172/JCI136824

CBE

Reinert LS, Rashidi AS, Tran DN, Katzilieris-Petras G, Hvidt AK, Gohr M, Fruhwürth S, Bodda C, Thomsen MK, Vendelbo MH, Khan AR, Hansen B, Bergström P, Agholme L, Mogensen TH, Christensen MH, Nyengaard JR, Sen GC, Zetterberg H, Verjans GM, Paludan SR. 2021. Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production. Journal of Clinical Investigation. 131(1):Article e136824. https://doi.org/10.1172/JCI136824

MLA

Vancouver

Reinert LS, Rashidi AS, Tran DN, Katzilieris-Petras G, Hvidt AK, Gohr M et al. Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production. Journal of Clinical Investigation. 2021 Jan;131(1). e136824. https://doi.org/10.1172/JCI136824

Author

Reinert, Line S ; Rashidi, Ahmad S ; Tran, Diana N ; Katzilieris-Petras, Georgios ; Hvidt, Astrid K ; Gohr, Mette ; Fruhwürth, Stefanie ; Bodda, Chiranjeevi ; Thomsen, Martin K ; Vendelbo, Mikkel H ; Khan, Ahmad R ; Hansen, Brian ; Bergström, Petra ; Agholme, Lotta ; Mogensen, Trine H ; Christensen, Maria H ; Nyengaard, Jens R ; Sen, Ganes C ; Zetterberg, Henrik ; Verjans, Georges Mgm ; Paludan, Søren R. / Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production. In: Journal of Clinical Investigation. 2021 ; Vol. 131, No. 1.

Bibtex

@article{8c0a5cd5dc0e4c03874c7f04e694f831,
title = "Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production",
abstract = "Protection of the brain from viral infections involves the type I IFN (IFN-I) system, defects in which render humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels lead to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we showed that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, whereas lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices or mice treated with a caspase inhibitor exhibited lower viral load and an improved infection outcome. Collectively, we identify an activation-induced apoptosis program in brain immune cells that downmodulates local immune responses.",
author = "Reinert, {Line S} and Rashidi, {Ahmad S} and Tran, {Diana N} and Georgios Katzilieris-Petras and Hvidt, {Astrid K} and Mette Gohr and Stefanie Fruhw{\"u}rth and Chiranjeevi Bodda and Thomsen, {Martin K} and Vendelbo, {Mikkel H} and Khan, {Ahmad R} and Brian Hansen and Petra Bergstr{\"o}m and Lotta Agholme and Mogensen, {Trine H} and Christensen, {Maria H} and Nyengaard, {Jens R} and Sen, {Ganes C} and Henrik Zetterberg and Verjans, {Georges Mgm} and Paludan, {S{\o}ren R}",
year = "2021",
month = jan,
doi = "10.1172/JCI136824",
language = "English",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "1",

}

RIS

TY - JOUR

T1 - Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production

AU - Reinert, Line S

AU - Rashidi, Ahmad S

AU - Tran, Diana N

AU - Katzilieris-Petras, Georgios

AU - Hvidt, Astrid K

AU - Gohr, Mette

AU - Fruhwürth, Stefanie

AU - Bodda, Chiranjeevi

AU - Thomsen, Martin K

AU - Vendelbo, Mikkel H

AU - Khan, Ahmad R

AU - Hansen, Brian

AU - Bergström, Petra

AU - Agholme, Lotta

AU - Mogensen, Trine H

AU - Christensen, Maria H

AU - Nyengaard, Jens R

AU - Sen, Ganes C

AU - Zetterberg, Henrik

AU - Verjans, Georges Mgm

AU - Paludan, Søren R

PY - 2021/1

Y1 - 2021/1

N2 - Protection of the brain from viral infections involves the type I IFN (IFN-I) system, defects in which render humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels lead to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we showed that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, whereas lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices or mice treated with a caspase inhibitor exhibited lower viral load and an improved infection outcome. Collectively, we identify an activation-induced apoptosis program in brain immune cells that downmodulates local immune responses.

AB - Protection of the brain from viral infections involves the type I IFN (IFN-I) system, defects in which render humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels lead to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we showed that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, whereas lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices or mice treated with a caspase inhibitor exhibited lower viral load and an improved infection outcome. Collectively, we identify an activation-induced apoptosis program in brain immune cells that downmodulates local immune responses.

UR - http://www.scopus.com/inward/record.url?scp=85098872691&partnerID=8YFLogxK

U2 - 10.1172/JCI136824

DO - 10.1172/JCI136824

M3 - Journal article

C2 - 32990676

VL - 131

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

M1 - e136824

ER -