Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation

ABSTRACT We previously reported that herpes simplex virus 1 (HSV-1) ICP22 binds to CD80 and suppresses CD80 expression in vitro and in vivo. Similar to ICP22, the cellular costimulatory molecules CD28, CTLA4, and PD-L1 also bind to CD80. In this study, we asked whether, similar to ICP22-null virus,...

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Autores principales:	Harry H. Matundan, Ujjaldeep Jaggi, Jack Yu, Omid Akbari, Homayon Ghiasi
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	HSV-1 antigen-presenting cells corneal scarring knockout latency ocular infection Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9776df8d282c476986c1363b6893cbc8
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spelling	oai:doaj.org-article:9776df8d282c476986c1363b6893cbc82021-11-10T18:37:50ZAbsence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation10.1128/mBio.01176-212150-7511https://doaj.org/article/9776df8d282c476986c1363b6893cbc82021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01176-21https://doaj.org/toc/2150-7511ABSTRACT We previously reported that herpes simplex virus 1 (HSV-1) ICP22 binds to CD80 and suppresses CD80 expression in vitro and in vivo. Similar to ICP22, the cellular costimulatory molecules CD28, CTLA4, and PD-L1 also bind to CD80. In this study, we asked whether, similar to ICP22-null virus, the absence of these costimulatory molecules will reduce HSV-1 infectivity. To test our hypothesis, CD28−/−, CD28−/− CTLA4−/−, PD-L1−/−, and wild-type control BALB/c mice were ocularly infected with HSV-1 strain KOS. Levels of virus replication in the eye, corneal scarring (CS), latency, and reactivation in infected mice were determined. Expression of different genes in the trigeminal ganglia (TG) of latently infected mice was also determined by NanoString and quantitative reverse transcription-PCR (qRT-PCR). In the absence of costimulatory molecules, latency levels were higher than those in wild-type control mice, but despite higher latency, a significant number of TG from infected knockout mice did not reactivate. Reduced reactivation correlated with downregulation of 26 similar cellular genes that are associated with inflammatory signaling and innate immune responses. These results suggest that lower reactivation directly correlates with lower expression of interferon signaling. Thus, despite having different modes of actions, we identified a similar function for CD28, CTLA4, and PD-L1 in HSV-1 reactivation that is dependent on their interactions with CD80. Therefore, blocking these interactions could be a therapeutic target for HSV-1-induced reactivation. IMPORTANCE Costimulatory molecules play an important role in activation of T cell responses, and T cells contribute to HSV-1-induced eye disease in the host. Similar to HSV-1 ICP22, the cellular costimulatory molecules CD28, CTLA4, and PD-L1 also bind to CD80. In this study, we have shown that the absence of these costimulatory molecules significantly reduced HSV-1 ex vivo reactivation. Therefore, inhibiting the binding of costimulatory molecules to CD80 could be used to reduce reactivation and, consequently, HSV-1-induced eye disease.Harry H. MatundanUjjaldeep JaggiJack YuOmid AkbariHomayon GhiasiAmerican Society for MicrobiologyarticleHSV-1antigen-presenting cellscorneal scarringknockoutlatencyocular infectionMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HSV-1 antigen-presenting cells corneal scarring knockout latency ocular infection Microbiology QR1-502
spellingShingle	HSV-1 antigen-presenting cells corneal scarring knockout latency ocular infection Microbiology QR1-502 Harry H. Matundan Ujjaldeep Jaggi Jack Yu Omid Akbari Homayon Ghiasi Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation
description	ABSTRACT We previously reported that herpes simplex virus 1 (HSV-1) ICP22 binds to CD80 and suppresses CD80 expression in vitro and in vivo. Similar to ICP22, the cellular costimulatory molecules CD28, CTLA4, and PD-L1 also bind to CD80. In this study, we asked whether, similar to ICP22-null virus, the absence of these costimulatory molecules will reduce HSV-1 infectivity. To test our hypothesis, CD28−/−, CD28−/− CTLA4−/−, PD-L1−/−, and wild-type control BALB/c mice were ocularly infected with HSV-1 strain KOS. Levels of virus replication in the eye, corneal scarring (CS), latency, and reactivation in infected mice were determined. Expression of different genes in the trigeminal ganglia (TG) of latently infected mice was also determined by NanoString and quantitative reverse transcription-PCR (qRT-PCR). In the absence of costimulatory molecules, latency levels were higher than those in wild-type control mice, but despite higher latency, a significant number of TG from infected knockout mice did not reactivate. Reduced reactivation correlated with downregulation of 26 similar cellular genes that are associated with inflammatory signaling and innate immune responses. These results suggest that lower reactivation directly correlates with lower expression of interferon signaling. Thus, despite having different modes of actions, we identified a similar function for CD28, CTLA4, and PD-L1 in HSV-1 reactivation that is dependent on their interactions with CD80. Therefore, blocking these interactions could be a therapeutic target for HSV-1-induced reactivation. IMPORTANCE Costimulatory molecules play an important role in activation of T cell responses, and T cells contribute to HSV-1-induced eye disease in the host. Similar to HSV-1 ICP22, the cellular costimulatory molecules CD28, CTLA4, and PD-L1 also bind to CD80. In this study, we have shown that the absence of these costimulatory molecules significantly reduced HSV-1 ex vivo reactivation. Therefore, inhibiting the binding of costimulatory molecules to CD80 could be used to reduce reactivation and, consequently, HSV-1-induced eye disease.
format	article
author	Harry H. Matundan Ujjaldeep Jaggi Jack Yu Omid Akbari Homayon Ghiasi
author_facet	Harry H. Matundan Ujjaldeep Jaggi Jack Yu Omid Akbari Homayon Ghiasi
author_sort	Harry H. Matundan
title	Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation
title_short	Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation
title_full	Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation
title_fullStr	Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation
title_full_unstemmed	Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation
title_sort	absence of cd28-ctla4-pd-l1 costimulatory molecules reduces herpes simplex virus 1 reactivation
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/9776df8d282c476986c1363b6893cbc8
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Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation

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