The Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice

Autophagy has been shown to play an essential role in defending against intracellular bacteria, viruses, and parasites. Mounting evidence suggests that autophagy plays different roles in the infection process of different pathogens. Until now, there has been no conclusive evidence regarding whether...

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Autores principales:	Jielin Wang, Xiaocen Wang, Pengtao Gong, Fu Ren, Xin Li, Nan Zhang, Xu Zhang, Xichen Zhang, Jianhua Li
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Neospora caninum autophagy mTOR TLR2 anti-infection innate immune Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c43b94f792004b568ead1b2e851024a7
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spelling	oai:doaj.org-article:c43b94f792004b568ead1b2e851024a72021-12-01T07:24:27ZThe Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice2235-298810.3389/fcimb.2021.788340https://doaj.org/article/c43b94f792004b568ead1b2e851024a72021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcimb.2021.788340/fullhttps://doaj.org/toc/2235-2988Autophagy has been shown to play an essential role in defending against intracellular bacteria, viruses, and parasites. Mounting evidence suggests that autophagy plays different roles in the infection process of different pathogens. Until now, there has been no conclusive evidence regarding whether host autophagy is involved in Neospora caninum infection. In the current study, we first monitored the activation of autophagy by N. caninum, which occurred mainly in the early stages of infection, and examined the role of host autophagy in N. caninum infection. Here, we presented evidence that N. caninum induced an increase in autophagic vesicles with double-membrane structures in macrophages at the early stage of infection. LC3-II expression peaked and decreased as infection continued. However, the expression of P62/SQSTM1 showed significant accumulation within 12 h of infection, indicating that autophagic flux was blocked. A tandem fluorescence protein mCherry-GFP-LC3 construct was used to corroborate the impaired autophagic flux. Subsequently, we found that N. caninum infection induced the activation of the TLR2–AKT–mTOR pathways. Further investigation revealed that TLR2–mTOR, accompanied by the blockade of autophagic flux, was responsible for impaired autophagy but was not associated with AKT. In vitro and in vivo, N. caninum replication was strongly blocked by the kinase inhibitor 3-methyladenine (3-MA, autophagy inhibitor). In contrast, rapamycin (Rapa, an autophagy inducer) was able to promote intracellular proliferation and reduce the survival rate of N. caninum-infected mice. On the other hand, the accumulation of autophagosomes facilitated the proliferation of N. caninum. Collectively, our findings suggest that activation of host autophagy facilitates N. caninum replication and may counteract the innate immune response of the host. In short, inhibition of the early stages of autophagy could potentially be a strategy for neosporosis control.Jielin WangJielin WangXiaocen WangPengtao GongFu RenXin LiNan ZhangXu ZhangXichen ZhangJianhua LiFrontiers Media S.A.articleNeospora caninumautophagymTORTLR2anti-infectioninnate immuneMicrobiologyQR1-502ENFrontiers in Cellular and Infection Microbiology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neospora caninum autophagy mTOR TLR2 anti-infection innate immune Microbiology QR1-502
spellingShingle	Neospora caninum autophagy mTOR TLR2 anti-infection innate immune Microbiology QR1-502 Jielin Wang Jielin Wang Xiaocen Wang Pengtao Gong Fu Ren Xin Li Nan Zhang Xu Zhang Xichen Zhang Jianhua Li The Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice
description	Autophagy has been shown to play an essential role in defending against intracellular bacteria, viruses, and parasites. Mounting evidence suggests that autophagy plays different roles in the infection process of different pathogens. Until now, there has been no conclusive evidence regarding whether host autophagy is involved in Neospora caninum infection. In the current study, we first monitored the activation of autophagy by N. caninum, which occurred mainly in the early stages of infection, and examined the role of host autophagy in N. caninum infection. Here, we presented evidence that N. caninum induced an increase in autophagic vesicles with double-membrane structures in macrophages at the early stage of infection. LC3-II expression peaked and decreased as infection continued. However, the expression of P62/SQSTM1 showed significant accumulation within 12 h of infection, indicating that autophagic flux was blocked. A tandem fluorescence protein mCherry-GFP-LC3 construct was used to corroborate the impaired autophagic flux. Subsequently, we found that N. caninum infection induced the activation of the TLR2–AKT–mTOR pathways. Further investigation revealed that TLR2–mTOR, accompanied by the blockade of autophagic flux, was responsible for impaired autophagy but was not associated with AKT. In vitro and in vivo, N. caninum replication was strongly blocked by the kinase inhibitor 3-methyladenine (3-MA, autophagy inhibitor). In contrast, rapamycin (Rapa, an autophagy inducer) was able to promote intracellular proliferation and reduce the survival rate of N. caninum-infected mice. On the other hand, the accumulation of autophagosomes facilitated the proliferation of N. caninum. Collectively, our findings suggest that activation of host autophagy facilitates N. caninum replication and may counteract the innate immune response of the host. In short, inhibition of the early stages of autophagy could potentially be a strategy for neosporosis control.
format	article
author	Jielin Wang Jielin Wang Xiaocen Wang Pengtao Gong Fu Ren Xin Li Nan Zhang Xu Zhang Xichen Zhang Jianhua Li
author_facet	Jielin Wang Jielin Wang Xiaocen Wang Pengtao Gong Fu Ren Xin Li Nan Zhang Xu Zhang Xichen Zhang Jianhua Li
author_sort	Jielin Wang
title	The Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice
title_short	The Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice
title_full	The Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice
title_fullStr	The Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice
title_full_unstemmed	The Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice
title_sort	protective role of tlr2 mediates impaired autophagic flux by activating the mtor pathway during neospora caninum infection in mice
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/c43b94f792004b568ead1b2e851024a7
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The Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice

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