Dataset Information

PD1⁺CCR2⁺CD8⁺ T Cells Infiltrate the Central Nervous System during Acute Japanese Encephalitis Virus Infection.

ABSTRACT: Japanese encephalitis (JE) is a viral encephalitis disease caused by Japanese encephalitis virus (JEV) infection. Uncontrolled inflammatory responses in the central nervous system (CNS) are a hallmark of severe JE. Although the CCR2-CCL2 axis is important for monocytes trafficking during JEV infection, little is known about its role in CNS trafficking of CD8⁺ T cells. Here, we characterized a mouse model of JEV infection, induced via intravenous injection (i.v.) and delineated the chemokines and infiltrating peripheral immune cells in the brains of infected mice. The CNS expression of chemokines, Ccl2, Ccl3, and Ccl5, and their receptors, Ccr2 or Ccr5, was significantly up-regulated after JEV infection and was associated with the degree of JE pathogenesis. Moreover, JEV infection resulted in the migration of a large number of CD8⁺ T cells into the CNS. In the brains of JEV-infected mice, infiltrating CD8⁺ T cells expressed CCR2 and CCR5 and were found to comprise mainly effector T cells (CD44⁺CD62L^-). JEV infection dramatically enhanced the expression of programmed death 1 (PD-1) on infiltrating CD8⁺ T cells in the brain, as compared to that on peripheral CD8⁺ T cells in the spleen. This effect was more pronounced on infiltrating CCR2⁺CD8⁺ T cells than on CCR2^-CD8⁺ T cells. In conclusion, we identified a new subset of CD8⁺ T cells (PD1⁺CCR2⁺CD8⁺ T cells) present in the CNS of mice during acute JEV infection. These CD8⁺ T cells might play a role in JE pathogenesis.

SUBMITTER: Zhang F

PROVIDER: S-EPMC6814683 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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PD1+CCR2+CD8+ T Cells Infiltrate the Central Nervous System during Acute Japanese Encephalitis Virus Infection.

Zhang Fang F Qi Linlin L Li Tong T Li Xiaojing X Yang Dan D Cao Shengbo S Ye Jing J Ye Jing J Wei Bin B Wei Bin B

Virologica Sinica 20190618 5

Japanese encephalitis (JE) is a viral encephalitis disease caused by Japanese encephalitis virus (JEV) infection. Uncontrolled inflammatory responses in the central nervous system (CNS) are a hallmark of severe JE. Although the CCR2-CCL2 axis is important for monocytes trafficking during JEV infection, little is known about its role in CNS trafficking of CD8+ T cells. Here, we characterized a mouse model of JEV infection, induced via intravenous injection (i.v.) and delineated the che ...[more]

PMID: 31215000

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Project description:BACKGROUND:Central nervous system (CNS) infections are important contributors to morbidity and mortality and the causative agents for ~50% patients are never identified. The causative agents of some CNS infections have distinct spatial and temporal patterns. METHODOLOGY/PRINCIPAL FINDINGS:Here we present the results of a spatial epidemiological and ecological analysis of CNS infections in Lao PDR (2003-2011). The data came from hospitalizations for suspected CNS infection at Mahosot Hospital in Vientiane. Out of 1,065 patients, 450 were assigned a confirmed diagnosis. While many communities in Lao PDR are in rural and remote locations, most patients in these data came from villages along major roads. Japanese encephalitis virus ((JEV); n = 94) and Cryptococcus spp. (n = 70) were the most common infections. JEV infections peaked in the rainy season and JEV patients came from villages with higher surface flooding during the same month as admission. JEV infections were spatially dispersed throughout rural areas and were most common in children. Cryptococcus spp. infections clustered near Vientiane (an urban area) and among adults. CONCLUSIONS/SIGNIFICANCE:The spatial and temporal patterns identified in this analysis are related to complex environmental, social, and geographic factors. For example, JEV infected patients came from locations with environmental conditions (surface water) that are suitable to support larger mosquito vector populations. Most patients in these data came from villages that are near major roads; likely the result of geographic and financial access to healthcare and also indicating that CNS diseases are underestimated in the region (especially from more remote areas). As Lao PDR is undergoing major developmental and environmental changes, the space-time distributions of the causative agents of CNS infection will also likely change. There is a major need for increased diagnostic abilities; increased access to healthcare, especially for rural populations; and for increased surveillance throughout the nation.

Project description:BackgroundJapanese encephalitis virus (JEV) is the leading cause of viral encephalitis in Asia. JEV infection of mice and humans can lead to an uncontrolled inflammatory response in the central nervous system (CNS), resulting in a detrimental outcome. Pigs act as important amplification and reservoir hosts, and JEV infection of pigs is mostly subclinical. Information on virus spread in the CNS and immune responses controlling JEV infection in the CNS of pigs, however remains scarce.MethodsNine-week-old pigs were inoculated intranasal or intradermal with a relevant dose of 105 TCID50 of JEV genotype 3 Nakayama strain. Clinical signs were assessed daily, and viral spread was followed by RT-qPCR. mRNA expression profiles were determined to study immune responses in the CNS.ResultsBesides a delay of 2 days to reach the peak viremia upon intranasal compared to intradermal inoculation, the overall virus spread via both inoculation routes was highly similar. JEV appearance in lymphoid and visceral organs was in line with a blood-borne JEV dissemination. JEV showed a particular tropism to the CNS but without the induction of neurological signs. JEV entry in the CNS probably occurred via different hematogenous and neuronal pathways, but replication in the brain was mostly efficiently suppressed and associated with a type I IFN-independent activation of OAS1 expression. In the olfactory bulb and thalamus, where JEV replication was not completely controlled by this mechanism, a short but strong induction of chemokine gene expression was detected. An increased IFNy expression was simultaneously observed, probably originating from infiltrating T cells, correlating with a fast suppression of JEV replication. The chemokine response was however not associated with the induction of a strong inflammatory response, nor was an induction of the NLRP3 inflammasome observed.ConclusionsThese findings indicate that an adequate antiviral response and an attenuated inflammatory response contribute to a favorable outcome of JEV infection in pigs and help to explain the limited neurological disease compared to other hosts. We show that the NLRP3 inflammasome, a key mediator of neurologic disease in mice, is not upregulated in pigs, further supporting its important role in JEV infections.

Dataset Information

PD1⁺CCR2⁺CD8⁺ T Cells Infiltrate the Central Nervous System during Acute Japanese Encephalitis Virus Infection.

Publications

PD1<sup>+</sup>CCR2<sup>+</sup>CD8<sup>+</sup> T Cells Infiltrate the Central Nervous System during Acute Japanese Encephalitis Virus Infection.

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