Transgenic CCL2 expression in the central nervous system results in a dysregulated immune response and enhanced lethality after coronavirus infection

Jonathan A Trujillo; Erica L Fleming; Stanley Perlman

doi:10.1128/JVI.03089-12

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Transgenic CCL2 expression in the central nervous system results in a dysregulated immune response and enhanced lethality after coronavirus infection

Journal article

Open access

Peer reviewed

Transgenic CCL2 expression in the central nervous system results in a dysregulated immune response and enhanced lethality after coronavirus infection

Jonathan A Trujillo, Erica L Fleming and Stanley Perlman

Journal of virology, Vol.87(5), pp.2376-2389

03/2013

DOI: 10.1128/JVI.03089-12

PMCID: PMC3571407

PMID: 23269787

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Abstract

Chemokine (C-C motif) ligand 2 (CCL2), a chemoattractant for macrophages, T cells, and cells expressing CCR2, is upregulated during acute and chronic inflammation. CCL2 has been implicated in both proinflammatory and anti-inflammatory responses and has been suggested as a target for therapy in some inflammatory disorders. To examine the role of CCL2 during virus infection, we infected mice transgenically expressing CCL2 in the central nervous system (CCL2 Tg) with an attenuated neurotropic coronavirus (rJ2.2 strain of mouse hepatitis virus). Infection of wild-type mice with rJ2.2 results in mild acute encephalitis, followed by a nonlethal, chronic demyelinating disease. Proinflammatory innate and adaptive immune responses mediate virus clearance. In marked contrast, CCL2 Tg mice infected with rJ2.2 ineffectively cleared virus and rapidly succumbed to the infection. CCL2 Tg mice mounted a dysregulated immune response, characterized by augmented accumulation of regulatory Foxp3(+)CD4(+) T cells and of nitric-oxide- and YM-1-expressing macrophages and microglia, suggestive of mixed M1/M2 macrophage activation. Further, macrophages from infected CCL2 Tg brains relative to non-Tg controls were less activated/mature, expressing lower levels of major histocompatibility complex class II (MHC-II), CD86, and CD40. Collectively, these results show that persistent CCL2 overexpression establishes and sustains an immunological milieu that is both inflammatory and immunosuppressive and predisposes mice to a defective immune response to a minimally lethal virus.

Microglia - metabolism

Brain - virology

Coronavirus Infections - mortality

Brain - metabolism

CD4-Positive T-Lymphocytes - immunology

Murine hepatitis virus - immunology

CD40 Antigens - biosynthesis

Inflammation - metabolism

Microglia - immunology

Doxorubicin - analogs & derivatives

Chemokine CCL2 - metabolism

Macrophages - immunology

Forkhead Transcription Factors - biosynthesis

Nitric Oxide - biosynthesis

Mice, Inbred C57BL

Chemokine CCL2 - genetics

Mice, Transgenic

Inflammation - immunology

Coronavirus Infections - immunology

Macrophage Activation

Immunosuppression

Macrophages - metabolism

Animals

B7-2 Antigen - biosynthesis

Histocompatibility Antigens Class II - immunology

Coronavirus Infections - virology

Mice

Histocompatibility Antigens Class II - genetics

Brain - immunology

Doxorubicin - biosynthesis

Details

Title: Subtitle: Transgenic CCL2 expression in the central nervous system results in a dysregulated immune response and enhanced lethality after coronavirus infection
Creators: Jonathan A Trujillo - Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, USA
Erica L Fleming
Stanley Perlman
Resource Type: Journal article
Publication Details: Journal of virology, Vol.87(5), pp.2376-2389
DOI: 10.1128/JVI.03089-12
PMID: 23269787
PMCID: PMC3571407
NLM abbreviation: J Virol
ISSN: 0022-538X
eISSN: 1098-5514
Publisher: United States
Grant note: T32 GM007337 / NIGMS NIH HHS R01 NS036592 / NINDS NIH HHS
Language: English
Date published: 03/2013
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9983777472102771

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