Critical role for a high-affinity chemokine-binding protein in γ-herpesvirus-induced lethal meningitis

Victor Van Berkel, Beth Levine, Sharookh B. Kapadia, James E. Goldman, Samuel H. Speck, Herbert W. Virgin IV

Research output: Contribution to journalArticle

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Abstract

Chemokines are involved in recruitment and activation of hematopoietic cells in sites of infection and inflammation. The M3 gene of the γ-herpesvirus γHV68 encodes an abundant secreted protein that binds CC chemokines with high affinity. We report here that this gene is essential for efficient induction of lethal meningitis by γHV68. An M3 mutant γHV68 -M3.stop) was 100-fold less virulent than wild-type or marker rescue control (γHV68-M3.MR) viruses after intracerebral inoculation. After intracerebral inoculation, γHV68-M3.stop grew to lower titers than γHV68 or γHV68 or γHV68-M3.MR in the brain but spread to and grew normally in the spleen and lung. Expression of several CC chemokines was significantly induced in the CNS by γHV68 infection. Consistent with M3 acting by blockade of CC chemokine action, γHV68 induced a neutrophilic meningeal inflammatory infiltrate, while γHV68-M3.stop induced an infiltrate in which lymphocytes and macrophages predominated. In contrast to the important role of M3 in lethal meningitis, M3 was not required for establishment or reactivation from latent infection or induction of chronic arteritis. These data suggest a role for chemokines in the protection of the nervous system from viral infection and that the M3 protein acts in a tissue-specific fashion during acute but not chronic γHV68 infection to limit CC chemokine-induced inflammatory responses.

Original languageEnglish (US)
Pages (from-to)905-914
Number of pages10
JournalJournal of Clinical Investigation
Volume109
Issue number7
DOIs
StatePublished - 2002

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CC Chemokines
Herpesviridae
Meningitis
Chemokines
Carrier Proteins
Infection
Arteritis
Essential Genes
Virus Diseases
Nervous System
Proteins
Spleen
Macrophages
Lymphocytes
Viruses
Inflammation
Lung
Brain
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Critical role for a high-affinity chemokine-binding protein in γ-herpesvirus-induced lethal meningitis. / Van Berkel, Victor; Levine, Beth; Kapadia, Sharookh B.; Goldman, James E.; Speck, Samuel H.; Virgin IV, Herbert W.

In: Journal of Clinical Investigation, Vol. 109, No. 7, 2002, p. 905-914.

Research output: Contribution to journalArticle

Van Berkel, Victor ; Levine, Beth ; Kapadia, Sharookh B. ; Goldman, James E. ; Speck, Samuel H. ; Virgin IV, Herbert W. / Critical role for a high-affinity chemokine-binding protein in γ-herpesvirus-induced lethal meningitis. In: Journal of Clinical Investigation. 2002 ; Vol. 109, No. 7. pp. 905-914.
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