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

Area of Science:

• Virology
• Immunology
• Neuroscience

Background:

• Chemokines are crucial for immune cell trafficking during infection and inflammation.
• The gamma-herpesvirus gammaHV68 M3 gene product is a secreted protein that binds CC chemokines.

Purpose of the Study:

• To investigate the role of the gammaHV68 M3 gene in viral pathogenesis, specifically in the induction of meningitis.
• To determine if M3 protein influences immune cell infiltration in the central nervous system (CNS).

Main Methods:

• Generation and characterization of an M3 mutant gammaHV68 (gammaHV68-M3.stop).
• Intracerebral inoculation of mice with wild-type gammaHV68, M3 mutant, and control viruses.
• Quantification of viral titers in different organs (brain, spleen, lung).
• Analysis of inflammatory cell infiltrates in the CNS.

Main Results:

• The M3 mutant gammaHV68 was 100-fold less virulent, causing significantly lower viral titers in the brain compared to wild-type virus.
• gammaHV68 infection induced CC chemokine expression and a neutrophilic inflammatory infiltrate in the CNS.
• The M3 mutant induced a predominantly lymphocytic and macrophagic infiltrate, suggesting M3 blocks chemokine-mediated neutrophil recruitment.
• M3 was not essential for viral latency, reactivation, or chronic arteritis induction.

Conclusions:

• The gammaHV68 M3 protein plays a critical role in inducing lethal meningitis, likely by blocking CC chemokine activity.
• M3 functions in a tissue-specific manner during acute infection to modulate CNS inflammatory responses.
• These findings highlight the importance of chemokines in protecting the nervous system against viral infections.