Neutrophils and viral-induced neurologic disease

Abstract

Infection of the central nervous system (CNS) by neurotropic viruses represents an increasing worldwide problem in terms of morbidity and mortality for people of all ages. Although unique structural features of the blood-brain-barrier (BBB) provide a physical and physiological barrier, a number of neurotropic viruses are able to enter the CNS resulting in a variety of pathological outcomes. Nonetheless, antigen-specific lymphocytes are ultimately able to accumulate within the CNS and contribute to defense by reducing or eliminating the invading viral pathogen. Alternatively, infiltration of activated cells of the immune system may be detrimental, as these cells can contribute to neuropathology that may result in long-term cellular damage or death. More recently, myeloid cells e.g. neutrophils have been implicated in contributing to both host defense and disease in response to viral infection of the CNS. This review highlights recent studies using coronavirus-induced neurologic disease as a model to determine how neutrophils affect effective control of viral replication as well as demyelination.

Keywords: Chemokine receptors; Chemokines; Mouse hepatitis virus; Neutrophils.

Fig. 1

Derivation and characterization of a mouse model in which CXCL1 expression within the CNS is under control of a Doxycycline promoter. (A) Cartoon depiction of experimental strategy to generate double (dbl) transgenic (tg) mice in which expression of mouse CXCL1 is under control of the GFAP promoter upon doxycycline treatment. (B) Cortex tissue from double tg and single tg post-natal day 1 (P1) mice was dissociated and enriched for astrocytes. Following 24-h of Dox (100 ng/ml) treated double tg astrocyte cultures, immunofluorescence confirmed CXCL1 expression within GFAP-positive astrocytes while vehicle treatment yielded no CXCL1 fluorescence. (C) Within the SC, dox-treated double tg mice had statistically significant increases in CXCL1 mRNA expression over Dox-treated single tg mice at days 7 and 12 p.i. Images adapted from with permission.

Fig. 2

Elevated CXCL1 expression is associated with increased demyelination. Histopathological analysis of spinal cords of double tg mice reveals an increase in demyelination. (A) Representative luxol fast blue (LFB)-stained spinal cords reveals increased (p < 0.05) demyelination in JHMV-infected Dox-treated double tg mice compared to single tg controls. (B) Flow cytometric analysis revealed a significant increase in the frequency and total number of neutrophils within the spinal cord of JHMV-infected Dox-treated double tg mice compared to single tg mice. Representative immunofluorescence staining further demonstrated a significant increase in the number of Ly6B.2-positive neutrophils (yellow arrowheads) within the spinal cord parenchyma of JHMV-infected double tg compared to single tg mice; red arrowheads indicate neutrophils located within the spinal cord meninges. Quantification of neutrophils within the spinal cords indicated an overall increase (p < 0.05) in Dox-treated double tg mice compared to Dox-treated single tg mice. (C) Representative LFB-stained spinal cord sections from JHMV-infected double tg mice treated with either control IgG2a or anti-Ly6G antibody between days 3–15 p.i. Quantification of the severity of demyelination revealed reduced white matter damage in mice treated with anti-Ly6G antibody compared to mice treated with isogenic IgG2a control antibody. Images adapted from with permission.