Pathogenesis of Semliki Forest Virus Encephalitis

The severity of West Nile virus (WNV) infection in immunocompetent animals is highly strain dependent, ranging from avirulent to highly neuropathogenic. Here, we investigate the nature of this strain-specific restriction by analyzing the replication of avirulent (WNV-MAD78) and highly virulent (WNV-NY) strains in neurons, astrocytes, and microvascular endothelial cells, which comprise the neurovascular unit within the central nervous system (CNS). We demonstrate that WNV-MAD78 replicated in and traversed brain microvascular endothelial cells as efficiently as WNV-NY. Likewise, similar levels of replication were detected in neurons. Thus, WNV-MAD78's nonneuropathogenic phenotype is not due to an intrinsic inability to replicate in key target cells within the CNS. In contrast, replication of WNV-MAD78 was delayed and reduced compared to that of WNV-NY in astrocytes. The reduced susceptibility of astrocytes to WNV-MAD78 was due to a delay in viral genome replication and an interferon-independent reduction in cell-to-cell spread. Together, our data suggest that astrocytes regulate WNV spread within the CNS and therefore are an attractive target for ameliorating WNV-induced neuropathology.

Section: Discussionsupporting

confidence: 82%

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

Hussmann

Samuel

Kim

et al. 2013

“…As with the AR339 strain of SV, infection of neonatal mice with the A7(74) strain of SFV leads to fatal encephalitis, but mice that are at least 2 weeks of age recover uneventfully (44). A7(74) replicates productively, spreads efficiently, and leads to the death of neurons during axonogenesis and synaptogenesis, whereas replication is restricted in mature neurons (14,15,43). Type 3 reovirus, induces an acute necrotizing and lethal encephalitis in newborn mice but a nonfatal infection in older animals (39).…”

Section: Discussionmentioning

confidence: 99%

“…Age-dependent resistance to virus replication is also a characteristic of a number of other neurotropic viruses, including Semliki Forest virus (SFV) (14,15,43), Japanese encephalitis virus (JEV) (32,42,56), mouse hepatitis virus (48), measles virus (19,22), reovirus (39), blue-tongue virus (5), parvoviruses (6, 7), influenza virus (26), and herpesviruses (1,2,40,55). As with the AR339 strain of SV, infection of neonatal mice with the A7(74) strain of SFV leads to fatal encephalitis, but mice that are at least 2 weeks of age recover uneventfully (44).…”

Section: Discussionmentioning

confidence: 99%

Characterization of an In Vitro Model of Alphavirus Infection of Immature and Mature Neurons

Vernon

Griffin

2005

Terminally differentiated, mature neurons are essential cells that are not easily regenerated. Neurotropic viruses, such as Sindbis virus (SV), cause encephalomyelitis through their ability to replicate in neurons. SV causes the death of immature neurons, while mature neurons can often survive infection. The lack of a reproducible and convenient neuronal cell culture system has hindered a detailed study of the differences in levels of virus replication between immature and mature neurons and the molecular events involved in virus clearance from mature neurons. We have characterized SV replication in immortalized CSM14.1 rat neuronal cells that can be differentiated into neurons. During differentiation, CSM14.1 cells ceased dividing, developed neuronal morphology, and expressed neuron-specific cell markers. SV infection of undifferentiated CSM14.1 cells was efficient and resulted in high levels of virus replication and cell death. SV infection of differentiated CSM14.1 cells was less efficient and resulted in the production of 10-to 100-fold less virus and cell survival. In undifferentiated cells, SV induced a rapid shutdown of cellular protein synthesis and pE2 was efficiently processed to E2 (ratio of E2 to pE2, 2.14). In differentiated cells, the SV-induced shutdown of cellular protein synthesis was transient and pE2 was the primary form of E2 in cells (ratio of E2 to pE2, 0.0426). We conclude that age-dependent restriction of virus replication is an intrinsic property of maturing neurons and that the CSM14.1 cell line is a convenient model system for investigating the interactions of alphaviruses with neurons at various stages of differentiation.Viral encephalitis due to infection with arthropod-borne viruses is an important cause of mortality and often results in significant long-term neurological deficits in those that survive (8,31,46). The enveloped, message-sense RNA virus Sindbis virus (SV) is the prototype alphavirus in the family Togaviridae and is related to viruses known to cause encephalitis and arthritis in humans (47). Neurons are the primary target cell for SV in mice (28), and the outcome of infection is determined by both host and viral factors (20,21,37,50,52). An important host determinant is the maturity of the neuronal population infected. Immature animals replicate virus in the central nervous system (CNS) to higher titers than mature animals and are highly susceptible to fatal disease, dying within 3 to 4 days after infection (20,29,37). Adult animals infected with the same strain of SV survive and, in the absence of a virus-specific immune response, develop persistent infection (20, 34). Immunocompetent mature animals can recover from infection and clear virus from the CNS through noncytolytic mechanisms involving anti-viral glycoprotein antibody (34) and gamma interferon (3). However, an understanding of the mechanisms underlying these virus-host interactions has been hampered by the lack of a convenient in vitro system for study.The availability of a reproducible and convenient in vit...

“…However, this paradigm is not universal, and several studies have indicated a significant role for antigen-specific T cells in organ pathology. Thus, cellular injury as a consequence of T-cellmediated inflammation and/or the destruction of virus-infected target cells by cytotoxic T cells has been associated with pathology in several experimental models and human diseases, including lethal viral infections of the central nervous system (CNS) (4,6,8,9,19,21,24,44,45,50,58,65). Although the mechanisms by which T cells participate in the control of viral infection without causing collateral damage (such as neurological deficit) remain poorly defined, a consensus is that the development of tissue pathology coincides with a massive extravasation of mononuclear cells to the site of virus replication, a process regulated by the increased expression of adhesion molecules on the nearby vasculature (62,68).…”

mentioning

confidence: 99%

Regulation of Immune Response and Inflammatory Reactions against Viral Infection by VCAM-1

Zhang

Huang

et al. 2008

The migration of activated antigen-specific immune cells to the target tissues of virus replication is controlled by the expression of adhesion molecules on the vascular endothelium that bind to ligands on circulating lymphocytes. Here, we demonstrate that the adhesion pathway mediated by vascular cell adhesion molecule 1 (VCAM-1) plays a role in regulating T-cell-mediated inflammation and pathology in nonlymphoid tissues, including the central nervous system (CNS) during viral infection. The ablation of VCAM-1 expression from endothelial and hematopoietic cells using a loxP-Cre recombination strategy had no major effect on the induction or overall tissue distribution of antigen-specific T cells during a systemic infection with lymphocytic choriomeningitis virus (LCMV), except in the case of lung tissue. However, enhanced resistance to lethal LCM and the significantly reduced magnitude and duration of footpad swelling observed in VCAM-1 mutant mice compared to B6 controls suggest a significant role for VCAM-1 in promoting successful local inflammatory reactions associated with efficient viral clearance and even life-threatening immunopathology under particular infection conditions. Interestingly, analysis of the infiltrating populations in the brains of intracerebrally infected mice revealed that VCAM-1 deletion significantly delayed migration into the CNS of antigen-presenting cells (macrophages and dendritic cells), which are critical for optimal stimulation of migrating virusspecific CD8؉ T cells initiating a pathological cascade. We propose that the impaired migration of these accessory cells in the brain may explain the improved clinical outcome of infection in VCAM-1 mutant mice. Thus, these results underscore the potential role of VCAM-1 in regulating the immune response and inflammatory reactions against viral infections.