Lethal Silver-Haired Bat Rabies Virus Infection Can Be Prevented by Opening the Blood-Brain Barrier

The neurotropic rabies virus (RABV) has developed several evasive strategies, including immunoevasion, to successfully infect the nervous system (NS) and trigger a fatal encephalomyelitis. Here we show that expression of LGP2, a protein known as either a positive or negative regulator of the RIG-I-mediated innate immune response, is restricted in the NS. We used a new transgenic mouse model (LGP2 TG) overexpressing LGP2 to impair the innate immune response to RABV and thus revealed the role of the RIG-I-mediated innate immune response in RABV pathogenesis. After infection, LGP2 TG mice exhibited reduced expression of inflammatory/ chemoattractive molecules, beta interferon (IFN-␤), and IFN-stimulated genes in their NS compared to wild-type (WT) mice, demonstrating the inhibitory function of LGP2 in the innate immune response to RABV. Surprisingly, LGP2 TG mice showed more viral clearance in the brain and lower morbidity than WT mice, indicating that the host innate immune response, paradoxically, favors RABV neuroinvasiveness and morbidity. LGP2 TG mice exhibited similar neutralizing antibodies and microglia activation to those of WT mice but showed a reduction of infiltrating CD4؉ T cells and less disappearance of infiltrating CD8 ؉ T cells. This occurred concomitantly with reduced neural expression of the IFN-inducible protein B7-H1, an immunoevasive protein involved in the elimination of infiltrated CD8 ؉ T cells. Our study shows that the host innate immune response favors the infiltration of T cells and, at the same time, promotes CD8؉ T cell elimination. Thus, to a certain extent, RABV exploits the innate immune response to develop its immunoevasive strategy.Rabies virus (RABV) is a negative-strand RNA virus that infects mainly neurons and exploits the nervous system (NS) network to ensure its progression from the site of entry (bite site) to the site of exit, the salivary glands. The virulence of RABV relies on several factors, such as its capacity to avoid premature death of infected neurons and its property of escaping the immune response. Different mechanisms have been proposed to explain the inefficiency of the immune response against RABV infection (24). RABV infection induces immune unresponsiveness (6, 53), limits T cell infiltration into the NS (44), and keeps the blood-brain barrier tightly closed (37,45). It also promotes the destruction of migratory CD8 ϩ T cells in the NS through the upregulation of immunoevasive proteins such as B7-H1 (1, 27, 28). B7-H1 (also known as PD-1 ligand and CD274) is interferon (IFN) inducible and is usually expressed by immune cells. It contributes to dampening proliferation, cytokine production, and cytolytic activity (20,28,48).During its migration in the NS, RABV has to deal with the first line of defense against pathogens: the host innate immune response. RABV infection activates the innate immune sensor RIG-I, and likely also 22), and triggers classical type I IFN, chemoattractive, and inflammatory responses in infected cells, which could be responsible for set...

Section: T Cells and Less Disappearance Of Infiltrating Cd8 ؉ T Cellsmentioning

confidence: 99%

Ambivalent Role of the Innate Immune Response in Rabies Virus Pathogenesis

Chopy

Pothlichet

Lafage

et al. 2011

“…Due to such cases and to research using animal models of RABV infection (6)(7)(8), many believe that the immune system may be capable of clearing RABV from the brain without causing irreparable immunopathology. It is clear, however, that therapeutic intervention will be necessary in the vast majority of cases.…”

mentioning

confidence: 99%

Expression of Interferon Gamma by a Recombinant Rabies Virus Strongly Attenuates the Pathogenicity of the Virus via Induction of Type I Interferon

Barkhouse

Garcia

Bongiorno

et al. 2015

Self Cite

Previous animal model experiments have shown a correlation between interferon gamma (IFN-␥) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-␥ by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-␥ gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBN␥. Morbidity and mortality were monitored in mice infected intranasally with SPBN␥ or SPBN(؊) control virus to determine the degree of attenuation caused by the expression of IFN-␥. Incorporation of IFN-␥ into the rabies virus genome highly attenuated the virus. SPBN␥ has a 50% lethal dose (LD 50) more than 100-fold greater than SPBN(؊). In vitro and in vivo mouse experiments show that SPBN␥ infection enhances the production of type I interferons. Furthermore, knockout mice lacking the ability to signal through the type I interferon receptor (IFNAR ؊/؊ ) cannot control the SPBN␥ infection and rapidly die. These data suggest that IFN-␥ production has antiviral effects in rabies, largely due to the induction of type I interferons. IMPORTANCE Survival from rabies is dependent upon the early control of virus replication and spread. Once the virus reaches the central nervous system (CNS), this becomes highly problematic. Studies of CNS immunity to RABV have shown that control of replication begins at the onset of T cell entry and IFN-␥ production in the CNS prior to the appearance of virus-neutralizing antibodies.Moreover, antibody-deficient mice are able to control but not clear attenuated RABV from the CNS. We find here that IFN-␥ triggers the early production of type I interferons with the expected antiviral effects. We also show that engineering a lethal rabies virus to express IFN-␥ directly in the infected tissue reduces rabies virus replication and spread, limiting its pathogenicity in normal and immunocompromised mice. Therefore, vector delivery of IFN-␥ to the brain may have the potential to treat individuals who would otherwise succumb to infection with rabies virus. R abies virus (RABV) is the type species of the Lyssavirus genus in the Rhabdoviridae family. Its small, negative-stranded RNA genome contains only five true genes (1, 2). Although relatively simple, this zoonotic virus has a devastating impact worldwide. The majority of human rabies deaths occur in children in the developing world, and it is estimated that at least 55,000 humans die of rabies each year in Africa and Asia alone (3).Although RABV infection historically has been viewed as a death sentence once the virus reaches the brain, there is a small but growing number of humans who have survived rabies even though the virus entered the brain (4, 5). Due to such cases and to research using animal models of RABV infection (6-8), many believe that the immune system may be cap...

“…Generally, BBB integrity is compromised during infection, and this BBB disruption dictates the aforementioned alterations and brain injury in several neurotropic viruses (3)(4)(5)(6). Though most studies demonstrated the detrimental consequences of BBB breakdown during neurotropic virus infection, the opening of the BBB also prevents certain lethal viral CNS infections (7).…”

mentioning

confidence: 99%

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Chen

et al. 2014

h Though the compromised blood-brain barrier (BBB) is a pathological hallmark of Japanese encephalitis-associated neurological sequelae, the underlying mechanisms and the specific cell types involved are not understood. BBB characteristics are induced and maintained by cross talk between brain microvascular endothelial cells and neighboring elements of the neurovascular unit. In this study, we show a potential mechanism of disruption of endothelial barrier integrity during the course of Japanese encephalitis virus (JEV) infection through the activation of neighboring pericytes. We found that cultured brain pericytes were susceptible to JEV infection but were without signs of remarkable cytotoxicity. JEV-infected pericytes were found to release biologically active molecules which activated ubiquitin proteasome, degraded zonula occludens-1 (ZO-1), and disrupted endothelial barrier integrity in cultured brain microvascular endothelial cells. Infection of pericytes with JEV was found to elicit elevated production of interleukin-6 (IL-6), which contributed to the aforementioned endothelial changes. We further demonstrated that ubiquitin-protein ligase E3 component n-recognin-1 (Ubr 1) was a key upstream regulator which caused proteasomal degradation of ZO-1 downstream of IL-6 signaling. During JEV central nervous system trafficking, endothelial cells rather than pericytes are directly exposed to cell-free viruses in the peripheral bloodstream. Therefore, the results of this study suggest that subsequent to primary infection of endothelial cells, JEV infection of pericytes might contribute to the initiation and/or augmentation of Japanese encephalitis-associated BBB breakdown in concerted action with other unidentified barrier disrupting factors.