Comparative analysis of immune responses to Russian spring–summer encephalitis and Omsk hemorrhagic fever viruses in mouse models

Tigabu, Bersabeh; Juelich, Terry L.; Holbrook, Michael R.

doi:10.1016/j.virol.2010.08.021

Cited by 20 publications

(21 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We did not find significant amounts of virus in the brain or lungs, which also corresponds with what has been observed for OHFV [26]. Similar to what has been observed by others upon OHFV infection, AHFV induces a pro-inflammatory cytokine response early in the kidney and spleen, and differences in some hematologic parameters, namely leukopenia combined with decreases in lymphocytes, RBC count, hemoglobin levels, and hematocrit [28], indicating that AHFV Zaki-1 causes a sub-clinical hemorrhagic-like syndrome. Lethal infection of mice with TBEV is not associated with elevated body temperatures [40], while animals infected with KFDV in our study had transient fever during the later phase of disease.…”

Section: Discussionsupporting

confidence: 91%

Comparative Pathogenesis of Alkhumra Hemorrhagic Fever and Kyasanur Forest Disease Viruses in a Mouse Model

et al. 2014

Self Cite

View full text Add to dashboard Cite

Kyasanur Forest disease virus (KFDV) and Alkhumra hemorrhagic fever virus (AHFV) are genetically closely-related, tick-borne flaviviruses that cause severe, often fatal disease in humans. Flaviviruses in the tick-borne encephalitis (TBE) complex typically cause neurological disease in humans whereas patients infected with KFDV and AHFV predominately present with hemorrhagic fever. A small animal model for KFDV and AHFV to study the pathogenesis and evaluate countermeasures has been lacking mostly due to the need of a high biocontainment laboratory to work with the viruses. To evaluate the utility of an existing mouse model for tick-borne flavivirus pathogenesis, we performed serial sacrifice studies in BALB/c mice infected with either KFDV strain P9605 or AHFV strain Zaki-1. Strikingly, infection with KFDV was completely lethal in mice, while AHFV caused no clinical signs of disease and no animals succumbed to infection. KFDV and high levels of pro-inflammatory cytokines were detected in the brain at later time points, but no virus was found in visceral organs; conversely, AHFV Zaki-1 and elevated levels of cytokines were found in the visceral organs at earlier time points, but were not detected in the brain. While infection with either virus caused a generalized leukopenia, only AHFV Zaki-1 induced hematologic abnormalities in infected animals. Our data suggest that KFDV P9605 may have lost its ability to cause hemorrhagic disease as the result of multiple passages in suckling mouse brains. However, likely by virtue of fewer mouse passages, AHFV Zaki-1 has retained the ability to replicate in visceral organs, cause hematologic abnormalities, and induce pro-inflammatory cytokines without causing overt disease. Given these striking differences, the use of inbred mice and the virus passage history need to be carefully considered in the interpretation of animal studies using these viruses.

show abstract

Section: Discussionsupporting

confidence: 91%

Comparative Pathogenesis of Alkhumra Hemorrhagic Fever and Kyasanur Forest Disease Viruses in a Mouse Model

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similarly to our study, the extent of BBB permeability was in direct association with increased levels of cytokines, clinical sickness, and virus titer in the brains of JEV-infected mice [27]. Robust release of some of the investigated cytokines/chemokines in the brains of TBEV-infected mice has also been recently demonstrated by other authors [28], [29]. It is known that the overproduction of proinflammatory cytokines, including TNF-α and IL-6, enhances neuronal injury [30] and increases BBB permeability [31], [32].…”

Section: Discussionsupporting

confidence: 87%

Breakdown of the Blood-Brain Barrier during Tick-Borne Encephalitis in Mice Is Not Dependent on CD8+ T-Cells

et al. 2011

View full text Add to dashboard Cite

Tick-borne encephalitis (TBE) virus causes severe encephalitis with serious sequelae in humans. The disease is characterized by fever and debilitating encephalitis that can progress to chronic illness or fatal infection. In this study, changes in permeability of the blood-brain barrier (BBB) in two susceptible animal models (BALB/c, and C57Bl/6 mice) infected with TBE virus were investigated at various days after infection by measuring fluorescence in brain homogenates after intraperitoneal injection of sodium fluorescein, a compound that is normally excluded from the central nervous system. We demonstrate here that TBE virus infection, in addition to causing fatal encephalitis in mice, induces considerable breakdown of the BBB. The permeability of the BBB increased at later stages of TBE infection when high virus load was present in the brain (i.e., BBB breakdown was not necessary for TBE virus entry into the brain), and at the onset of the first severe clinical symptoms of the disease, which included neurological signs associated with sharp declines in body weight and temperature. The increased BBB permeability was in association with dramatic upregulation of proinflammatory cytokine/chemokine mRNA expression in the brain. Breakdown of the BBB was also observed in mice deficient in CD8+ T-cells, indicating that these cells are not necessary for the increase in BBB permeability that occurs during TBE. These novel findings are highly relevant to the development of future therapies designed to control this important human infectious disease.

show abstract

“…Thus, our findings demonstrate that a similar chemokine expres- sion pattern during viral encephalitis is evident regardless of the pathogen. Similar, but more limited, observations have been made for a number of viruses that cause encephalitis, including herpes simplex virus 1 (42), tick-borne encephalitis virus (43), and lyssaviruses (44). Based on our FACS data, we have demonstrated that mostly CD8 ϩ T cells and monocytes infiltrate the brain during SFV infection.…”

Section: Discussionsupporting

confidence: 84%

Defining the Chemokine Basis for Leukocyte Recruitment during Viral Encephalitis

Michlmayr

McKimmie

Pingen

et al. 2014

J Virol

View full text Add to dashboard Cite

The encephalitic response to viral infection requires local chemokine production and the ensuing recruitment of immune and inflammatory leukocytes. Accordingly, chemokine receptors present themselves as plausible therapeutic targets for drugs aimed at limiting encephalitic responses. However, it remains unclear which chemokines are central to this process and whether leukocyte recruitment is important for limiting viral proliferation and survival in the brain or whether it is predominantly a driver of coincident inflammatory pathogenesis. Here we examine chemokine expression and leukocyte recruitment in the context of avirulent and virulent Semliki Forest virus (SFV) as well as West Nile virus infection and demonstrate rapid and robust expression of a variety of inflammatory CC and CXC chemokines in all models. On this basis, we define a chemokine axis involved in leukocyte recruitment to the encephalitic brain during SFV infection. CXCR3 is the most active; CCR2 is also active but less so, and CCR5 plays only a modest role in leukocyte recruitment. Importantly, inhibition of each of these receptors individually and the resulting suppression of leukocyte recruitment to the infected brain have no effect on viral titer or survival following infection with a virulent SFV strain. In contrast, simultaneous blockade of CXCR3 and CCR2 results in significantly reduced mortality in response to virulent SFV infection. In summary, therefore, our data provide an unprecedented level of insight into chemokine orchestration of leukocyte recruitment in viral encephalitis. Our data also highlight CXCR3 and CCR2 as possible therapeutic targets for limiting inflammatory damage in response to viral infection of the brain. IMPORTANCEBrain inflammation (encephalitis) in response to viral infection can lead to severe illness and even death. This therefore represents an important clinical problem and one that requires the development of new therapeutic approaches. Central to the pathogenesis of encephalitis is the recruitment of inflammatory leukocytes to the infected brain, a process driven by members of the chemokine family. Here we provide an in-depth analysis of the chemokines involved in leukocyte recruitment to the virally infected brain and demonstrate that simultaneous blockade of two of these receptors, namely, CXCR3 and CCR2, does not alter viral titers within the brain but markedly reduces inflammatory leukocyte recruitment and enhances survival in a murine model of lethal viral encephalitis. Our results therefore highlight chemokine receptors as plausible therapeutic targets in treating viral encephalitis.

show abstract

Comparative analysis of immune responses to Russian spring–summer encephalitis and Omsk hemorrhagic fever viruses in mouse models

Cited by 20 publications

References 29 publications

Comparative Pathogenesis of Alkhumra Hemorrhagic Fever and Kyasanur Forest Disease Viruses in a Mouse Model

Comparative Pathogenesis of Alkhumra Hemorrhagic Fever and Kyasanur Forest Disease Viruses in a Mouse Model

Breakdown of the Blood-Brain Barrier during Tick-Borne Encephalitis in Mice Is Not Dependent on CD8+ T-Cells

Defining the Chemokine Basis for Leukocyte Recruitment during Viral Encephalitis

Contact Info

Product

Resources

About