Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs
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(2020) 17:278
RESEARCH
Open Access
Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs Angela D. A. Cornelius1,2†, Shirin Hosseini3,4†, Sarah Schreier5†, David Fritzsch5†, Loreen Weichert1,5, Kristin Michaelsen-Preusse3, Markus Fendt6,7 and Andrea Kröger1,5,7,8*
Abstract Background: Tick-borne encephalitis virus (TBEV) is an important human pathogen that can cause the serious illness tick-borne encephalitis (TBE). Patients with clinical symptoms can suffer from severe meningoencephalitis with sequelae that include cognitive disorders and paralysis. While less than 30% of patients with clinical symptoms develop meningoencephalitis, the number of seropositive individuals in some regions indicates a much higher prevalence of TBEV infections, either with no or subclinical symptoms. The functional relevance of these subclinical TBEV infections and their influence on brain functions, such as learning and memory, has not been investigated so far. Methods: To compare the effect of low and high viral replication in the brain, wildtype and Irf-7−/− mice were infected with Langat virus (LGTV), which belongs to the TBEV-serogroup. The viral burden was analyzed in the olfactory bulb and the hippocampus. Open field, elevated plus maze, and Morris water maze experiments were performed to determine the impact on anxiety-like behavior, learning, and memory formation. Spine density of hippocampal neurons and activation of microglia and astrocytes were analyzed. Results: In contrast to susceptible Irf-7−/− mice, wildtype mice showed no disease signs upon LGTV infection. Detection of viral RNA in the olfactory bulb revealed CNS infections in wildtype and Irf-7−/− mice. Very low levels of viral replication were detectable in the hippocampus of wildtype mice. Although wildtype mice develop no disease signs, they showed reduced anxiety-like behavior and impaired memory formation, whereas Irf-7−/− mice were not affected. This impairment was associated with a significant decrease in spine density of neurons in the hippocampal CA1 region of wildtype mice. Microglia activation and astrogliosis were detected in the hippocampus. Conclusion: In this study, we demonstrate that subclinical infections by viruses from the TBEV-serogroup affected anxiety-like behavior. Virus replication in the olfactory bulb induced far-reaching effects on hippocampal neuron morphology and impaired hippocampus-dependent learning and memory formation. Keywords: Tick-borne encephalitis virus, Langat virus, Type I interferon, Inapparent infection, Hippocampus, Learning and memory
* Correspondence: [email protected] † Angela D. A. Cornelius, Shirin Hosseini, Sarah Schreier and David Fritzsch contributed equally to this work. 1 Innate Immunity and Infection, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany 5 Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany Full list of author information is available a
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