Impaired beta-oxidation increases vulnerability to influenza A infection.

Influenza A virus (IAV) infection casts a significant burden on society. It has particularly high morbidity and mortality rates in patients suffering from metabolic disorders. The aim of this study was to relate metabolic changes with IAV susceptibility using well-characterized inbred mouse models.

Quantitative trait locus mapping identifies a locus linked to striatal dopamine and points to collagen IV alpha-6 chain as a novel regulator of striatal axonal branching in mice.

Dopaminergic neurons (DA neurons) are controlled by multiple factors, many involved in neurological disease. Parkinson's disease motor symptoms are caused by the demise of nigral DA neurons, leading to loss of striatal dopamine (DA). Here, we measured DA concentration in the dorsal striatum of 32 members of Collaborative Cross (CC) family and their eight founder strains.

OP7, a novel influenza A virus defective interfering particle: production, purification, and animal experiments demonstrating antiviral potential.

The novel influenza A virus (IAV) defective interfering particle "OP7" inhibits IAV replication in a co-infection and was previously suggested as a promising antiviral agent. Here, we report a batch-mode cell culture-based production process for OP7. In the present study, a seed virus containing standard virus (STV) and OP7 was used.

Orchestrates Gene Regulatory Variation in Mouse Ventral Midbrain During Aging.

Dopaminergic neurons in the midbrain are of particular interest due to their role in diseases such as Parkinson's disease and schizophrenia. Genetic variation between individuals can affect the integrity and function of dopaminergic neurons but the DNA variants and molecular cascades modulating dopaminergic neurons and other cells types of ventral midbrain remain poorly defined. Three genetically diverse inbred mouse strains - C57BL/6J, A/J, and DBA/2J - differ significantly in their genomes (∼7 million variants), motor and cognitive behavior, and susceptibility to neurotoxins.

A New Synuclein-Transgenic Mouse Model for Early Parkinson's Reveals Molecular Features of Preclinical Disease.

Understanding Parkinson's disease (PD), in particular in its earliest phases, is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end-stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful in investigating PD progression.

Complex Genetic Architecture Underlies Regulation of Influenza-A-Virus-Specific Antibody Responses in the Collaborative Cross.

Host genetic factors play a fundamental role in regulating humoral immunity to viral infection, including influenza A virus (IAV). Here, we utilize the Collaborative Cross (CC), a mouse genetic reference population, to study genetic regulation of variation in antibody response following IAV infection. CC mice show significant heritable variation in the magnitude, kinetics, and composition of IAV-specific antibody response.

H2 influenza A virus is not pathogenic in Tmprss2 knock-out mice.

The host cell protease TMPRSS2 cleaves the influenza A virus (IAV) hemagglutinin (HA). Several reports have described resistance of Tmprss2 knock-out (KO) mice to IAV infection but IAV of the H2 subtype have not been examined yet. Here, we demonstrate that TMPRSS2 is able to cleave H2-HA in cell culture and that Tmprss2 mice are resistant to infection with a re-assorted PR8_HA(H2) virus.

A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes.

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males.

Tmprss2 knock-out mice are resistant to H10 influenza A virus pathogenesis.

The surface protein haemagglutinin (HA) of influenza A viruses (IAV) needs to be cleaved by a host protease to become functional. Here, we investigated if IAV of the H10 subtype also requires TMPRSS2 for replication and pathogenesis in mice. We first showed in cell culture that TMPRSS2 is able to cleave H10-HA.

Exchange of amino acids in the H1-haemagglutinin to H3 residues is required for efficient influenza A virus replication and pathology in Tmprss2 knock-out mice.

The haemagglutinin (HA) of H1N1 and H3N2 influenza A virus (IAV) subtypes has to be activated by host proteases. Previous studies showed that H1N1 virus cannot replicate efficiently in Tmprss2 knock-out mice whereas H3N2 viruses are able to replicate to the same levels in Tmprss2 as in wild type (WT) mice. Here, we investigated the sequence requirements for the HA molecule that allow IAV to replicate efficiently in the absence of TMPRSS2.

TMPRSS11A activates the influenza A virus hemagglutinin and the MERS coronavirus spike protein and is insensitive against blockade by HAI-1.

The influenza virus hemagglutinin (HA) facilitates viral entry into target cells. Cleavage of HA by host cell proteases is essential for viral infectivity, and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease (TTSP) TMPRSS2 has been identified as an HA activator in cell culture and in the infected host.

Of mice and men: the host response to influenza virus infection.

Influenza virus (IV) infections represent a very serious public health problem. At present, no established biomarkers exist to support diagnosis for respiratory viral infections and more importantly for severe IV disease. Studies in animal models are extremely important to understand the biological, genetic, and environmental factors that contribute to severe IV disease and to validate biomarker candidates from human studies.

Absence of regulator of G-protein signaling 4 does not protect against dopamine neuron dysfunction and injury in the mouse 6-hydroxydopamine lesion model of Parkinson's disease.

Regulator of G-protein signaling 4 (RGS4), a member of the RGS family of proteins that inactivate G-proteins, has gained interest as a potential drug target for neurological disorders, such as epilepsy and Parkinson's disease (PD). In the case of PD, the main current options for alleviating motor symptoms are dopamine replacement therapies, which have limitations because of side effects and reduced effectiveness over the long term. Research on new nondopaminergic PD drug targets has indicated that inhibition of RGS4 could be an effective adjuvant treatment option.

Influenza H3N2 infection of the collaborative cross founder strains reveals highly divergent host responses and identifies a unique phenotype in CAST/EiJ mice.

Background: Influenza A virus is a zoonotic pathogen that poses a major threat to human and animal health. The severe course of influenza infection is not only influenced by viral virulence factors but also by individual differences in the host response. To determine the extent to which the genetic background can modulate severity of an infection, we studied the host responses to influenza infections in the eight genetically highly diverse Collaborative Cross (CC) founder mouse strains.

Lst1 deficiency has a minor impact on course and outcome of the host response to influenza A H1N1 infections in mice.

Background: Previously, we performed a quantitative trait locus (QTL) mapping study in BXD recombinant inbred mice to identify host genetic factors that confer resistance to influenza A virus infection. We found Lst1 (leukocyte specific transcript 1) as one of the most promising candidate genes in the Qivr17-2 locus because it is non-functional in DBA/2 J mice. Several studies have proposed that LST1 plays a role in the immune response to inflammatory diseases in humans and has additional immune-regulatory functions.

Systems biology and systems genetics - novel innovative approaches to study host-pathogen interactions during influenza infection.

Influenza represents a serious threat to public health with thousands of deaths each year. A deeper understanding of the host-pathogen interactions is urgently needed to evaluate individual and population risks for severe influenza disease and to identify new therapeutic targets. Here, we review recent progress in large scale omics technologies, systems genetics as well as new mathematical and computational developments that are now in place to apply a systems biology approach for a comprehensive description of the multidimensional host response to influenza infection.

Meeting report of the European mouse complex genetics network SYSGENET.

The second scientific meeting of the European systems genetics network for the study of complex genetic human disease using genetic reference populations (SYSGENET) took place at the Center for Cooperative Research in Biosciences in Bilbao, Spain, December 10-12, 2012. SYSGENET is funded by the European Cooperation in the Field of Scientific and Technological Research (COST) and represents a network of scientists in Europe that use mouse genetic reference populations (GRPs) to identify complex genetic factors influencing disease phenotypes (Schughart, Mamm Genome 21:331-336, 2010). About 50 researchers working in the field of systems genetics attended the meeting, which consisted of 27 oral presentations, a poster session, and a management committee meeting.

Structural and functional concepts in current mouse phenotyping and archiving facilities.

Collecting and analyzing available information on the building plans, concepts, and workflow from existing animal facilities is an essential prerequisite for most centers that are planning and designing the construction of a new animal experimental research unit. Here, we have collected and analyzed such information in the context of the European project Infrafrontier, which aims to develop a common European infrastructure for high-throughput systemic phenotyping, archiving, and dissemination of mouse models. A team of experts visited 9 research facilities and 3 commercial breeders in Europe, Canada, the United States, and Singapore.

Distinct gene loci control the host response to influenza H1N1 virus infection in a time-dependent manner.

Background: There is strong but mostly circumstantial evidence that genetic factors modulate the severity of influenza infection in humans. Using genetically diverse but fully inbred strains of mice it has been shown that host sequence variants have a strong influence on the severity of influenza A disease progression. In particular, C57BL/6J, the most widely used mouse strain in biomedical research, is comparatively resistant.

The transcription factors Nkx2.2 and Nkx2.9 play a novel role in floor plate development and commissural axon guidance.

The transcription factors Nkx2.2 and Nkx2.9 have been proposed to execute partially overlapping functions in neuronal patterning of the ventral spinal cord in response to graded sonic hedgehog signaling.

Molecular control of spinal accessory motor neuron/axon development in the mouse spinal cord.

Within the developing vertebrate spinal cord, motor neuron subtypes are distinguished by the settling positions of their cell bodies, patterns of gene expression, and the paths their axons follow to exit the CNS. The inclusive set of cues required to guide a given motor axon subtype from cell body to target has yet to be identified, in any species. This is attributable, in part, to the unavailability of markers that demarcate the complete trajectory followed by a specific class of spinal motor axons.