Publications by authors named "Andreas Beineke"

111 Publications

Challenging diagnostic work-up of a massive fluid-filled structure in the cranial abdomen of a cat.

Tierarztl Prax Ausg K Kleintiere Heimtiere 2021 Oct 12. Epub 2021 Oct 12.

Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation.

A 9-year-old female, neutered European shorthair cat was presented with acute vomiting, obvious jaundice and painful enlargement of the abdomen. Icteric skin and mucous membranes in addition to severe bilirubinaemia (mainly direct bilirubin) and a large increase in liver enzyme activities were the main findings at the initial examination. Radio- and ultrasonographic evaluation revealed a massive fluid-filled structure caudal to the liver displacing abdominal organs, in particular the stomach. As this structure with a diameter of 8-10 cm occupied considerable space in the cranioventral abdomen, a detailed ultrasonographic examination of the liver and the gallbladder, and determination of the structure's association with a particular abdominal organ was initially impossible. Via ultrasound-assisted puncture under general anaesthesia 300 ml of an almost clear fluid could be aspirated. Cytological examination revealed a cyst content-like fluid with cell detritus.Further ultrasonographic and computed tomographic diagnostics followed by abdominal laparotomy finally enabled diagnosis of a cystic dilatation of the entire common bile duct and accumulation of white bile. Histopathological examination after euthanasia (requested by the owner) identified lymphoplasmacytic cholangitis and necrosis of the duodenal papilla. The massive dilatation of the common bile duct complicated its definite diagnosis by diagnostic imaging methods. It was most likely caused by a longer-standing obstruction of the bile flow by lymphoplasmacytic cholangitis with necrosis and granulation tissue formation in the area of the duodenal papilla. An interesting but initially misleading feature was the presence of white bile. The etiology of this extremely rare condition remains obscure but in the described case a manifestation of impaired hepatocyte function secondary to biliary stasis is suspected to be the cause.
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http://dx.doi.org/10.1055/a-1518-6202DOI Listing
October 2021

Polyadenine insertion disrupting the G6PC1 gene in German Pinschers with glycogen storage disease type Ia (GSD1A).

Anim Genet 2021 Oct 5. Epub 2021 Oct 5.

Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, 3001, Switzerland.

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http://dx.doi.org/10.1111/age.13146DOI Listing
October 2021

Neural Injury and Repair in a Novel Neonatal Mouse Model of Listeria Monocytogenes Meningoencephalitis.

J Neuropathol Exp Neurol 2021 Sep;80(9):861-867

Department of Neuropathology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany.

To improve the therapy of neonatal central nervous system infections, well-characterized animal models are urgently needed. The present study analyzes neuropathological alterations with particular focus on neural injury and repair in brains of neonatal mice with Listeria monocytogenes (LM) meningitis/meningoencephalitis using a novel nasal infection model. The hippocampal formation and frontal cortex of 14 neonatal mice with LM meningitis/meningoencephalitis and 14 uninfected controls were analyzed by histology, immunohistochemistry, and in situ tailing for morphological alterations. In the dentate gyrus of the hippocampal formation of mice with LM meningitis/meningoencephalitis, an increased density of apoptotic neurons visualized by in situ tailing (p = 0.04) and in situ tailing plus immunohistochemistry for activated Caspase-3 (p < 0.0001) was found. A decreased density of dividing cells stained with an anti-PCNA-antibody (p < 0.0001) and less neurogenesis visualized by anti-calretinin (p < 0.0001) and anti-calbindin (p = 0.01) antibodies were detected compared to uninfected controls. The density of microglia was higher in LM meningitis (p < 0.0001), while the density of astrocytes remained unchanged. Infiltrating monocytes and neutrophilic granulocytes likely contributed to tissue damage. In conclusion, in the brains of LM-infected mice a strong immune response was observed which led to neuronal apoptosis and an impaired neural regeneration. This model appears very suitable to study therapies against long-term sequelae of neonatal LM meningitis.
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http://dx.doi.org/10.1093/jnen/nlab079DOI Listing
September 2021

Transcriptome analysis following neurotropic virus infection reveals faulty innate immunity and delayed antigen presentation in mice susceptible to virus-induced demyelination.

Brain Pathol 2021 Jul 6:e13000. Epub 2021 Jul 6.

Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.

Viral infections of the central nervous system cause acute or delayed neuropathology and clinical consequences ranging from asymptomatic courses to chronic, debilitating diseases. The outcome of viral encephalitis is partially determined by genetically programed immune response patterns of the host. Experimental infection of mice with Theiler's murine encephalomyelitis virus (TMEV) causes diverse neurologic diseases, including TMEV-induced demyelinating disease (TMEV-IDD), depending on the used mouse strain. The aim of the present study was to compare initial transcriptomic changes occurring in the brain of TMEV-infected SJL (TMEV-IDD susceptible) and C57BL/6 (TMEV-IDD resistant) mice. Animals were infected with TMEV and sacrificed 4, 7, or 14 days post infection. RNA was isolated from brain tissue and analyzed by whole-transcriptome sequencing. Selected differences were confirmed on a protein level by immunohistochemistry. In mock-infected SJL and C57BL/6 mice, >200 differentially expressed genes (DEGs) were detected. Following TMEV-infection, the number of DEGs increased to >700. Infected C57BL/6 mice showed a higher expression of transcripts related to antigen presentation via major histocompatibility complex (MHC) I, innate antiviral immune responses and cytotoxicity, compared with infected SJL animals. Expression of many of those genes was weaker or delayed in SJL mice, associated with a failure of viral clearance in this mouse strain. SJL mice showed prolonged elevation of MHC II and chemotactic genes compared with C57BL/6 mice, which presumably facilitates the induction of chronic demyelinating disease. In addition, elevated expression of several genes associated with immunomodulatory or -suppressive functions was observed in SJL mice. The exploratory study confirms previous observations in the model and provides an extensive list of new immunologic parameters potentially contributing to different outcomes of viral encephalitis in two mouse strains.
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http://dx.doi.org/10.1111/bpa.13000DOI Listing
July 2021

CARD9 Deficiency Increases Hippocampal Injury Following Acute Neurotropic Picornavirus Infection but Does Not Affect Pathogen Elimination.

Int J Mol Sci 2021 Jun 29;22(13). Epub 2021 Jun 29.

Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.

Neurotropic viruses target the brain and contribute to neurologic diseases. Caspase recruitment domain containing family member 9 (CARD9) controls protective immunity in a variety of infectious disorders. To investigate the effect of CARD9 in neurotropic virus infection, CARD9 and corresponding C57BL/6 wild-type control mice were infected with Theiler's murine encephalomyelitis virus (TMEV). Brain tissue was analyzed by histology, immunohistochemistry and molecular analyses, and spleens by flow cytometry. To determine the impact of CARD9 deficiency on T cell responses in vitro, antigen presentation assays were utilized. Genetic ablation of CARD9 enhanced early pro-inflammatory cytokine responses and accelerated infiltration of T and B cells in the brain, together with a transient increase in TMEV-infected cells in the hippocampus. CARD9 mice showed an increased loss of neuronal nuclear protein mature neurons and doublecortin neuronal precursor cells and an increase in β-amyloid precursor protein damaged axons in the hippocampus. No effect of CARD9 deficiency was found on the initiation of CD8 T cell responses by flow cytometry and co-culture experiments using virus-exposed dendritic cells or microglia-enriched glial cell mixtures, respectively. The present study indicates that CARD9 is dispensable for the initiation of early antiviral responses and TMEV elimination but may contribute to the modulation of neuroinflammation, thereby reducing hippocampal injury following neurotropic virus infection.
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http://dx.doi.org/10.3390/ijms22136982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268812PMC
June 2021

In vivo oxygen measurement in cerebrospinal fluid of pigs to determine physiologic and pathophysiologic oxygen values during CNS infections.

BMC Neurosci 2021 06 28;22(1):45. Epub 2021 Jun 28.

Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany.

During infection and inflammation, a reduced oxygen level clearly affects cellular functions. Oxygen levels during CNS infections are unknown. Here we established and evaluated an in vivo measurement system to characterize the oxygen level in parallel with bacterial numbers (CFU/mL), the cell number and pH level inside the CSF of healthy compared to Streptococcus suis-infected pigs. The animals were anesthetized over a seven-hour period with isoflurane in air/oxygen at physiologic arterial partial pressure of oxygen. Oxygen levels in CSF of anesthetized pigs were compared to euthanized pigs. The detected partial pressure of oxygen in the CSF remained constant in a range of 47-63 mmHg, independent of the infection status (bacterial or cell number). In contrast, the pH value showed a slight drop during infection, which correlated with cell and bacterial number in CSF. We present physiologic oxygen and pH values in CSF during the onset of bacterial meningitis.
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http://dx.doi.org/10.1186/s12868-021-00648-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240281PMC
June 2021

Intratumoral Canine Distemper Virus Infection Inhibits Tumor Growth by Modulation of the Tumor Microenvironment in a Murine Xenograft Model of Canine Histiocytic Sarcoma.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany.

Histiocytic sarcomas refer to highly aggressive tumors with a poor prognosis that respond poorly to conventional treatment approaches. Oncolytic viruses, which have gained significant traction as a cancer therapy in recent decades, represent a promising option for treating histiocytic sarcomas through their replication and/or by modulating the tumor microenvironment. The live attenuated canine distemper virus (CDV) vaccine strain Onderstepoort represents an attractive candidate for oncolytic viral therapy. In the present study, oncolytic virotherapy with CDV was used to investigate the impact of this virus infection on tumor cell growth through direct oncolytic effects or by virus-mediated modulation of the tumor microenvironment with special emphasis on angiogenesis, expression of selected MMPs and TIMP-1 and tumor-associated macrophages in a murine xenograft model of canine histiocytic sarcoma. Treatment of mice with xenotransplanted canine histiocytic sarcomas using CDV induced overt retardation in tumor progression accompanied by necrosis of neoplastic cells, increased numbers of intratumoral macrophages, reduced angiogenesis and modulation of the expression of MMPs and TIMP-1. The present data suggest that CDV inhibits tumor growth in a multifactorial way, including direct cell lysis and reduction of angiogenesis and modulation of MMPs and their inhibitor TIMP-1, providing further support for the concept of its role in oncolytic therapies.
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http://dx.doi.org/10.3390/ijms22073578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037597PMC
March 2021

A Comparative Transcriptome Analysis of Human and Porcine Choroid Plexus Cells in Response to Serotype 2 Infection Points to a Role of Hypoxia.

Front Cell Infect Microbiol 2021 8;11:639620. Epub 2021 Mar 8.

Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

() is an important opportunistic pathogen, which can cause septicemia and meningitis in pigs and humans. Previous observations in -infected pigs revealed lesions at the choroid plexus (CP). experiments with primary porcine CP epithelial cells (PCPEC) and human CP epithelial papilloma (HIBCPP) cells demonstrated that can invade and traverse the CP epithelium, and that the CP contributes to the inflammatory response cytokine expression. Here, next generation sequencing (RNA-seq) was used to compare global transcriptome profiles of PCPEC and HIBCPP cells challenged with serotype (ST) 2 infected , and of pigs infected . Identified differentially expressed genes (DEGs) were, amongst others, involved in inflammatory responses and hypoxia. The RNA-seq data were validated quantitative PCR of selected DEGs. Employing Gene Set Enrichment Analysis (GSEA), 18, 28, and 21 enriched hallmark gene sets (GSs) were identified for infected HIBCPP cells, PCPEC, and in the CP of pigs suffering from ST2 meningitis, respectively, of which eight GSs overlapped between the three different sample sets. The majority of these GSs are involved in cellular signaling and pathways, immune response, and development, including inflammatory response and hypoxia. In contrast, suppressed GSs observed during and ST2 infections included those, which were involved in cellular proliferation and metabolic processes. This study suggests that similar cellular processes occur in infected human and porcine CP epithelial cells, especially in terms of inflammatory response.
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http://dx.doi.org/10.3389/fcimb.2021.639620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982935PMC
July 2021

De novo ZIC2 frameshift variant associated with frontonasal dysplasia in a Limousin calf.

BMC Genomics 2021 Jan 2;22(1). Epub 2021 Jan 2.

Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, 30559, Hannover, Germany.

Background: Bovine frontonasal dysplasias like arhinencephaly, synophthalmia, cyclopia and anophthalmia are sporadic congenital facial malformations. In this study, computed tomography, necropsy, histopathological examinations and whole genome sequencing on an Illumina NextSeq500 were performed to characterize a stillborn Limousin calf with frontonasal dysplasia. In order to identify private genetic and structural variants, we screened whole genome sequencing data of the affected calf and unaffected relatives including parents, a maternal and paternal halfsibling.

Results: The stillborn calf exhibited severe craniofacial malformations. Nose and maxilla were absent, mandibles were upwardly curved and a median cleft palate was evident. Eyes, optic nerve and orbital cavities were not developed and the rudimentary orbita showed hypotelorism. A defect centrally in the front skull covered with a membrane extended into the intracranial cavity. Aprosencephaly affected telencephalic and diencephalic structures and cerebellum. In addition, a shortened tail was seen. Filtering whole genome sequencing data revealed a private frameshift variant within the candidate gene ZIC2 in the affected calf. This variant was heterozygous mutant in this case and homozygous wild type in parents, half-siblings and controls.

Conclusions: We found a novel ZIC2 frameshift mutation in an aprosencephalic Limousin calf. The origin of this variant is most likely due to a de novo mutation in the germline of one parent or during very early embryonic development. To the authors' best knowledge, this is the first identified mutation in cattle associated with bovine frontonasal dysplasia.
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http://dx.doi.org/10.1186/s12864-020-07350-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777292PMC
January 2021

The Cell Tropism of Porcine Respiratory Coronavirus for Airway Epithelial Cells Is Determined by the Expression of Porcine Aminopeptidase N.

Viruses 2020 10 23;12(11). Epub 2020 Oct 23.

Institute of Virology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.

Porcine respiratory coronavirus (PRCoV) infects the epithelial cells in the respiratory tract of pigs, causing a mild respiratory disease. We applied air-liquid interface (ALI) cultures of well-differentiated porcine airway cells to mimic the respiratory tract epithelium in vitro and use it for analyzing the infection by PRCoV. As reported for most coronaviruses, virus entry and virus release occurred mainly via the apical membrane domain. A novel finding was that PRCoV preferentially targets non-ciliated and among them the non-mucus-producing cells. Aminopeptidase N (APN), the cellular receptor for PRCoV was also more abundantly expressed on this type of cell suggesting that APN is a determinant of the cell tropism. Interestingly, differentiation-dependent differences were found both in the expression of pAPN and the susceptibility to PRCoV infection. Cells in an early differentiation stage express higher levels of pAPN and are more susceptible to infection by PRCoV than are well-differentiated cells. A difference in the susceptibility to infection was also detected when tracheal and bronchial cells were compared. The increased susceptibility to infection of bronchial epithelial cells was, however, not due to an increased abundance of APN on the cell surface. Our data reveal a complex pattern of infection in porcine differentiated airway epithelial cells that could not be elucidated with immortalized cell lines. The results are expected to have relevance also for the analysis of other respiratory viruses.
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http://dx.doi.org/10.3390/v12111211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690903PMC
October 2020

Role of Bacterial and Host DNases on Host-Pathogen Interaction during Meningitis.

Int J Mol Sci 2020 Jul 25;21(15). Epub 2020 Jul 25.

Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.

is a zoonotic agent causing meningitis in pigs and humans. Neutrophils, as the first line of defense against infections, release neutrophil extracellular traps (NETs) to entrap pathogens. In this study, we investigated the role of the secreted nuclease A of (SsnA) as a NET-evasion factor in vivo and in vitro. Piglets were intranasally infected with strain 10 or an isogenic mutant. DNase and NET-formation were analyzed in cerebrospinal fluid (CSF) and brain tissue. Animals infected with strain 10 or S. suis 10ΔssnA showed the presence of NETs in CSF and developed similar clinical signs. Therefore, SsnA does not seem to be a crucial virulence factor that contributes to the development of meningitis in pigs. Importantly, DNase activity was detectable in the CSF of both infection groups, indicating that host nucleases, in contrast to bacterial nuclease SsnA, may play a major role during the onset of meningitis. The effect of DNase 1 on neutrophil functions was further analyzed in a 3D-cell culture model of the porcine blood-CSF barrier. We found that DNase 1 partially contributes to enhanced killing of by neutrophils, especially when plasma is present. In summary, host nucleases may partially contribute to efficient innate immune response in the CSF.
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http://dx.doi.org/10.3390/ijms21155289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432635PMC
July 2020

Lagovirus europeus GI.2 (rabbit hemorrhagic disease virus 2) infection in captive mountain hares (Lepus timidus) in Germany.

BMC Vet Res 2020 May 27;16(1):166. Epub 2020 May 27.

Institute of Pathology, University of Veterinary Medicine Hanover, Foundation, Buenteweg, 17 30559, Hannover, Germany.

Background: Rabbit hemorrhagic disease virus (RHDV, Lagovirus europeus GI.1) induces a contagious and highly lethal hemorrhagic disease in rabbits. In 2010 a new genotype of lagovirus (GI.2), emerged in Europe, infecting wild and domestic population of rabbits and hares.

Case Presentation: We describe the infection with a GI.2 strain, "Bremerhaven-17", in captive mountain hares (Lepus timidus) in a zoo facility in Germany. Postmortem examination revealed RHD-like lesions including necrotizing hepatitis. RT-qPCR and AG-ELISA confirmed presence of GI.2. Recombination and phylogenetic analysis grouped the identified strain with other GI.2 strains, sharing nucleotide identity of 91-99%.

Conclusion: Our findings confirm that mountain hares are susceptible to GI.2 infection, due to a past recombination event facilitating virus spillover from sympatric rabbits.
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http://dx.doi.org/10.1186/s12917-020-02386-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254734PMC
May 2020

Relevance of inducible nitric oxide synthase for immune control of subspecies infection in mice.

Virulence 2020 12;11(1):465-481

Institute for Microbiology, University of Veterinary Medicine Hannover, Hannover, Germany.

subspecies (MAP) causes Johne's disease (JD), an incurable chronic intestinal bowel disease in ruminants. JD occurs worldwide and causes enormous economic burden in dairy industry. Research on JD pathobiology is hampered by its complexity which cannot completely be mimicked by small animal models. As a model the mouse allows dissecting some pathogenicity features of MAP. However, for unknown reasons MAP exhibits reduced growth in granulomas of infected mice compared to other subspecies. Here, we characterized immune reactions of MAP-infected C57BL/6 mice. After infection, mice appeared fully immunocompetent. A strong antigen-specific T cell response was elicited indicated by IFNγ production of splenic T cells re-stimulated with MAP antigens. Function of splenic dendritic cells and proliferation of adoptively transferred antigen-specific CD4 T cells was unaltered. Isolated splenic myeloid cells from infected mice revealed that MAP resides in CD11b macrophages. Importantly, sorted CD11bCD11c cells expressed high level of type 2 nitric oxide synthase (NOS2) but only low levels of pro- and anti-inflammatory cytokines. Correspondingly, MAP-infected MAC2 expressing myeloid cells in spleen and liver granuloma displayed strong expression of NOS2. In livers of infected mice higher bacterial loads, more granuloma and larger areas of tissue damage were observed 5 weeks post infection compared to wild type mice. , MAP was sensitive to NO released by a NO-donor. Thus, a strong T cell response and concomitant NOS2/NO activity appears to control MAP infection, but allows development of chronicity and pathogen persistence. A similar mechanism might explain persistence of MAP in ruminants.
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http://dx.doi.org/10.1080/21505594.2020.1763055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239028PMC
December 2020

Expression of claudin-11 in canine prepubertal testes, and in canine adult testes showing normal spermatogenesis, impaired spermatogenesis, or testicular neoplasia.

Theriogenology 2020 May 5;148:122-131. Epub 2020 Mar 5.

Institute for Anatomy, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173, Hannover, Germany. Electronic address:

The blood-testis barrier (BTB) consists of different cell-to-cell connections, including tight junction proteins like claudin-11 (CLDN11). For dogs, only limited data is published dealing with these proteins in general. Therefore, their physiological relevance, their postnatal expression, and their distribution pattern in pathological conditions, e.g. in altered spermatogenesis and testicular neoplasia were assessed. Canine testes from routine castrations, and those sent in for diagnostic purposes were investigated. Based on morphological evaluation, the dogs and testes were divided into groups: (1) dogs with normal spermatogenesis, (2) four months old prepubertal dogs, (3) intratubular seminoma, (4) diffuse seminoma, (5) Sertoli cell tumours (SCT), (6) Leydig cell tumours (LCT), and (7) dogs with impaired spermatogenesis (e.g. mixed atrophy). In order to examine possible alterations of the BTB components, immunohistochemistry (IHC) and immunofluorescence using a commercial antibody against CLDN11 was performed. Sertoli cell (SC) nuclei (SOX9) and peritubular myoid cells (smooth-muscle-actin, SMA) were also assessed using IHC. Additionally, semi-quantitative Western-blot (WB) and RT-PCR analyses of CLDN11 were conducted. In tubules with normal spermatogenesis, IHC of CLDN11 revealed a basolateral staining at BTB localisation. In prepubertal cords, CLDN11 was diffusely expressed along the cytoplasmic extensions of SCs supposing that the BTB was neither built up nor functional, yet. A shift from weakly expressed CLDN11 between/in residual SCs in intratubular seminoma to only small CLDN11 immunopositive stained spots in the cytoplasm of remaining SOX9-positive SCs in diffuse seminoma was detectable. Reduction or even loss of CLDN11 expression in diffuse seminoma was confirmed using RT-PCR and WB analyses, thus indicating that in seminoma, CLDN11 was downregulated at transcriptional level and completely lost its sealing function. Basal SCs in SCT still showed a CLDN11/SOX9 co-localisation, suggesting that luminal neoplastic SCs undergo de-differentiation during tumour progression. In LCT, no CLDN11 was detectable. Dogs with mixed atrophy showed an upregulation of CLDN11 in tubules with spermatogenic arrest on mRNA and protein level, leading to the conclusion that within these tubules regulatory mechanisms lost their equilibrium. For the first time, the spatial expression of CLDN11 in prepubertal canine testis, impaired spermatogenesis, intratubular seminoma and its absence in diffuse seminoma and LCT was shown. Since altered CLDN11 levels could be part of adaptive mechanisms to modify BTB integrity, further functional investigations to characterize the canine BTB need to be conducted.
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http://dx.doi.org/10.1016/j.theriogenology.2020.03.001DOI Listing
May 2020

Beneficial and Detrimental Effects of Regulatory T Cells in Neurotropic Virus Infections.

Int J Mol Sci 2020 Mar 2;21(5). Epub 2020 Mar 2.

Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, D-30559 Hannover, Germany.

Neurotropic viruses infect the central nervous system (CNS) and cause acute or chronic neurologic disabilities. Regulatory T cells (Treg) play a critical role for immune homeostasis, but may inhibit pathogen-specific immunity in infectious disorders. The present review summarizes the current knowledge about Treg in human CNS infections and their animal models. Besides dampening pathogen-induced immunopathology, Treg have the ability to facilitate protective responses by supporting effector T cell trafficking to the infection site and the development of resident memory T cells. Moreover, Treg can reduce virus replication by inducing apoptosis of infected macrophages and attenuate neurotoxic astrogliosis and pro-inflammatory microglial responses. By contrast, detrimental effects of Treg are caused by suppression of antiviral immunity, allowing for virus persistence and latency. Opposing disease outcomes following Treg manipulation in different models might be attributed to differences in technique and timing of intervention, infection route, genetic background, and the host's age. In addition, mouse models of virus-induced demyelination revealed that Treg are able to reduce autoimmunity and immune-mediated CNS damage in a disease phase-dependent manner. Understanding the unique properties of Treg and their complex interplay with effector cells represents a prerequisite for the development of new therapeutic approaches in neurotropic virus infections.
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http://dx.doi.org/10.3390/ijms21051705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084400PMC
March 2020

Clinical, cytogenetic and molecular genetic characterization of a tandem fusion translocation in a male Holstein cattle with congenital hypospadias and a ventricular septal defect.

PLoS One 2020 10;15(1):e0227117. Epub 2020 Jan 10.

Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.

Hypospadias, disorder of sex development (DSD), is a sporadic congenital abnormality of the genital region in male ruminants, which is characterized by a non-fused urethra during fetal development. Detailed clinical examination classified the hypospadias phenotype of a male Holstein calf studied here as the perineal type. In combined use of cytogenetic analysis and whole genome sequencing, a non-mosaic, pseudo-monosomy 59, XY + tan(18;27) was detected. This chromosomal aberration had its origin in a tandem fusion translocation of the bovine autosomes (BTA) 18 and 27 with an accompanying loss of genomic sequences mainly in the distal end of BTA 18 and the proximal end of BTA 27. The resulting phenotype included hypospadias, growth retardation and ventricular septal defect.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227117PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953810PMC
April 2020

Study of congenital Morgagnian cataracts in Holstein calves.

PLoS One 2019 26;14(12):e0226823. Epub 2019 Dec 26.

Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.

Cataracts are focal to diffuse opacities of the eye lens causing impaired vision or complete blindness. For bilateral congenital cataracts in Red Holsteins a perfectly cosegregating mutation within the CPAMD8 gene (CPAMD8:g.5995966C>T) has been reported. We genotyped the CPAMD8:g.5995966C>T variant in Holstein calves affected by congenital bilateral congenital cataracts, their unaffected relatives and randomly selected herd mates. Ophthalmological examinations were performed in all affected individuals to confirm a congenital cataract. Whole genome sequencing was employed to screen variants in candidate genes for the Morgagnian cataract phenotype. In the present study, 3/35 cases were confirmed as homozygous mutated and 6/14 obligate carriers. Further 7/46 unaffected animals related with these cases were heterozygous mutated for the CPAMD8:g.5995966C>T variant. However 32 cases with a congenital cataract showed the wild type for the CPAMD8 variant. We did not identify variants in the candidate genes CPAMD8 and NID1 or in their close neighborhood as strongly associated with the congenital cataract phenotype in Holstein calves with the CPAMD8 wild type. In conclusion, the CPAMD8:g.5995966C>T variant is insufficient to explain the majority of Morgagnian congenital cataract phenotypes in Holsteins. It is very likely that congenital bilateral cataracts may be genetically heterogeneous and not yet known variants in genes other than CPAMD8 and NID1 are involved.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226823PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932804PMC
April 2020

HSV-1 triggers paracrine fibroblast growth factor response from cortical brain cells via immediate-early protein ICP0.

J Neuroinflammation 2019 Dec 2;16(1):248. Epub 2019 Dec 2.

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.

Background: Herpes simplex virus-1 (HSV-1) infections of the central nervous system (CNS) can result in HSV-1 encephalitis (HSE) which is characterized by severe brain damage and long-term disabilities. Different cell types including neurons and astrocytes become infected in the course of an HSE which leads to an activation of glial cells. Activated glial cells change their neurotrophic factor profile and modulate inflammation and repair. The superfamily of fibroblast growth factors (FGFs) is one of the largest family of neurotrophic factors comprising 22 ligands. FGFs induce pro-survival signaling in neurons and an anti-inflammatory answer in glial cells thereby providing a coordinated tissue response which favors repair over inflammation. Here, we hypothesize that FGF expression is altered in HSV-1-infected CNS cells.

Method: We employed primary murine cortical cultures comprising a mixed cell population of astrocytes, neurons, microglia, and oligodendrocytes. Astrocyte reactivity was morphometrically monitored by an automated image analysis algorithm as well as by analyses of A1/A2 marker expression. Altered FGF expression was detected by quantitative real-time PCR and its paracrine FGF activity. In addition, HSV-1 mutants were employed to characterize viral factors important for FGF responses of infected host cells.

Results: Astrocytes in HSV-1-infected cortical cultures were transiently activated and became hypertrophic and expressed both A1- and A2-markers. Consistently, a number of FGFs were transiently upregulated inducing paracrine neurotrophic signaling in neighboring cells. Most prominently, FGF-4, FGF-8, FGF-9, and FGF-15 became upregulated in a switch-on like mechanism. This effect was specific for CNS cells and for a fully functional HSV-1. Moreover, the viral protein ICP0 critically mediated the FGF switch-on mechanism.

Conclusions: HSV-1 uses the viral protein ICP0 for the induction of FGF-expression in CNS cells. Thus, we propose that HSV-1 triggers FGF activity in the CNS for a modulation of tissue response upon infection.
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http://dx.doi.org/10.1186/s12974-019-1647-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889453PMC
December 2019

Neutrophil Extracellular Traps in the Pathogenesis of Equine Recurrent Uveitis (ERU).

Cells 2019 11 27;8(12). Epub 2019 Nov 27.

Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Bünteweg 17, D-30559 Hannover, Germany.

Equine recurrent uveitis (ERU) is considered one of the most important eye diseases in horses and typically appears with relapsing inflammatory episodes without systemic effects. Various disorders have been described as an initial trigger, including infections. Independent of the initiating cause, there are numerous indications that ERU is an immune-mediated disease. We investigated whether neutrophil extracellular traps (NETs) are part of the ERU pathogenesis. Therefore, vitreous body fluids (VBF), sera, and histological sections of the eye from ERU-diseased horses were analyzed for the presence of NET markers and compared with horses with healthy eyes. In addition, NET formation by blood derived neutrophils was investigated in the presence of VBF derived from horses with healthy eyes versus ERU-diseased horses using immunofluorescence microscopy. Interestingly, NET markers like free DNA, histone-complexes, and myeloperoxidase were detected in higher amounts in samples from ERU-diseased horses. Furthermore, in vitro NET formation was higher in neutrophils incubated with VBF from diseased horses compared with those animals with healthy eyes. Finally, we characterized the ability of equine cathelicidins to induce NETs, as potential NET inducing factors in ERU-diseased horses. In summary, our findings lead to the hypothesis that ERU-diseased horses develop more NETs and that these may contribute to the pathogenesis of ERU.
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http://dx.doi.org/10.3390/cells8121528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953072PMC
November 2019

A de novo in-frame duplication in the COL1A2 gene in a Lagotto Romagnolo dog with osteogenesis imperfecta.

Anim Genet 2019 Dec 29;50(6):786-787. Epub 2019 Aug 29.

Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, 3001, Switzerland.

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http://dx.doi.org/10.1111/age.12843DOI Listing
December 2019

Split spinal cord malformations in 4 Holstein Friesian calves.

BMC Vet Res 2019 Aug 28;15(1):307. Epub 2019 Aug 28.

Clinic for Cattle, University of Veterinary Medicine Hannover, Hanover, Germany.

Background: The split spinal cord malformation (SSCM) is an uncommon congenital malformation of the vertebral canal in which parts of the spinal cord are longitudinally duplicated. In SSCM Type I, each spinal cord has its own dura tube. In the SSCM Type II, both parts of the spinal cord are surrounded by a common dura tube.

Cases Presentation: During the clinical examination one calf showed ambulatory paresis and 3 calves non-ambulatory paraparesis. Calf 4 additionally had a congenital tremor. The examination of calf 4 using magnetic resonance imaging (MRI) showed a median hydrosyringomyelia at the level of the 4th lumbar vertebra. The caudal part of this liquid-filled cavity was split longitudinally through a thin septum. From there, the spinal cord structures duplicated with an incomplete division, so that the transverse section of the spinal cord appeared peanut-shaped and in each half a central canal could be observed. The pathological-anatomical examination after euthanasia showed a duplication of the spinal cord in the area of the lumbar vertebral column in all calves. The histopathological examination revealed two central lumbar vertebral column channels. The two spinal cord duplicates were each surrounded by two separate meninges in calf 2 (SSCM type I); in the other calves (1, 3, 4, and) the two central canals and the spinal cord were covered by a common meninx (SSCM type II). A pedigree analysis of calves 2, 3 and 4 showed a degree of relationship suggestive of a hereditary component. This supports the hypothesis of a possible recessive inheritance due to common ancestors, leading to partial genetic homozygosity.

Conclusions: The clinical appearance of SSCM can vary widely. In calves with congenital paralysis SSCM should always be considered as a differential diagnosis. A reliable diagnosis intra vitam is possible only with laborious imaging procedures such as MRI. Further studies on the heritability of this malformation are necessary to confirm a genetic cause of this disease.
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http://dx.doi.org/10.1186/s12917-019-2055-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712784PMC
August 2019

Histopathological characterization of Toxocara canis- and T. cati-induced neurotoxocarosis in the mouse model.

Parasitol Res 2019 Sep 27;118(9):2591-2600. Epub 2019 Jul 27.

Institute for Parasitology, Centre for Infection Medicine, University of Veterinary Medicine Hannover, Buenteweg 17, 30559, Hanover, Germany.

Infective larvae of Toxocara canis and T. cati, the common roundworms of dogs and cats, may invade the central nervous system of paratenic hosts, including humans, causing neurotoxocarosis (NT). Previous studies on NT in the model organism "mouse" have indicated distinct differences between T. canis and T. cati regarding larval migration patterns as well as the severity of clinical symptoms and behavioural alterations. The objective of the present study was to provide an extensive characterization of the underlying histopathological alterations, comparing T. canis- and T. cati-induced changes in different brain areas over the course of murine infection. Four histological sections of five brains each of T. canis- and T. cati-infected as well as uninfected C57Bl/6 mice were investigated 7, 14, 28, 42, 70 and 98 days post infection (dpi), while brains of T. cati-infected and control mice were also available 120 and 150 dpi. In addition to haematoxylin-eosin and luxol fast blue-cresyl violet staining, immunohistochemistry was employed to study microglia/macrophage cell morphology and to detect accumulation of β-amyloid precursor protein (β-APP) as an indicator of axonal damage. Haemorrhages, eosinophilic vasculitis and activated microglia/macrophages were detected in both infection groups starting 7 dpi, followed by eosinophilic meningitis in cerebra as from 14 dpi. Overall, little differences in the proportion of animals affected by these alterations were found between the two infection groups. In contrast, the proportion of animals displaying β-APP accumulation was significantly higher in the T. canis than T. cati group as from 28 dpi regarding the cerebrum as well as at 98 dpi regarding the cerebellum. In T. canis-infected mice, myelinophagic microglia/macrophages ("gitter cells") appeared as from 14 dpi, whereas these were first observed at 70 dpi in T. cati-infected animals. The proportion of animals displaying demyelination and/or gitter cells in the cerebrum was significantly higher in the T. canis than T. cati group as from 28 dpi, and at 28 and 42 dpi regarding the cerebellum. Earlier and more severe neurodegeneration during T. canis- than T. cati-induced NT, especially in the cerebrum, may explain the differences in behavioural alterations observed in previous studies. In addition to differences in larval migration preferences, immunological processes may contribute to these patterns, which warrant further investigation.
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http://dx.doi.org/10.1007/s00436-019-06395-7DOI Listing
September 2019

Comparison of Reported Spinal Cord Lesions in Progressive Multiple Sclerosis with Theiler's Murine Encephalomyelitis Virus Induced Demyelinating Disease.

Int J Mol Sci 2019 Feb 25;20(4). Epub 2019 Feb 25.

Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.

Background: Spinal cord (SC) lesions in Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions in MS and TMEV-IDD focusing on spatial and temporal distribution of demyelination, inflammation, SC atrophy (SCA), and axonal degeneration/loss in major descending motor pathways.

Methods: TMEV and mock-infected mice were investigated clinically once a week. SC tissue was collected at 42, 98, 147, and 196 days post infection, and investigated using hematoxylin and eosin (HE) staining, immunohistochemistry targeting myelin basic protein (demyelination), Mac3 (microglia/macrophages), phosphorylated neurofilaments (axonal damage) and transmission electron microscopy.

Results: Demyelination prevailed in SC white matter in TMEV-IDD, contrasting a predominant gray matter involvement in MS. TMEV-infected mice revealed a significant loss of axons similar to MS. Ultrastructural analysis in TMEV-IDD revealed denuded axons, degenerative myelin changes, axonal degeneration, as well as remyelination. SCA is a consistent finding in the SC of MS patients and was also detected at a late time point in TMEV-IDD.

Conclusion: This comparative study further indicates the suitability of TMEV-IDD as animal model also for the investigation of progressive SC lesions in MS.
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http://dx.doi.org/10.3390/ijms20040989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413032PMC
February 2019

Cytokine expression and lymphocyte proliferative capacity in diseased harbor porpoises (Phocoena phocoena) - Biomarkers for health assessment in wildlife cetaceans.

Environ Pollut 2019 Apr 29;247:783-791. Epub 2019 Jan 29.

Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany. Electronic address:

Harbor porpoises (Phocoena phocoena) in the North and Baltic Seas are exposed to anthropogenic influences including acoustic stress and environmental contaminants. In order to evaluate immune responses in healthy and diseased harbor porpoise cells, cytokine expression analyses and lymphocyte proliferation assays, together with toxicological analyses were performed in stranded and bycaught animals as well as in animals kept in permanent human care. Severely diseased harbor porpoises showed a reduced proliferative capacity of peripheral blood lymphocytes together with diminished transcription of transforming growth factor-β and tumor necrosis factor-α compared to healthy controls. Toxicological analyses revealed accumulation of polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyltrichloroethane (DDT) in harbor porpoise blood samples. Correlation analyses between blood organochlorine levels and immune parameters revealed no direct effects of xenobiotics upon lymphocyte proliferation or cytokine transcription, respectively. Results reveal an impaired function of peripheral blood leukocytes in severely diseased harbor porpoises, indicating immune exhaustion and increased disease susceptibility.
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http://dx.doi.org/10.1016/j.envpol.2019.01.079DOI Listing
April 2019

Facets of Theiler's Murine Encephalomyelitis Virus-Induced Diseases: An Update.

Int J Mol Sci 2019 Jan 21;20(2). Epub 2019 Jan 21.

Department of Pathology, University of Veterinary Medicine, Bünteweg 17, 30559 Hannover, Germany.

Theiler's murine encephalomyelitis virus (TMEV), a naturally occurring, enteric pathogen of mice is a Cardiovirus of the Picornaviridae family. Low neurovirulent TMEV strains such as BeAn cause a severe demyelinating disease in susceptible mice following intracerebral infection. Furthermore, TMEV infections of mice cause acute polioencephalitis initiating a process of epileptogenesis that results in spontaneous recurrent epileptic seizures in approximately 50% of affected mice. Moreover, mice develop cardiac lesions after an intraperitoneal high-dose application of TMEV. Consequently, TMEV-induced diseases are widely used as animal models for multiple sclerosis, epilepsy, and myocarditis. The present review summarizes morphological lesions and pathogenic mechanisms triggered by TMEV with a special focus on the development of hippocampal degeneration and seizures in mice as well as demyelination in the spinal cord in mice. Furthermore, a detailed description of innate and adaptive immune responses is given. TMEV studies provide novel insights into the complexity of organ- and mouse strain-specific immunopathology and help to identify factors critical for virus persistence.
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http://dx.doi.org/10.3390/ijms20020448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358740PMC
January 2019

Effects of a Change from an Indoor-Based Total Mixed Ration to a Rotational Pasture System Combined With a Moderate Concentrate Feed Supply on Rumen Fermentation of Dairy Cows.

Animals (Basel) 2018 Nov 10;8(11). Epub 2018 Nov 10.

Institute of Animal Nutrition, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 38116 Braunschweig, Germany.

In spring, transition from a total mixed ration (TMR) to pasture requires rumen adaptions for the cow. It had been shown that transition period does not necessarily mean an increased risk for subacute ruminal acidosis (SARA). After adaption to pasture, however, supplying low amounts of concentrate did indicate increased risk, but caused no adverse effects on rumen morphology and absorption capacity. The present study aimed to investigate the effect of transition, and how a supply of 4.5 kg dry matter concentrate·cow · day during fulltime grazing influenced different rumen parameters. During a 12-week trial eleven rumen-cannulated dairy cows were observed during transition from confinement to pasture (PG; = 6) and compared to cows fed TMR indoors (CG; = 5). The CG stayed on a TMR based ration (35% corn silage, 35% grass silage, 30% concentrate; dry matter basis), whereas the PG slowly switched to a pasture-based ration (week 0 and 1 = TMR, week 2 = TMR and 3 h pasture·day, week 3 and 4 = TMR and 12 h pasture·day, and week 5 to 11 = pasture combined with 4.5 kg DM concentrate · cow·day). Papillae surface area decreased during transition and increased again during fulltime grazing, while the fractional absorption rate of volatile fatty acids (VFA) was not influenced. This suggests only a limited effect of papillae surface area on VFA absorption rate. Feeding changes resulted in different fermentation profiles of VFA. Changing ratio of starch to sugar during transition to fulltime grazing plus concentrate supply did not lead to lower rumen pH. In conclusion, the concentrate supply combined with high fermentable grass during fulltime grazing increased papillae surface area but did not affect absorption rate or rumen pH, so that risk for SARA was not increased.
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http://dx.doi.org/10.3390/ani8110205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262550PMC
November 2018

Impaired spermatogenesis, tubular wall disruption, altered blood-testis barrier composition and intratubular lymphocytes in an infertile Beagle dog - a putative case of autoimmune orchitis.

Histol Histopathol 2019 May 7;34(5):525-535. Epub 2018 Nov 7.

Institute for Anatomy, University of Veterinary Medicine Hannover, Hannover, Germany.

Impairment of blood-testis barrier integrity can be observed during inflammation, infection, trauma and experimental autoimmune orchitis, which is inducible in rodents. In the present study, an initially fertile two-year-old Beagle dog was presented with a decline in total sperm number resulting in azoospermia within five months, verified by twice-monthly semen analyses. The dog was clinically healthy with bilateral small testes and showed normal thyroid function. Bacterial cultures of semen were negative and serum biochemical analyses showed no abnormal findings. To determine causes of azoospermia, the dog was castrated. Histological examinations of hematoxylin-eosin stained testicular sections revealed impaired spermatogenesis, seminiferous tubules with spermatogenic arrest or Sertoli-cell-only syndrome as well as focal interstitial and even intratubular lymphocytic infiltrations. Germ cell sloughing, apoptosis and giant cells were also observed in some tubules. Subsequent immunostainings of smooth-muscle-actin, claudin3, claudin11 and connexin43 demonstrated, for the first time, a mechanical and functional disruption of the tubular wall and alterations of blood-testis barrier proteins in these tubules. Presence of claudin3 and claudin11 in canine testis was confirmed using RT-PCR and sequencing and/ or Western-blot analyses. All findings suggested a possible spontaneous autoimmune orchitis to be the underlying cause for the observed azoospermia.
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http://dx.doi.org/10.14670/HH-18-058DOI Listing
May 2019

Presence of Infected Gr-1CD11bCD11c Monocytic Myeloid Derived Suppressor Cells Subverts T Cell Response and Is Associated With Impaired Dendritic Cell Function in -Infected Mice.

Front Immunol 2018 16;9:2317. Epub 2018 Oct 16.

Institute for Microbiology, University of Veterinary Medicine Hannover, Hannover, Germany.

Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with immunomodulatory function. To study the mechanism by which MDSC affect antimicrobial immunity, we infected mice with two strains of differential virulence, highly virulent subsp. strain 25291 (MAA) and low virulent subsp. strain 104 (MAH). Intraperitoneal infection with MAA, but not MAH, caused severe disease and massive splenic infiltration of monocytic MDSC (M-MDSC; Gr-1CD11bCD11c) expressing inducible NO synthase (Nos2) and bearing high numbers of mycobacteria. Depletion experiments demonstrated that M-MDSC were essential for disease progression. NO production by M-MDSC influenced antigen-uptake and processing by dendritic cells and proliferation of CD4 T cells. M-MDSC were also induced in MAA-infected mice lacking Nos2. In these mice CD4 T cell expansion and control of infection were restored. However, T cell inhibition was only partially relieved and arginase (Arg) 1-expressing M-MDSC were accumulated. Likewise, inhibition of Arg1 also partially rescued T cell proliferation. Thus, mycobacterial virulence results in the induction of M-MDSC that block the T cell response in a Nos2- and Arg1-dependent manner.
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http://dx.doi.org/10.3389/fimmu.2018.02317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198055PMC
October 2019

The olfactory epithelium as a port of entry in neonatal neurolisteriosis.

Nat Commun 2018 10 15;9(1):4269. Epub 2018 Oct 15.

Institute for Microbiology, University of Veterinary Medicine Hannover, D-30173, Hannover, Germany.

Bacterial infections of the central nervous system (CNS) remain a major cause of mortality in the neonatal population. Commonly used parenteral infection models, however, do not reflect the early course of the disease leaving this critical step of the pathogenesis largely unexplored. Here, we analyzed nasal exposure of 1-day-old newborn mice to Listeria monocytogenes (Lm). We found that nasal, but not intragastric administration, led to early CNS infection in neonate mice. In particular, upon bacterial invasion of the olfactory epithelium, Lm subsequently spread along the sensory neurons entering the brain tissue at the cribriform plate and causing a significant influx of monocytes and neutrophils. CNS infection required listeriolysin for penetration of the olfactory epithelium and ActA, a mediator of intracellular mobility, for translocation into the brain tissue. Taken together, we propose an alternative port of entry and route of infection for neonatal neurolisteriosis and present a novel infection model to mimic the clinical features of late-onset disease in human neonates.
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http://dx.doi.org/10.1038/s41467-018-06668-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189187PMC
October 2018

A recessive lethal chondrodysplasia in a miniature zebu family results from an insertion affecting the chondroitin sulfat domain of aggrecan.

BMC Genet 2018 10 11;19(1):91. Epub 2018 Oct 11.

Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, 30559, Hannover, Germany.

Background: Congenital skeletal malformations represent a heterogeneous group of disorders affecting bone and cartilage development. In cattle, particular chondrodysplastic forms have been identified in several miniature breeds. In this study, a phenotypic characterization was performed of an affected Miniature Zebu calf using computed tomography, necropsy and histopathological examinations, whole genome sequencing of the case and its parents on an Illumina NextSeq 500 in 2 × 150 bp paired-end mode and validation using Sanger sequencing and a Kompetitive Allele Specific PCR assay. Samples from the family of an affected Miniature Zebu with bulldog syndrome including parents and siblings, 42 healthy Miniature Zebu not related with members of the herd and 88 individuals from eight different taurine cattle breeds were available for validation.

Results: A bulldog-like Miniature Zebu calf showing a large bulging head, a short and compressed body and extremely short and stocky limbs was delivered after a fetotomy. Computed tomography and necropsy revealed severe craniofacial abnormalities including a shortening of the ventral nasal conchae, a cleft hard palate, rotated limbs as well as malformed and fused vertebrae and ribs. Histopathologic examination showed a disorganization of the physeal cartilage with disorderly arranged chondrocytes in columns and a multifocal closed epiphyseal plate. Whole-genome sequencing of this malformed Miniature Zebu calf, its dam and sire and subsequent comparative sequence analysis revealed a one base pair insertion (ACAN:c.5686insC) located within the cartilage development gene aggrecan (ACAN) exclusively homozygous in the affected calf and heterozygous in its parents. This variant was predicted to cause a frameshift (p.Val1898fsTer9) and thus a truncation of the chondroitin sulfate domain as well as a loss of the C-terminal globular domain of ACAN. It perfectly co-segregated with the lethal bulldog syndrome in Miniature Zebus.

Conclusions: We found a novel mutation in ACAN causing a recessive lethal chondrodysplasia in Miniature Zebu cattle. A diagnostic test for this mutation is now available for Miniature Zebu breeders preventing further cases of bulldog syndrome by targeted matings. To the authors' best knowledge, this is the first case of a Miniature Zebu associated with an ACAN mutation.
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http://dx.doi.org/10.1186/s12863-018-0678-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180608PMC
October 2018
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