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Mathias Ackermann

Publications and source records attributed to Mathias Ackermann.

28 records · Page 2Linked to original sources
PubMed2004

Interplay between alpha/beta and gamma interferons with B, T, and natural killer cells in the defense against herpes simplex virus type 1.

The essential components of the immune system that control primary and chronic infection with herpes simplex virus type 1 (HSV-1) in mice were investigated. Infection within the first few days can be controlled by alpha/beta interferon (IFN-alpha/beta) alone without significant contribution of B, T, or NK cells. IFN-alpha/beta and IFN-gamma cooperate in the elimination of virus in the absence of these lymphocytes. In contrast, B, T, or NK cells appear to be required to control persistent infection with HSV-1. These results suggest that distinct and essential immune elements are recruited in a time-dependent fashion to control acute and persistent HSV-1 infection.

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PubMed2004

Herpes simplex virus type 1 amplicons and their hybrid virus partners, EBV, AAV, and retrovirus.

HSV-1 amplicons can accommodate foreign DNA of any size up to 150 kbp. Genomic sequences as well as cDNA, large transcriptional regulatory sequences for cell type-specific expression, or multiple transgenes can be inserted in a modular fashion. HSV-1 amplicon vectors deliver DNA efficiently into the cell nucleus as an extrachromosomal, non-replicating circular concatenate, which is rapidly diluted, at least in dividing cells. Consequently, transgene expression is lost within days to weeks in dividing cells, but may be retained for months in non-dividing cells. In contrast, vectors based on Epstein-Barr virus, adeno-associated virus, or retroviruses can mediate long-term transgene expression, as vector DNA is retained by episomal replication or chromosomal integration. Hybrid amplicons use genetic elements from HSV-1 that allow replication and packaging of the vector DNA into HSV-1 virions, thereby conserving the large transgene capacity of HSV-1, and genetic elements from other viruses that confer genetic stability to the vector DNA within transduced cells. Additional strategies to sustain genetic material in infected cells include the incorporation of recombinases from different bacteriophages or transposable elements of the Tc1/mariner family in the amplicon vector. Moreover, modification of the HSV-1 virion itself offers a myriad of possibilities to improve gene delivery by targeting specific cell populations or transporting foreign proteins, such as Cre recombinase or the adeno-associated virus Rep protein, which can control the fate and expression of the therapeutic transgene.

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PubMed2003

Flt3 ligand-treated neonatal mice have increased innate immunity against intracellular pathogens and efficiently control virus infections.

Flt-3 ligand (FL), a hematopoetic growth factor, increases the number of dendritic cells (DCs), B cells, and natural killer cells in adult mice but the effect in neonates was unknown. We show that FL treatment of newborn mice induced a >100-fold increase in the innate resistance against infection with herpes simplex virus type 1 and Listeria monocytogenes. This resistance required interferon (IFN)-alpha/beta for viral and interleukin (IL)-12 for bacterial infections. Long-term survival after viral but not bacterial infection was increased approximately 100-fold by FL treatment. After treatment, CD11c(+)/major histocompatibility complex type II(+) and CD11c(+)/B220(+) DC lineage cells were the only cell populations increased in the spleen, liver, peritoneum, and skin. DC induction was independent of IFNs, IL-2, -4, -7, -9, -15, and mature T and B cells. The data suggest that FL increases the number of DCs in neonates and possibly in other immune-compromised individuals, which in turn improves IFN-alpha/beta- and IL-12-associated immune responses.

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PubMed2003

Identification and quantification of ovine gammaherpesvirus 2 DNA in fresh and stored tissues of pigs with symptoms of porcine malignant catarrhal fever.

Cases of porcine malignant catarrhal fever were analyzed by a combination of identification and quantitation of ovine gammaherpesvirus 2 DNA in a variety of paraffin-embedded tissues from diseased pigs, serology, and exclusion of primary porcine gammaherpesviruses. In spite of reduced signal due to fixation and paraffin embedding, ovine gammaherpesvirus 2 DNA in pig brains exceeded the amounts found in sheep brains by orders of magnitude.

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PubMed2002

Herpesviruses: balance in power and powers imbalanced.

The first veterinary herpesvirus symposium, organized under the patronage of the European Society for Veterinary Virology (ESVV) and the Swiss Societies for Microbiology (SGM-SSM), was held at the University of Zurich, Switzerland, on 22nd and 23rd of March 2001. The congress was divided into six sessions. The first session was dedicated to introductory lectures towards the main topics of the symposium, namely pathogenesis, immune response, and gene therapy. Session 2 was committed to new insights into herpesvirus-related gene therapy and vaccination. Specific and general aspects of the immune response against herpesviruses were presented in session 3, while session 4 was dedicated to virus replication. Session 5 was dedicated to a variety of poster presentations. Finally, session 6 revealed new insight into the pathogenesis of different herpesviruses. The present article summarizes the contributions and draws a new view of the herpesviruses. The herpesviruses have apparently found a multi-dimensionally balanced position between the powers of "cytopathogenicity" and "tumorigenicity" on one hand and "immunogenicity" and "tolerogenicity" on the other hand. As long as the different powers stay in balance, no or little clinical disease may be expected in association with herpesvirus infections. However, unbalanced actions of those powers may lead to disease.

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PubMed2002

In vitro and in vivo detection of Mx gene products in bovine cells following stimulation with alpha/beta interferon and viruses.

This study focused on products of the bovine Mx1 gene as specific markers for acute viral infections. The rationale for this is the fact that viral infections are commonly paralleled by the synthesis, release, and remote action of alpha/beta interferons (IFN-alpha/beta). Released IFN-alpha/beta act through specific receptors present on nucleated cells to transduce signals for the transcription of numerous IFN-regulated genes, such as the ones for double-stranded-RNA-dependent protein kinase, 2'-5'-oligoadenylate synthetase, or the Mx proteins. In this study, cultured MDBK cells and bovine white blood cells (WBC) were treated with recombinant IFN-alpha or infected with either bovine herpesvirus 1 (BHV-1) or bovine rotavirus (BRV). Treatment of cultured cells with IFN-alpha was followed within 4 h by a time- and dose-dependent accumulation of intracytoplasmic Mx protein as revealed by immunostaining and Western blot immunoassay. This was preceded by a distinct rise of Mx mRNA in similarly treated cells, as revealed by a newly established quantitative TaqMan PCR technique. The two viruses displayed a cell-dependent in vitro ability to induce Mx proteins, which was limited to bovine WBC with BHV-1 and to MDBK cells with BRV. The established methods were successfully used to show that infection of calves with a noncytopathic strain of bovine viral diarrhea virus, a pestivirus, was followed within 2 days postinfection by strong expression of both Mx mRNA and Mx proteins in WBC.

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PubMed2002

Analysis of the pathogenetic basis for shedding and transmission of ovine gamma herpesvirus 2.

Ovine herpesvirus 2 (OvHV-2), a member of the viral subfamily Gammaherpesvirinae, shares numerous similarities with human herpesvirus 8 (HHV-8). Both viruses are apathogenic in their healthy original host, may cause lymphoprolipherative diseases, cannot routinely be propagated in cell culture, and may be sexually transmitted. However, the pathways of sexual transmission of these viruses, as well as the underlying pathogenetic dynamics, are not well understood. Organs from naturally OvHV-2-infected, as well as OvHV-2-free, sheep were quantitatively analyzed for OvHV-2 by the DNA amplification techniques. The dynamics of OvHV-2 multiplication and excretion were monitored after experimental infections and, most importantly, subsequent to vasectomy. The OvHV-2 DNA load in various tissues and internal organs was not merely reflecting the viral DNA load in the bloodstream, which suggested compartmentalization of OvHV-2. Moreover, OvHV-2 DNA was detected at several portals for virus shedding, i.e., the respiratory, alimentary, and urogenital tracts. Transient OvHV-2 excretion was detected in ejaculates of experimentally infected rams. Upon vasectomy, OvHV-2 DNA reappeared in the ejaculatory plasma, but the titers did not decline after reaching a peak. Spiking and fractionation experiments revealed an inhibitory activity, associated with the spermatozoa, which was able to suppress detection of viral DNA but which was no longer present in samples from vasectomized animals. Therefore, epidemiological studies on viruses that may be transmitted by the ejaculatory pathway and for whose tracing nucleic acid amplification methods are used, i.e., OvHV-2, HHV-8, and the human immunodeficiency virus, should include vasectomized males.

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PubMed2002

Herpes simplex virus type 1/adeno-associated virus hybrid vectors mediate site-specific integration at the adeno-associated virus preintegration site, AAVS1, on human chromosome 19.

Herpes simplex virus type 1 (HSV-1)-based amplicon vectors have a large transgene capacity and can efficiently infect many different cell types. One disadvantage of HSV-1 vectors is their instability of transgene expression. By contrast, vectors based on adeno-associated virus (AAV) can either persist in an episomal form or integrate into the host cell genome, thereby supporting long-term gene expression. AAV expresses four rep genes, rep68, -78, -40, and -52. Of those, rep68 or rep78 are sufficient to mediate site-specific integration of the AAV DNA into the host cell genome. The major disadvantage of AAV vectors is the small transgene capacity ( approximately 4.6 kb). In this study, we constructed HSV/AAV hybrid vectors that contained, in addition to the standard HSV-1 amplicon elements, AAV rep68, rep78, both rep68 and -78, or all four rep genes and a reporter gene that was flanked by the AAV inverted terminal repeats (ITRs). Southern blots of Hirt DNA from cells transfected with the hybrid vectors and HSV-1 helper DNA demonstrated that both the AAV elements and the HSV-1 elements were functional in the context of the hybrid vector. All hybrid vectors could be packaged into HSV-1 virions, although those containing rep sequences had lower titers than vectors that did not. Site-specific integration at AAVS1 on human chromosome 19 was directly demonstrated by PCR and sequence analysis of ITR-AAVS1 junctions in hybrid vector-transduced 293 cells. Cell clones that stably expressed the transgene for at least 12 months could easily be isolated without chemical selection. In the majority of these clones, the transgene cassette was integrated at AAVS1, and no sequences outside the ITR cassette, rep in particular, were present as determined by PCR, ITR rescue/replication assays, and Southern analysis. Some of the clones contained random integrations of the transgene cassette alone or together with sequences outside the ITR cassette. These data indicate that the long-term transgene expression observed following transduction with HSV/AAV hybrid vectors is, at least in part, supported by chromosomal integration of the transgene cassette, both randomly and site specifically.

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