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Institute
Hantaviren in Deutschland
(2018)
Hantaviren sind Kleinsäuger-assoziierte Krankheitserreger, die vor allem in Nagetieren, aber auch in Spitzmäusen, Maulwürfen und Fledermäusen vorkommen. Ziel dieser Arbeit ist es, einen aktuellen Überblick zur Epidemiologie und Ökologie der Hantaviren in Deutschland zu geben und Modelle zur Vorhersage von Virusausbrüchen zu diskutieren. In Deutschland werden die meisten humanen Erkrankungsfälle beim Menschen durch das von der Rötelmaus (Myodes glareolus) übertragene Puumalavirus (PUUV) verursacht. PUUV ist mit der westlichen evolutionären Linie der Rötelmaus assoziiert und fehlt im östlichen und nördlichen Teil Deutschlands. Ein zweites humanpathogenes Hantavirus ist das Dobrava-Belgrad-Virus (DOBV), Genotyp Kurkino, dessen Reservoir die vor allem im östlichen Teil Deutschlands vorkommende Brandmaus (Apodemus agrarius) ist. Ein PUUV-verwandtes Hantavirus ist das selten humanpathogene Tulavirus (TULV), das mit der Feldmaus (Microtus arvalis) assoziiert ist. Darüber hinaus wurden mit dem Seewis-, Asikkala- und Brugesvirus Spitzmaus- und Maulwurf-assoziierte Hantaviren mit noch unklarer Humanpathogenität gefunden.
Die humanen Erkrankungen sind jeweils mit den verschiedenen Hantaviren in deren regionaler Verteilung assoziiert und können mild bis schwer, aber auch subklinisch verlaufen. Das Auftreten von Häufungen humaner, durch PUUV verursachter Erkrankungen in den Jahren 2007, 2010, 2012, 2015 und 2017 korreliert mit dem Auftreten einer starken Fruktifikation der Buche („Buchenmast“) im jeweiligen Vorjahr. Auf der Basis von Wetterparametern sind Modelle zur Vorhersage von PUUV-Erkrankungshäufungen entwickelt worden, die zukünftig validiert und optimiert werden müssen. Neben dem Ausmaß des Virusvorkommens im Reservoir wird das Risiko humaner Infektionen durch das Expositionsverhalten des Menschen beeinflusst. Durch die Anwendung von Prognosemodellen soll der öffentliche Gesundheitsdienst in die Lage versetzt werden, räumlich und zeitlich gezielte und sachgerechte Präventionsempfehlungen für die Bevölkerung abzugeben.
Chronic kidney disease (CKD) is associated with excessive mortality from cardiovascular disease (CVD). Endothelial dysfunction, an early manifestation of CVD, is consistently observed in CKD patients and might be linked to structural defects of the microcirculation including microvascular rarefaction. However, patterns of microvascular rarefaction in CKD and their relation to functional deficits in perfusion and oxygen delivery are currently unknown. In this in-vivo microscopy study of the cremaster muscle microcirculation in BALB/c mice with moderate to severe uremia, we show in two experimental models (adenine feeding or subtotal nephrectomy), that serum urea levels associate incrementally with a distinct microangiopathy. Structural changes were characterized by a heterogeneous pattern of focal microvascular rarefaction with loss of coherent microvascular networks resulting in large avascular areas. Corresponding microvascular dysfunction was evident by significantly diminished blood flow velocity, vascular tone, and oxygen uptake. Microvascular rarefaction in the cremaster muscle paralleled rarefaction in the myocardium, which was accompanied by a decrease in transcription levels not only of the transcriptional regulator HIF-1 alpha, but also of its target genes Angpt-2, TIE-1 and TIE-2, Flkt-1 and MMP-9, indicating an impaired hypoxia-driven angiogenesis. Thus, experimental uremia in mice associates with systemic microvascular disease with rarefaction, tissue hypoxia and dysfunctional angiogenesis.
The matrix metalloproteinases (MMP) MMP-2 and MMP-9 are physiological regulators of vascular remodelling. Their dysregulation could contribute to vascular calcification. We examined the role of the MMP-2 and MMP-9 in uraemic vascular calcification in vivo and in vitro. The impact of pharmacological MMP inhibition on the development of media calcifications was explored in an aggressive animal model of uraemic calcification. In addition, the selective effects of addition and inhibition, respectively, of MMP-2 and MMP-9 on calcium-/phosphate-induced calcifications were studied in a murine cell line of vascular smooth muscle cells (VSMCs). High-dose calcitriol treatment of uraemic rats given a high phosphate diet induced massive calcifications, apoptosis and increased gene expressions of MMP-2, MMP-9 and of osteogenic transcription factors and proteins in aortic VSMC. The MMP inhibitor doxycycline prevented the VSMC transdifferentiation to osteoblastic cells, suppressed transcription of mediators of matrix remodelling and almost completely blocked aortic calcifications while further increasing apoptosis. Similarly, specific inhibitors of either MMP-2 or -9, or of both gelatinases (Ro28-2653) and a selective knockdown of MMP-2/-9 mRNA expression blocked calcification of murine VSMC induced by calcification medium (CM). In contrast to MMP inhibition, recombinant MMP-2 or MMP-9 enhanced CM-induced calcifications and the secretion of gelatinases. These data indicate that both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodelling and the initiation of vascular calcification. Their inhibition seems a promising strategy in the prevention of vascular calcifications.
An increase in zoonotic infections in humans in recent years has led to a high level of public interest. However, the extent of infestation of free-living small mammals with pathogens and especially parasites is not well understood. This pilot study was carried out within the framework of the "Rodent-borne pathogens" network to identify zoonotic parasites in small mammals in Germany. From 2008 to 2009, 111 small mammals of 8 rodent and 5 insectivore species were collected. Feces and intestine samples from every mammal were examined microscopically for the presence of intestinal parasites by using Telemann concentration for worm eggs, Kinyoun staining for coccidia, and Heidenhain staining for other protozoa. Adult helminths were additionally stained with carmine acid for species determination. Eleven different helminth species, five coccidians, and three other protozoa species were detected. Simultaneous infection of one host by different helminths was common. Hymenolepis spp. (20.7%) were the most common zoonotic helminths in the investigated hosts. Coccidia, including Eimeria spp. (30.6%), Cryptosporidium spp. (17.1%), and Sarcocystis spp. (17.1%), were present in 40.5% of the feces samples of small mammals. Protozoa, such as Giardia spp. and amoebae, were rarely detected, most likely because of the repeated freeze-thawing of the samples during preparation. The zoonotic pathogens detected in this pilot study may be potentially transmitted to humans by drinking water, smear infection, and airborne transmission.