Pathology of Puumala Hantavirus Infection in Macaques

Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland.
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(8):e3035. DOI: 10.1371/journal.pone.0003035
Source: PubMed


Hantaviruses are globally important human pathogens that cause hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Capillary leakage is central to hantaviral diseases, but how it develops, has remained unknown. It has been hypothesized that the pathogenesis of hantavirus infection would be a complex interplay between direct viral effects and immunopathological mechanisms. Both of these were studied in the so far best model of mild hemorrhagic fever with renal syndrome, i.e. cynomolgus macaques infected with wild-type Puumala hantavirus. Viral RNA detected by in situ hybridization and nucleocapsid protein detected by immunohistochemical staining were observed in kidney, spleen and liver tissues. Inflammatory cell infiltrations and tubular damage were found in the kidneys, and these infiltrations contained mainly CD8-type T-cells. Importantly, these results are consistent with those obtained from patients with hantaviral disease, thus showing that the macaque model of hantavirus infection mimics human infection also on the tissue level. Furthermore, both the markers of viral replication and the T-cells appeared to co-localize in the kidneys to the sites of tissue damage, suggesting that these two together might be responsible for the pathogenesis of hantavirus infection.

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    • "(A) Alveolar hemorrhage in MJNV 04–55 infected hamster, group I (age b 24 h), No. 2; (B) interstitial pneumonia in MJNV 04–55 infected hamster, group I (age b 24 h), No. 5; (C) severe congestion in MJNV 04–55 infected hamster, group III (Age 10 days), No. 4; (D) interstitial pneumonia and congestion in MJNV 04–55 infected hamster, group IV (Age 14 days), No. 8; (E) interstitial thickening in MJNV 04–55 infected hamster, group VII (age 56 days), No. 6; (F) alveolar old hemorrhage and congestion in MJNV 05–11 infected hamster, group III (age 10 days), No. 2; (G) interstitial pneumonia, severe alveolar hemorrhage and congestion in MJNV 05–11 infected hamster, group V (age 21 days), No. 2; (H) lung from control uninfected hamster. H&E stain; original magnifications, ×200. in situ hybridization and localization of PUUV NP by immunohistochemistry in kidney, spleen and liver tissues, as well as elevated cytokine levels, are consistent with those observed in patients with HFRS (Klingström et al., 2002; Sironen et al., 2008). At the same time, mild, transient proteinuria and azotemia were produced in cynomolgus monkeys and a chimpanzee (Pan troglodytes) following intravenous inoculation with Prospect Hill virus, a putative nonpathogenic hantavirus harbored by meadow voles (Yanagihara et al., 1988). "
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    ABSTRACT: To gain insights into the pathogenicity of Imjin virus (MJNV), a newfound hantavirus isolated from the Ussuri white-toothed shrew (Crocidura lasiura), groups of Syrian hamsters (Mesocricetus auratus) of varying ages (<1, 5, 10, 14, 21, 35 and 56days) were inoculated by the intraperitoneal route with 1000 pfu of MJNV strains 04-55 and 05-11. MJNV-infected Syrian hamsters, aged 21days or less, exhibited reduced activity, weight loss, respiratory distress, hind-limb paralysis and seizures. Death ensued 1 to 6days after onset of clinical disease. MJNV RNA was detected in brain and other major organs by RT-PCR and real time-PCR. Histopathological examination showed alveolar hemorrhage, interstitial pneumonia and severe pulmonary congestion; focal hepatic necrosis and portal inflammation; and acute meningoencephalitis. By immunohistochemistry, MJNV antigen was detected in pulmonary microvascular endothelial cells and glial cells. Older hamsters (35 and 56days of age) developed subclinical infection without histopathological changes. Future studies are warranted to determine the pathophysiologic bases for the differential age susceptibility of Syrian hamsters to lethal MJNV disease.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 09/2015; 36. DOI:10.1016/j.meegid.2015.09.009 · 3.02 Impact Factor
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    • "PUUV nucleocapsid antigen was located mainly in endothelial cells of capillaries or larger vessels in the lamina propria. This finding accords with previous reports from patients with HCPS, with experimental PUUV infection in cynomolgus macaques and from our recent report [25], [34], [35]. Almost all hantavirus infections (especially southern Germany) are caused by PUUV [7], [33], although Tula virus and Dobrava-Belgrade virus circulates in Germany and might cause symptomatic infections in humans [36]–[39]. "
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    ABSTRACT: Background Puumala virus (PUUV) is the most important hantavirus species in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute renal injury (AKI) with thrombocytopenia and frequently gastrointestinal symptoms. Methods 456 patients with serologically and clinically confirmed NE were investigated at time of follow-up in a single clinic. The course of the NE was investigated using medical reports. We identified patients who had endoscopy with intestinal biopsy during acute phase of NE. Histopathological, immunohistochemical and molecular analyses of the biopsies were performed. Results Thirteen patients underwent colonoscopy or gastroscopy for abdominal pain, diarrhea, nausea and vomiting during acute phase of NE. Immunohistochemistry (IHC) revealed PUUV nucleocapsid antigen in 11 biopsies from 8 patients; 14 biopsies from 5 patients were negative for PUUV nucleocapsid antigen. IHC localized PUUV nucleocapsid antigen in endothelial cells of capillaries or larger vessels in the lamina propria. Rate of AKI was not higher and severity of AKI was not different in the PUUV-positive compared to the PUUV-negative group. All IHC positive biopsies were positive for PUUV RNA using RT-PCR. Phylogenetic reconstruction revealed clustering of all PUUV strains from this study with viruses previously detected from the South-West of Germany. Long-term outcome was favorable in both groups. Conclusions In patients with NE, PUUV nucleocapsid antigen and PUUV RNA was detected frequently in the intestine. This finding could explain frequent GI-symptoms in NE patients, thus demonstration of a more generalized PUUV infection. The RT-PCR was an effective and sensitive method to detect PUUV RNA in FFPE tissues. Therefore, it can be used as a diagnostic and phylogenetic approach also for archival materials. AKI was not more often present in patients with PUUV-positive IHC. This last finding should be investigated in larger numbers of patients with PUUV infection.
    PLoS ONE 05/2014; 9(5):e98397. DOI:10.1371/journal.pone.0098397 · 3.23 Impact Factor
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    • "Infecting hamsters with these viruses results in disease with characteristics similar to those of human HPS, including interstitial pneumonitis and microvascular leakage. No small animal model exists for HFRS, though HFRS-like illness has been observed in cynomolgus macaques infected with a Puumala virus strain that was propagated in the rodent host and not tissue culture-adapted (Klingstrom et al. 2002; Sironen et al. 2008). Currently, in vivo experiments using small molecule tyrosine kinase inhibitors have been initiated in hantavirus-infected hamsters (Dolgin 2012). "
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    ABSTRACT: Viral hemorrhagic diseases are a group of systemic viral infections with worldwide distribution and are significant causes of global mortality and morbidity. The hallmarks of viral hemorrhagic fevers are plasma leakage, thrombocytopenia, coagulopathy and hemorrhagic manifestations. The molecular mechanisms leading to plasma leakage in viral hemorrhagic fevers are not well understood. A common theme has emerged in which a complex interplay between pathogens, host immune response, and endothelial cells leads to the activation of endothelial cells and perturbation of barrier integrity. In this article, two clinically distinct viral hemorrhagic fevers caused by dengue viruses and hantaviruses are discussed to highlight their similarities and differences that may provide insights into the pathogenesis and therapeutic approach.
    Cell and Tissue Research 03/2014; 355(3). DOI:10.1007/s00441-014-1841-9 · 3.57 Impact Factor
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