Ongoing spillover of Hantaan and Gou hantaviruses from rodents is associated with hemorrhagic fever with renal syndrome (HFRS) in China.

BACKGROUND: Longquan City, Zhejiang province, China, has been seriously affected by hemorrhagic fever with renal syndrome (HFRS) since the first cases were registered in 1974. To understand the epidemiology and emergence of HFRS in Longquan, which may be indicative of large parts of rural China, we studied long-term incidence patterns and performed a molecular epidemiological investigation of the causative hantaviruses in human and rodent populations. METHOD/PRINCIPAL FINDINGS: During 1974-2011, 1866 cases of HFRS were recorded in Longquan, including 20 deaths. In 2011, the incidence of HFRS remained high, with 19.61 cases/100,000 population, despite the onset of vaccination in 1997. During 1974-1998, HFRS cases in Longquan occurred mainly in winter, while in the past decade the peak of HFRS has shifted to the spring. Notably, the concurrent prevalence of rodent-borne hantaviruses in the region was also high. Phylogenetic analyses of viral sequences recovered from rodents in Longquan revealed the presence of novel genetic variants of Gou virus (GOUV) in Rattus sp. rats and Hantaan virus (HTNV) in the stripe field mice, respectively. Strikingly, viral sequences sampled from infected humans were very closely related to those from rodents. CONCLUSIONS/SIGNIFICANCE: HFRS represents an important public health problem in Longquan even after years of preventive measures. Our data suggest that continual spillover of the novel genetic variant of GOUV and the new genetic lineage of HTNV are responsible for the high prevalence of HFRS in humans. In addition, this is the first report of GOUV associated with human HFRS cases, and our data suggest that GOUV is now the major cause of HFRS in this region.

Phylogeny and origins of hantaviruses harbored by bats, insectivores, and rodents.

Hantaviruses are among the most important zoonotic pathogens of humans and the subject of heightened global attention. Despite the importance of hantaviruses for public health, there is no consensus on their evolutionary history and especially the frequency of virus-host co-divergence versus cross-species virus transmission. Documenting the extent of hantavirus biodiversity, and particularly their range of mammalian hosts, is critical to resolving this issue. Here, we describe four novel hantaviruses (Huangpi virus, Lianghe virus, Longquan virus, and Yakeshi virus) sampled from bats and shrews in China, and which are distinct from other known hantaviruses. Huangpi virus was found in Pipistrellus abramus, Lianghe virus in Anourosorex squamipes, Longquan virus in Rhinolophus affinis, Rhinolophus sinicus, and Rhinolophus monoceros, and Yakeshi virus in Sorex isodon, respectively. A phylogenetic analysis of the available diversity of hantaviruses reveals the existence of four phylogroups that infect a range of mammalian hosts, as well as the occurrence of ancient reassortment events between the phylogroups. Notably, the phylogenetic histories of the viruses are not always congruent with those of their hosts, suggesting that cross-species transmission has played a major role during hantavirus evolution and at all taxonomic levels, although we also noted some evidence for virus-host co-divergence. Our phylogenetic analysis also suggests that hantaviruses might have first appeared in Chiroptera (bats) or Soricomorpha (moles and shrews), before emerging in rodent species. Overall, these data indicate that bats are likely to be important natural reservoir hosts of hantaviruses.

[Genetic characteristics of hantaviruses carried by Microtus maximowixzii in Yakeshi of Inner Mongolia, China].

OBJECTIVE: To analyze the viral genetic characteristics of hantaviruses carried by Microtus maximowixzii in Yakeshi of Inner Mongolia Autonomous Region and its relationship with Hantaan virus (HTNV) and Seoul virus (SEOV) viruses as well as to identify the natural host of Khabarovsk virus (KHAV). METHODS: HV specific RNAs were detected by RT-PCR. Complete S and M segment were amplified from the RNA-positive samples. Phylogenetic analysis were performed to estimate the genetic characterization and the relationship with other hantaviruses. RESULTS: Fifty two Microtus maximowixzii voles were captured in Yakeshi areas. Of those voles, hantaviral RNA was tested positive in 5 samples (9.62%). Complete S and M segments sequences were obtained from 5 and 2 lung samples, respectively. The complete S segment was consisted of 1848 to 1861 bp, and the M segment consisted of 3662 bp. These viruses were closely related to each other with 92.5% - 96.4% for the S segment sequences and 88.9% - 95.4% for the M segment sequences. They shared a higher identity with KHAV found previously in Yakeshi and KHAV of Russia. However, they were obviously different from the other hantavirus species. The 5 strains had the consistent secondary structure of nucleocapsid protein (NP) and glycoprotein (GP). When further comparing their secondary structures with those of HTNV and SEOV, our results indicated that there were no obvious differences in NP between KHAV and both HNTV, SEOV but with obvious difference in GP. Based on the S and M segment sequences, phylogenetic analyses revealed that these 5 strains clustered together with KHAV and formed a distinct lineage. Furthermore, all known KHAV strains could be divided into two small branches with a nucleotide divergence more than 5.3%. CONCLUSION: Our research data revealed that KHAV was highly endemic among Microtus maximowixzii in Yakeshi area which supported the notion that Microtus maximowixzii had been the natural host of KHAV in the area.

Infection and pathogenesis of Huaiyangshan virus (a novel tick-borne bunyavirus) in laboratory rodents.

A novel tick-borne bunyavirus (Huaiyangshan virus, HYSV), which causes haemorrhagic fever-like disease, has recently been reported in China. So far no animal experiments have been performed to study its pathogenesis. Towards developing an animal model for HYSV fever, newborn and adult mice and rats and golden hamsters were inoculated intracerebrally or intraperitoneally with HYSV. Newborn rats and newborn mice, especially Kunming (KM) mice, appeared highly susceptible. Remarkably, the KM mice that died of the HYSV infection developed large necrotic areas in the liver, while no obvious pathological changes were observed within the other organs. PCR and immunohistochemical analyses of the post-mortem material detected both HYSV antigen and RNA in almost all organs, indicating a systemic infection. Our data demonstrate that HYSV can cause a lethal infection of both newborn mice and newborn rats with apparent pathological damage of the liver. This animal model may help to understand the pathogenesis of the HYSV infection in humans.

[SIRT1 inhibits IL-1ß mRNA transcription in lipopolysaccharide tolerant THP-1 cells].

OBJECTIVE: To explore the role of silent information regulation 2 homolog 1 (SIRT1) in the regulation of IL-1ß mRNA transcription in lipopolysaccharide (LPS) tolerant THP-1 cells. METHODS: THP-1 human promonocyte model of endotoxin tolerance that simulates the sepsis leukocyte phenotype was used. Chromatin immunoprecipitation assay (ChIP) and real-time PCR were applied to quantify the binding of SIRT1 and histone H3 lys9/H4 lys16 acetylation to IL-1ß promoter. IL-1ß mRNA transcription was studied after knocking down the SIRT1. RESULTS: The binding of SIRT1 to IL-1ß promoter increased about 5 times in tolerant THP-1 cells (P < 0.05), which was accompanied by the low level of histone H3 lys9/H4 lys16 acetylation (P < 0.05, compared with normal cells). Knocking-down of SIRT1 increased the transcription of IL-1ß mRNA up to the level of 68% of normal cells (P < 0.05), which was accompanied by the increase of histone H3 lys9/H4 lys16 acetylation (P < 0.05). However, there was no significant difference of p65 lys310 acetylation between normal and tolerant cells. CONCLUSION: SIRT1 inhibited the IL-1ß mRNA transcription in tolerant THP-1 cells but had not related to p65 lys310 acetylation. However, it was related to IL-1ß promoter acetylation.