Wu-Chun Cao

Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice

The recent Zika virus (ZIKV) epidemic in Latin America coincided with a marked increase in microcephaly in newborns. However, the causal link between maternal ZIKV infection and malformation of the fetal brain has not been firmly established. Here we show a vertical transmission of ZIKV in mice and a marked effect on fetal brain development. We found that intraperitoneal (i.p.) injection of a contemporary ZIKV strain in pregnant mice led to the infection of radial glia cells (RGs) of dorsal ventricular zone of the fetuses, the primary neural progenitors responsible for cortex development, and caused a marked reduction of these cortex founder cells in the fetuses. Interestingly, the infected fetal mice exhibited a reduced cavity of lateral ventricles and a discernable decrease in surface areas of the cortex. This study thus supports the conclusion that vertically transmitted ZIKV affects fetal brain development and provides a valuable animal model for the evaluation of potential therapeutic or preventative strategies.

Environmental factors contributing to the spread of H5N1 avian influenza in mainland China

BACKGROUND Since late 2003, highly pathogenic avian influenza (HPAI) outbreaks caused by infection with H5N1 virus has led to the deaths of millions of poultry and more than 10 thousands of wild birds, and as of 18-March 2008, at least 373 laboratory-confirmed human infections with 236 fatalities, have occurred. The unrestrained worldwide spread of this disease has caused great anxiety about the potential of another global pandemic. However, the effect of environmental factors influencing the spread of HPAI H5N1 virus is unclear. METHODOLOGY/PRINCIPAL FINDINGS A database including incident dates and locations was developed for 128 confirmed HPAI H5N1 outbreaks in poultry and wild birds, as well as 21 human cases in mainland China during 2004-2006. These data, together with information on wild bird migration, poultry densities, and environmental variables (water bodies, wetlands, transportation routes, main cities, precipitation and elevation), were integrated into a Geographical Information System (GIS). A case-control design was used to identify the environmental factors associated with the incidence of the disease. Multivariate logistic regression analysis indicated that minimal distance to the nearest national highway, annual precipitation and the interaction between minimal distance to the nearest lake and wetland, were important predictive environmental variables for the risk of HPAI. A risk map was constructed based on these factors. CONCLUSIONS/SIGNIFICANCE Our study indicates that environmental factors contribute to the spread of the disease. The risk map can be used to target countermeasures to stop further spread of the HPAI H5N1 at its source.

Landscape elements and Hantaan virus-related hemorrhagic fever with renal syndrome, People's Republic of China.

Hemorrhagic fever with renal syndrome (HFRS) is an important public health problem in the People’s Republic of China, accounting for 90% of human cases reported globally. In this study, a landscape epidemiologic approach, combined with geographic information system and remote sensing techniques, was applied to increase our understanding of HFRS due to Hantaan virus and its relationship with landscape elements in China. The landscape elements considered were elevation, normalized difference vegetation index (NDVI), precipitation, annual cumulative air temperature, land surface temperature, soil type, and land use. Multivariate logistic regression analysis showed that HFRS incidence was remarkably associated with elevation, NDVI, precipitation, annual cumulative air temperature, semihydromorphic soils, timber forests, and orchards. These findings have important applications for targeting HFRS interventions in mainland China.

Circulation of Coxsackievirus A10 and A6 in Hand-Foot-Mouth Disease in China, 2009–2011

Coxsackieviruses A10 (CV-A10) and A6 (CV-A6) have been associated with increasingly occurred sporadic hand-foot-mouth disease (HFMD) cases and outbreak events globally. However, our understanding of epidemiological and genetic characteristics of these new agents remains far from complete. This study was to explore the circulation of CV-A10 and CV-A6 in HFMD and their genetic characteristics in China. A hospital based surveillance was performed in three heavily inflicted regions with HFMD from March 2009 to August 2011. Feces samples were collected from children with clinical diagnosis of HFMD. The detection and genotyping of enteroviruses was performed by real-time PCR and sequencing of 5′UTR/VP1 regions. Phylogenetic analysis and selection pressure were performed based on the VP1 sequences. Logistic regression model was used to identify the effect of predominant enterovirus serotypes in causing severe HFMD. The results showed 92.0% of 1748 feces samples were detected positive for enterovirus, with the most frequently presented serotypes as EV-71 (944, 54.0%) and CV-A16 (451, 25.8%). CV-A10 and CV-A6 were detected as a sole pathogen in 82 (4.7%) and 44 (2.5%) cases, respectively. Infection with CV-A10 and EV-71 were independently associated with high risk of severe HFMD (OR = 2.66, 95% CI: 1.40–5.06; OR = 4.81, 95% CI: 3.07–7.53), when adjusted for age and sex. Phylogenetic analysis revealed that distinct geographic and temporal origins correlated with the gene clusters based on VP1 sequences. An overall ω value of the VP1 was 0.046 for CV-A10 and 0.047 for CV-A6, and no positively selected site was detected in VP1 of both CV-A10 and CV-A6, indicating that purifying selection shaped the evolution of CV-A10 and CV-A6. Our study demonstrates variety of enterovirus genotypes as viral pathogens in causing HFMD in China. CV-A10 and CV-A6 were co-circulating together with EV-71 and CV-A16 in recent years. CV-A10 infection might also be independently associated with severe HFMD.

Documenting the SARS epidemic in mainland China

In 2003, the world was confronted with the emergence of anew and in many cases fatal infectious disease, severe acuterespiratory syndrome (SARS). SARS was caused by a novelcoronavirus, which was provisionally termed SARS-asso-ciated coronavirus (SARS-CoV) (Drosten et al. 2003;Ksiazek et al. 2003). The earliest cases of SARS occurred inmid-November 2002 in Guangdong Province, China. SARSwas first recognised in February 2003, when cases with anatypical pneumonia of unknown cause began appearingamong hospital staff in Guangzhou, China. Within weeks,similar outbreaks occurred in Hanoi, Hong Kong, Toronto,Singapore and Taiwan. Soon thereafter, cases were beingreported from 32 countries and areas (later corrected to29). After July 2003, SARS came under control thanks toenormous efforts made by national and internationalorganisations. More than 8000 cases were reportedworldwide, with over 5000 from mainland China, makingthe country the epicentre of the outbreak (WHO 2004).During the SARS outbreak in China, epidemiologicaland clinical information were obtained in difficult cir-cumstances. The available data were only to a limitedextent analysed and reported, and mainly in Chineseliterature. There is a need for a comprehensive documen-tation of the SARS epidemic in China, accessible to theinternational scientific community. Following the epi-demic, the European Union provided research funds toincrease European preparedness for emerging infectiousdiseases, and as an important component to learn as muchas possible from the experience of the People’s Republic ofChina with regard to controlling SARS. This researchprogramme was titled SARSControl: ‘Effective andAcceptable Strategies for the Control of SARS and newemerging infections in China and Europe’. From 2005 to2008, multidisciplinary research activities were under-taken, including in-depth studies of the Chinese situation,which are now reported in this supplement.The supplement covers a wide range of studies. The firstessential step was to bring together all available epidemi-ological data in one comprehensive database, whichrequired data collection and cleaning, where necessaryreturning to original hospital records. This exerciseresulted in a database containing epidemiological infor-mation of all known 5327 SARS cases, including 343deaths, from mainland China. The first paper in thissupplement presents the database and describes the contextin which the data were originally collected (Feng et al.2009a). The following three papers exploit the databasethrough a description of, respectively, the geographicspread of SARS (Fang et al. 2009); case fatality ratio (Jiaet al. 2009); and key epidemiological parameters such asduration of onset of disease to recovery or death (Fenget al. 2009b). These first four papers are followed by twocomparative reviews. One is on the major control measurestaken by China and other SARS-affected countries andareas (Ahmad et al. 2009). The other is on serologicalconfirmation of SARS to assess possible over-reporting ofSARS patients in mainland China (Liu et al. 2009a). Next,three hospital-based papers provide, respectively, a case–control study of risk factors among healthcare workers inBeijing, including the impact of protective measures (Liuet al. 2009b); a description of clinical characteristics ofSARS patients in a hospital in Tianjin that experienced alarge outbreak (Wei et al. 2009); and an analysis of thetransmissibility of SARS and the effectiveness of controlmeasures in three major hospital outbreaks (Cooper et al.2009). Some consequences of SARS are described in thefollowing three papers: an important long-term clinicalconsequence is the high proportion of avascular osteone-crosis in SARS patients treated with corticosteroids, asdescribed in a cohort study of former SARS patients (Lvet al. 2009). The economic impact of the outbreak isdescribed in a paper analysing indicators of social andeconomic activity in Beijing, such as leisure activities,transport, and tourism (Beutels et al. 2009). A positiveconsequence of SARS is illustrated by a review of Chineseliterature describing the stark increase of papers onmodelling of infectious diseases following the outbreak,representing scientific capacity building in China (Han

Spatio-Temporal Distribution of Malaria in Yunnan Province, China

The spatio-temporal distribution pattern of malaria in Yunnan Province, China was studied using a geographic information system technique. Both descriptive and temporal scan statistics revealed seasonal fluctuation in malaria incidences in Yunnan Province with only one peak during 1995-2000, and two apparent peaks from 2001 to 2005. Spatial autocorrelation analysis indicated that malaria incidence was not randomly distributed in the province. Further analysis using spatial scan statistics discovered that the high risk areas were mainly clustered at the bordering areas with Myanmar and Laos, and in Yuanjiang River Basin. There were obvious associations between Plasmodium vivax and Plasmodoium falciparum malaria incidences and climatic factors with a clear 1-month lagged effect, especially in cluster areas. All these could provide information on where and when malaria prevention and control measures would be applied. These findings imply that countermeasures should target high risk areas at suitable times, when climatic factors facilitate the transmission of malaria.

Spatial analysis of malaria in Anhui province, China

BackgroundMalaria has re-emerged in Anhui Province, China, and this province was the most seriously affected by malaria during 2005–2006. It is necessary to understand the spatial distribution of malaria cases and to identify highly endemic areas for future public health planning and resource allocation in Anhui Province.MethodsThe annual average incidence at the county level was calculated using malaria cases reported between 2000 and 2006 in Anhui Province. GIS-based spatial analyses were conducted to detect spatial distribution and clustering of malaria incidence at the county level.ResultsThe spatial distribution of malaria cases in Anhui Province from 2000 to 2006 was mapped at the county level to show crude incidence, excess hazard and spatial smoothed incidence. Spatial cluster analysis suggested 10 and 24 counties were at increased risk for malaria (P < 0.001) with the maximum spatial cluster sizes at < 50% and < 25% of the total population, respectively.ConclusionThe application of GIS, together with spatial statistical techniques, provide a means to quantify explicit malaria risks and to further identify environmental factors responsible for the re-emerged malaria risks. Future public health planning and resource allocation in Anhui Province should be focused on the maximum spatial cluster region.

Combining spatial-temporal and phylogenetic analysis approaches for improved understanding on global H5N1 transmission.

Background Since late 2003, the highly pathogenic influenza A H5N1 had initiated several outbreak waves that swept across the Eurasia and Africa continents. Getting prepared for reassortment or mutation of H5N1 viruses has become a global priority. Although the spreading mechanism of H5N1 has been studied from different perspectives, its main transmission agents and spread route problems remain unsolved. Methodology/Principal Findings Based on a compilation of the time and location of global H5N1 outbreaks from November 2003 to December 2006, we report an interdisciplinary effort that combines the geospatial informatics approach with a bioinformatics approach to form an improved understanding on the transmission mechanisms of H5N1 virus. Through a spherical coordinate based analysis, which is not conventionally done in geographical analyses, we reveal obvious spatial and temporal clusters of global H5N1 cases on different scales, which we consider to be associated with two different transmission modes of H5N1 viruses. Then through an interdisciplinary study of both geographic and phylogenetic analysis, we obtain a H5N1 spreading route map. Our results provide insight on competing hypotheses as to which avian hosts are responsible for the spread of H5N1. Conclusions/Significance We found that although South China and Southeast Asia may be the virus pool of avian flu, East Siberia may be the source of the H5N1 epidemic. The concentration of migratory birds from different places increases the possibility of gene mutation. Special attention should be paid to East Siberia, Middle Siberia and South China for improved surveillance of H5N1 viruses and monitoring of migratory birds.

Human Infection with Candidatus Neoehrlichia mikurensis, China

To identify Candidatus Neoehrlichia mikurensis infection in northeastern China, we tested blood samples from 622 febrile patients. We identified in 7 infected patients and natural foci for this bacterium. Field surveys showed that 1.6% of ticks and 3.8% of rodents collected from residences of patients were also infected.

Isolation, identification and genomic characterization of the Asian lineage Zika virus imported to China

1 Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China 2 Graduate School, Guangxi Medical University, Xining 530021, China 3 The Central Laboratory of Health Quarantine, Shenzhen Travel Healthcare Center, Shenzhen Entry-Exit Inspection and Quarantine Bureau, Shenzhen 518033, China 4 Laboratory Animal Center, Academy of Military Medical Science, Beijing 100071, China 5 Graduate School, Anhui Medical University, Hefei 230032, China