Large-Scale Comparative Analyses of Tick Genomes Elucidate Their Genetic Diversity and Vector Capacities.

Among arthropod vectors, ticks transmit the most diverse human and animal pathogens, leading to an increasing number of new challenges worldwide. Here we sequenced and assembled high-quality genomes of six ixodid tick species and further resequenced 678 tick specimens to understand three key aspects of ticks: genetic diversity, population structure, and pathogen distribution. We explored the genetic basis common to ticks, including heme and hemoglobin digestion, iron metabolism, and reactive oxygen species, and unveiled for the first time that genetic structure and pathogen composition in different tick species are mainly shaped by ecological and geographic factors. We further identified species-specific determinants associated with different host ranges, life cycles, and distributions. The findings of this study are an invaluable resource for research and control of ticks and tick-borne diseases.

Haemaphysalis longicornis Ticks as Reservoir and Vector of Severe Fever with Thrombocytopenia Syndrome Virus in China.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever in East Asia caused by SFTS virus (SFTSV), a newly discovered phlebovirus. The Haemaphysalis longicornis tick has been suspected to be the vector of SFTSV. To determine whether SFTSV can be transmitted among ticks, from ticks to animals, and from animals to ticks, we conducted transmission studies between developmental stages of H. longicornis ticks and between ticks and mice. Using reverse transcription PCR, we also analyzed the prevalence of SFTSV infection among H. longicornis ticks collected from vegetation in Shandong Province, China. Our results showed a low prevalence of SFTSV among collected ticks (0.2%, 8/3,300 ticks), and we showed that ticks fed on SFTSV-infected mice could acquire the virus and transstadially and transovarially transmit it to other developmental stages of ticks. Furthermore, SFTSV-infected ticks could transmit the virus to mice during feeding. Our findings indicate ticks could serve as a vector and reservoir of SFTSV.

Changes in Cytokine Levels in Patients with Severe Fever with Thrombocytopenia Syndrome Virus.

Purpose: To characterize the cytokine profile of patients with severe fever with thrombocytopenia syndrome (SFTS) in relation to disease severity. Patients and Methods: 60 laboratory-confirmed SFTS patients and 12 healthy individuals from multi-centers in Shandong Province of China were included, and all patients were divided into fatal patients (9) and recovered patients (51) due to their final outcomes. Multiplex-microbead immunoassays were conducted to estimate levels of 27 cytokines in the sera of patients and controls. Results: The results showed that levels of IL-2, IL-4, IL-6, IL-7, IL-8, IL-15, IL-1RA, G-CSF, GM-CSF, IFN-γ, TNF-α, basic FGF, PDGF-BB, RANTES, IP-10, MIP-1α, MIP-1ß, MCP-1, and Eotaxin differed significantly among the SFTS fatal patients, recovered patients, and the healthy controls (all p<0.05). Compared to the healthy controls, the fatal patients and recovered patients had reduced levels of IL-2, IL-4, IL-7, PDGF-BB, RANTES, and Eotaxin, while the levels of PDGF-BB and RANTES were significantly lower in fatal patients compared to recovered patients. The increasing levels of IL-6, IL-8, IL-15, IL-1RA, G-CSF, GM-CSF, IFN-γ, TNF-α, basic FGF, IP-10, MIP-1α, MIP-1ß, and MCP-1 were observed in fatal patients (all p<0.05), and the levels of IL-6, IP-10, MIP-1α, and MCP-1 were significantly higher than other two groups. The Spearman correlation analysis indicated a positive correlation between platelet count and PDGF-BB levels (p<0.05), while the white blood cell count had a negative correlation with MIP-1 level (p<0.05). Conclusion: The research exhibited that the SFTS virus (SFTSV) caused an atypical manifestation of cytokines. The levels of IL-6, IP-10, MIP-1α, and MCP-1 had been observed a positive association with the severity of the illness.

Virome diversity shaped by genetic evolution and ecological landscape of Haemaphysalis longicornis.

BACKGROUND: Haemaphysalis longicornis is drawing attentions for its geographic invasion, extending population, and emerging disease threat. However, there are still substantial gaps in our knowledge of viral composition in relation to genetic diversity of H. longicornis and ecological factors, which are important for us to understand interactions between virus and vector, as well as between vector and ecological elements. RESULTS: We conducted the meta-transcriptomic sequencing of 136 pools of H. longicornis and identified 508 RNA viruses of 48 viral species, 22 of which have never been reported. Phylogenetic analysis of mitochondrion sequences divided the ticks into two genetic clades, each of which was geographically clustered and significantly associated with ecological factors, including altitude, precipitation, and normalized difference vegetation index. The two clades showed significant difference in virome diversity and shared about one fifth number of viral species that might have evolved to "generalists." Notably, Bandavirus dabieense, the pathogen of severe fever with thrombocytopenia syndrome was only detected in ticks of clade 1, and half number of clade 2-specific viruses were aquatic-animal-associated. CONCLUSIONS: These findings highlight that the virome diversity is shaped by internal genetic evolution and external ecological landscape of H. longicornis and provide the new foundation for promoting the studies on virus-vector-ecology interaction and eventually for evaluating the risk of H. longicornis for transmitting the viruses to humans and animals. Video Abstract.

Genetic variants of Orientia tsutsugamushi in domestic rodents, northern China.

We screened Orientia tsutsugamushi from 385 domestic rodents and 19 humans with scrub typhus in rural Tai'an District, Shandong Province, a new scrub typhus epidemic area in northern China. Sequence analysis identified 7 genotypes in the rodents, of which 2 were also identified in the humans.

[The infection status and epidemic rule of new bunia virus in the livestock and poultry in hilly area of Jiaodong peninsula].

OBJECTIVE: To understand the infection status and epidemic rule of new bunia virus in the livestock and poultry which are closely related with humans such as sheep, cattle, dogs, pigs and chicken in the hilly area of Jiaodong peninsula in Shandong province. METHODS: Penglai and Laizhou in the hilly area of Jiaodong peninsula in Shandong province where severe fever with thrombocytopenia syndrome cases occurred in 2010 were selected as experimental sites. During April to November in 2011, serum specimens of the sheep, cattle, dogs, pigs and chicken with ticks in endemic area were randomly collected by random number table.5 ml venous blood was collected in each livestocks or poultries and there were total 3576 samples.New bunia virus antibody in different species of livestocks or poultries serum was continuously detected using double antigen sandwich enzyme-linked immunosorbent assay, and the infection rates of new bunia virus between different species of livestocks or poultries and between Penglai and Laizhou were analyzed using chi-square test. RESULTS: Test results in 3576 samples of livestocks or poultries serum specimen showed that the infection rate was as high as 63% (636/1013) in sheep, 53% (444/841)in cattle, 46% (242/530) in chicken, 29% (104/362)in the dogs, and 1% (12/830) in pigs. There were significant differences of new bunia virus infection among different species (χ(2) = 815.26, P < 0.05).In Penglai, the infection rate was as high as 71% (400/563) in sheep, 57% (232/409)in cattle, 35% (93/266) in chicken, 44% (796/1819)in total, while in Laizhou, the infection rate was 53% (236/450)in sheep, 49% (212/432)in cattle, 56% (149/264)in chicken, 36% (642/1757)in total, their difference was statistically significant(χ(2) values were 37.04, 4.93, 24.63, 19.38, all P values were < 0.05).Infection rates of dogs and pigs showed no obvious fluctuation.However, there were two peaks of infection in sheep in summer and autumn, the infection rate was as high as 62% (68/110) in June and 86% (204/236) in November;There were two peaks of infection in cattle in spring and autumn, the infection rate was as high as 56% (53/94) in April and 73% (116/159) in November; there was only one peak of infection in chicken, the infection rate was as high as 65% (55/85) in September. CONCLUSION: The infection rate is higher in sheep, cattle, chickens and dogs in the hilly area of Jiaodong peninsula. The peak season is spring, summer and autumn.

[Analysis of clinical features and early warning indicators of death from hand, foot and mouth disease in Shandong province].

OBJECTIVE: To understand the clinical features of death from hand, foot and mouth disease (HFMD) and to explore the early warning index of HFMD death. METHODS: A total of 41 HFMD death cases were collected as case group in Shandong province between 2009 and 2011, and another 123 serious HFMD cases were selected as control group according to the similar gender, place of origin and hospital level, with the ratio at 1:3. We investigated the general situation, clinical treatment, past medical history, clinical symptoms and signs of the ill children, and applied the conditional logistic regression to explore early warning index of HFMD death. RESULTS: The rate of patients who had symptoms in nervous system, digestive system, circulatory system and respiratory system were separately 90.2% (37/41), 58.5% (24/41), 53.7% (22/41) and 90.2% (37/41) in case group; and the proportions were 44.7% (55/123), 13.8% (17/123), 10.6% (13/123) and 12.2% (15/123) respectively in control group. The difference between the two groups showed statistical significance (χ(2) = 25.881, 32.791, 34.011, 86.505, P < 0.05). In case group, 37 patients had neurogenic pulmonary edema, 26 patients got encephalitis, 15 patients had respiratory and circulatory failure, 7 patients got pulmonary hemorrhage, 4 patients had multiple organ failure, 4 patients got myocarditis and 1 patient had cerebral hernia. According to multi-factor logistic regression analysis, the early warning indicators of HFMD death included neck resistance (case group: 34.1% (14/41), control group: 4.1% (5/123); OR = 7.145, 95%CI: 1.748 - 29.204), vomiting (case group: 58.5% (24/41), control group: 13.8% (17/123); OR = 5.632, 95%CI: 1.793 - 17.685) and increase of heart rate (case group: 53.7% (22/41), control group: 10.6% (14/123), OR = 6.370, 95%CI: 1.517 - 26.743). CONCLUSION: In the process of clinical treatment and care, we should interfere the serious HFMD patients with neck resistance, vomiting and increase of heart rate, and thereby reduce the death from HFMD.

Metavirome of 31 tick species provides a compendium of 1,801 RNA virus genomes.

The increasing prevalence and expanding distribution of tick-borne viruses globally have raised health concerns, but the full repertoire of the tick virome has not been assessed. We sequenced the meta-transcriptomes of 31 different tick species in the Ixodidae and Argasidae families from across mainland China, and identified 724 RNA viruses with distinctive virome compositions among genera. A total of 1,801 assembled and complete or nearly complete viral genomes revealed an extensive diversity of genome architectures of tick-associated viruses, highlighting ticks as a reservoir of RNA viruses. We examined the phylogenies of different virus families to investigate virome evolution and found that the most diverse tick-associated viruses are positive-strand RNA virus families that demonstrate more ancient divergence than other arboviruses. Tick-specific viruses are often associated with only a few tick species, whereas virus clades that can infect vertebrates are found in a wider range of tick species. We hypothesize that tick viruses can exhibit both 'specialist' and 'generalist' evolutionary trends. We hope that our virome dataset will enable much-needed research on vertebrate-pathogenic tick-associated viruses.

Person-to-person transmission of severe fever with thrombocytopenia syndrome bunyavirus through blood contact.

Severe fever with thrombocytopenia syndrome bunyavirus is a newly discovered bunyavirus with high pathogenicity to human. The transmission model has been largely uncharacterized. Investigation on a cluster of severe fever with thrombocytopenia syndrome cases provided evidence of person-to-person transmission through blood contact to the index patient with high serum virus load.

Co-detection in the pathogenesis of severe hand-foot-mouth disease.

It still needs to be elucidated whether co-detection of EV71 with other intestinal tract viruses plays a role in the pathogenesis of severe hand-foot-mouth disease (HFMD). A total of 680 stool specimens collected from clinically diagnosed mild and severe-HFMD patients were tested for EV71, CA16, norovirus, bocavirus and rotavirus. The results showed that EV71 was significantly associated with severe-HFMD patients. Co-detection of EV71 with norovirus and rotavirus was also significantly associated with severe-HFMD patients: The OR (95 % CI) value was 6.466 (2.735, 15.283) and 7.561 (3.560, 16.057), p < 0.001, respectively. Co-detection of EV71 with rotavirus or norovirus is probably associated with severe HFMD.

[Analysis of epidemic features of scrub typhus between year 2006 and 2010 in Shandong province, China].

OBJECTIVE: To explore the epidemic features of scrub typhus between year 2006 and 2010 in Shandong Province. METHODS: Based on the data collected through Diseases Reporting Information System between year 2006 and 2010 in Shandong province, 1291 cases of scrub typhus were selected. The study described the population distribution features of the scrub typhus patients, and explored the temporal and spatial distribution features of the disease by applying the methods of spatial thematic mapping, inverse distance weighted, spatial autocorrelation analysis, spatial clustering analysis, temporal clustering analysis and spatial variation analysis in temporal trends based on Geographic Information software (ArcGIS 9.3) and Spatial Clustering Software (SatScan 7.0). RESULTS: The onset age of the 1291 patients ranged between 1 and 92 years old.639 out of 1291 patients were over 55 years old, accounting for 49.5%.640 patients were male and the other 651 patients were female, occupying 49.6% and 50.4% respectively. The gender ratio was 1:1.02. Patients were found in farmers, workers, students and preschool children. However, most of the cases were farmers, up to 84.8% (1095/1291). Global Moran's I index was 0.324 (P < 0.01). The local Moran's I index in 8 locations were proved to have statistical significance (P < 0.01); all of which were H-H clustering areas. Gangcheng (38 cases), Laicheng (154 cases), Xintai (160 cases) and Donggang (105 cases) were important locations, whose local Moran's I index were 2.111, 1.642, 1.277 and 0.775 respectively. The clustering period of scrub typhus in respective year were as follows: 2006.09.23 - 2006.11.20 (202 cases), 2007.10.02 - 2007.11.11 (197 cases), 2008.09.30 - 2008.11.07 (302 cases), 2009.09.25 - 2009.11.10 (204 cases), and 2010.10.05 - 2010.11.13 (226 cases), whose RR values were separately 45.55, 34.60, 50.64, 53.09 and 79.84 (P < 0.01). Two spatial clustering area were found in the study, one was the area centered Taian and Xintai with radiation radius at 58.28 km (542 cases) and the other one was the area centered Rizhao and Donggang with radiation radius at 22.68 km (134 cases), whose RR values were 4.52 and 3.96 (P < 0.01). The spatial features of the two clustering areas were inland low hills area and coastal hills area. The highest annual growth rate of the disease was 45.04%, found in the area centered Linyi and Mengyin counties, with the radiation radius at 45.82 km. The RR value was 3.68 (P < 0.01). CONCLUSION: The majority of the scrub typhus patients were middle-aged and elderly farmers. The epidemic peak was between the last 10 days of September and the first 10 days of November. A positive spatial correlation of the disease was found; and most cases clustered in inland low hills area and costal hills area; especially the area around Linyi and Mengyin, with the highest annual growth rates of the disease.

Epidemic character and environmental factors in epidemic areas of severe fever with thrombocytopenia syndrome in Shandong Province.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging lethal tick-borne disease that has been widely prevalent in East Asia in recent years, and raised an important public health problem in China. However, a comprehensive and thorough understanding of the current SFTS epidemic areas in Shandong Province is not available. Accordingly, a descriptive analysis was applied to explore the demographic and spatio-temporal features of SFTS cases in Shandong Province from 2010 to 2015. The division between epidemic areas and non-epidemic areas was given by maximum entropy niche model (MaxEnt) based on environmental factors such as temperature and precipitation. There were 1,786 SFTS cases between 2010 and 2015 in Shandong, mainly involving middle-aged and elderly individuals (age:40-80) and farmers (84.6 %). May-October was the high-incidence period and the SFTS cases were mostly clustered in the central and eastern regions of Shandong Province. In light of MaxEnt, 3 specific environmental features between dichotomous areas were identified, including 1) most epidemic areas are covered by acidic soils (Constituent ratio: 63.8 %) while 29.1 % coverage appears in non-epidemic areas, 2) compared with non-epidemic areas, the identical kinds of agricultural areas accounted for a higher constituent ratio (64.9 % vs. 42.7 %), and 3) lower level of annual temperature in epidemic areas compared to non-epidemic areas [Median: 13.2℃ vs. 14.2℃; (25th IQR, 75th IQR): (12.5, 13.7) vs. (13.6, 14.9)]. Our study suggests middle-aged and elderly farmers are high-risk population to be focused on in future prevention and acidic soils, agricultural activities as well lower temperature that may be related to increased SFTS incidence.

Human rabies in China: evidence-based suggestions for improved case detection and data gathering.

BACKGROUND: China still suffers heavily from rabies, although reported human cases continue to decrease year over year. There are far fewer laboratory-confirmed human cases than clinically diagnosed cases, which is a big problem that needs to be addressed. In this report, we summarize analyses of all specimens from human cases tested in our laboratory over the past 15 years, in order to promote laboratory diagnosis of rabies. METHODS: From 2005 to 2019, a total of 271 samples from 164 suspected rabies cases were collected from local hospitals by the local Centers for Disease Control and Prevention (CDCs) in China. Saliva, cerebrospinal fluid (CSF), serum (blood) and urine were collected for ante-mortem diagnosis, and brain tissue, neck skin tissue and cornea were collected for post-mortem diagnosis. All of the specimens were tested by reverse transcription-polymerase chain reaction (RT-PCR), and brain tissues were also tested using fluorescent antibody test (FAT). The number of positive test results obtained using different fluids or tissues, and at different stages of the disease, were compared using a chi-square test and a more effective sampling program is recommended. RESULTS: As the national reference laboratory for rabies surveillance in China, our laboratory has tested 271 samples from 164 suspected rabies cases collected by local CDCs since 2005. We found that saliva gave the highest number of positive test results (32%), compared with CSF and other fluids. We also found that serum or blood specimens collected in the last 3 days of life can test positive by RT-PCR. CONCLUSIONS: Serum or blood samples collected in the last 3 days of a patient's life can be used to measure viral RNA, which means that serum samples, as well as saliva and CSF, can be used to detect viral RNA for anti-mortem diagnosis of rabies. Because of our findings, we have modified our "National Surveillance Project for Human Rabies", by adding the collection and testing of serum samples from the end of the survival period. This will improve our national surveillance and laboratory diagnosis of human rabies.

Imported dengue serotype 1 outbreak in a non-endemic region, China, 2017: A molecular and seroepidemiological study.

OBJECTIVES: Beginning in June 2017, numerous dengue virus (DENV) infections occurred in the Jining City of Shandong Province, formerly a dengue-free region in East China. We sought to describe the clinical and epidemiological features of this outbreak. METHODS: We reviewed the clinical records and epidemiological data regarding a case series of patients diagnosed with DENV in Jining City, from June 30 to September 14, 2017. Diagnosis was confirmed by molecular method, culture, or rapid diagnostic tests. Sequencing of the DENV envelope gene or the whole viral genome was performed for 11 patients. Additionally, neutralizing antibodies against DENV was measured among patients and residents from their same villages. RESULTS: Data from 150 patients were evaluated in this outbreak. None were diagnosed with dengue hemorrhagic fever or dengue shock syndrome. The patients' ages ranged between 2-88 years (median 51 years, [IQR=37.5-64.3]), and 100 (66.7%) were female. Epidemiological analyses implicated a man who had visited Saudi Arabia as the likely source of the outbreak. Phylogenetic studies identified DENV serotype 1. Most of the patients demonstrated increases of neutralizing antibody titers one year after infection compared with titers three months after infection. The residents living in dengue-affected villages had a significant higher seroprevalence of 21.2% (95%CI 16.9-25.5) than residents (3.2%, 95%CI-0.36-6.7) living in a non-dengue-affected village. CONCLUSIONS: This report documents the first dengue outbreak in Shandong Province, China, in more than 60 years. It underscores the need for medical providers to record patients' travel histories and to consider dengue in their differential diagnoses.

Genome Analysis of Coxsackievirus A4 Isolates From Hand, Foot, and Mouth Disease Cases in Shandong, China.

Coxsackievirus A4 (CVA4) is one of the most prevalent pathogens associated with hand, foot and mouth disease (HFMD), an acute febrile illness in children, and is also associated with acute localized exanthema, myocarditis, hepatitis and pancreatitis. Despite this, limited CVA4 genome sequences are currently available. Herein, complete genome sequences from CVA4 strains (n = 21), isolated from patients with HFMD in Shandong province, China between 2014 and 2016, were determined and phylogenetically characterized. Phylogenetic analysis of the VP1 gene from a larger CVA4 collection (n = 175) showed that CVA4 has evolved into four separable genotypes: A, B, C, and D; and genotype D could be further classified in to two sub-genotypes: D1 and D2. Each of the 21 newly described genomes derived from isolates that segregated with sub-genotype D2. The CVA4 genomes displayed significant intra-genotypic genetic diversity with frequent synonymous substitutions occurring at the third codon positions, particularly within the P2 region. However, VP1 was relatively stable and therefore represents a potential target for molecular diagnostics assays and also for the rational design of vaccine epitopes. The substitution rate of VP1 was estimated to be 5.12 × 10-3 substitutions/site/year, indicative of ongoing CVA4 evolution. Mutations at amino acid residue 169 in VP1 gene may be responsible for differing virulence of CVA4 strains. Bayesian skyline plot analysis showed that the population size of CVA4 has experienced several dynamic fluctuations since 1948. In summary, we describe the phylogenetic and molecular characterization of 21 complete genomes from CVA4 isolates which greatly enriches the known genomic diversity of CVA4 and underscores the need for further surveillance of CVA4 in China.

Seroprevalence of Severe Fever with Thrombocytopenia Syndrome Virus in Hedgehog from China.

Severe fever with thrombocytopenia syndrome, an emerging hemorrhagic fever, is caused by severe fever with thrombocytopenia syndrome virus (SFTSV), a tick-borne bunyavirus. Information regarding SFTSV animal hosts is very limited. In this study, we showed that 64% (9/14) of hedgehogs in Shandong Province, China were seropositive to SFTSV antibody, suggesting that hedgehog could be a vertebrate parasitifer for SFTSV.

Seroprevalence of Enterovirus A71 and Coxsackievirus A16 in Healthy People in Shandong Province, China.

BACKGROUND: Hand, foot, and mouth disease has become very common in mainland of China in recent years, and enterovirus A71 and coxsackievirus A16 are its major etiologic factors. Here we investigated the seroprevalence of enterovirus A71 and coxsackievirus A16 based on a large group of healthy individuals in Shandong province, China. METHODS: A total of 1378 healthy individuals were tested for serum neutralizing antibodies against enterovirus A71 and coxsackievirus A16 using a micro neutralization test. RESULTS: The overall seroprevalence of enterovirus A71 neutralizing antibodies was 74.75%. It increased significantly from 48.84% in children aged 0-1 years old to 88.64% in those aged 20-29 years (p < 0.01) and decreased to 85.71% in adults > 40 years old with a significant gender-specific difference (p < 0.01). The overall coxsackievirus A16 antibody prevalence was 71.77%. It increased significantly from 39.53% in children aged 0-1 years to 80.68% in those aged 10-19 years (p < 0.01) and decreased to 75.63% in adults >40 years without a gender-specific difference. Nearly 50% of the children <1 year were susceptible to enterovirus A71 infection versus 40% to coxsackievirus A16 infection. Sample collection time and place also played a role in the enterovirus A71 and coxsackievirus A16 positive rates. The overall rates in January were significantly lower than those in April and August (p < 0.01); enterovirus A71 positive rates in Jinan city (capital city of Shandong province) were lower than those in Jining city and Zibo city (p < 0.05); and oxsackievirus A16 positive rates in Jining city were significantly higher than those in Jinan city and Zibo city (p < 0.01). CONCLUSION: There were significant differences among age groups, locations, and time points in the seroprevalence rates of enterovirus A71 and coxsackievirus A16 neutralizing antibodies in healthy people in Shandong province.

Correlation Between HLA-A, B and DRB1 Alleles and Severe Fever with Thrombocytopenia Syndrome.

OBJECTIVE: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever caused by a tick-borne bunyavirus (SFTSV) in East Asian countries. The role of human leukocyte antigen (HLA) in resistance and susceptibility to SFTSV is not known. We investigated the correlation of HLA locus A, B and DRB1 alleles with the occurrence of SFTS. METHODS: A total of 84 confirmed SFTS patients (patient group) and 501 unrelated non-SFTS patients (healthy individuals as control group) from Shandong Province were genotyped by PCR-sequence specific oligonucleotide probe (PCR-SSOP) for HLA-A, B and DRB1 loci.Allele frequency was calculated and compared using χ2 test or the Fisher's exact test. A corrected P value was calculated with a bonferronis correction. Odds Ratio (OR) and 95% confidence intervals (CI) were calculated by Woolf's method. RESULTS: A total of 11 HLA-A, 23 HLA-B and 12 HLA-DRB1 alleles were identified in the patient group, whereas 15 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles were detected in the control group. The frequencies of A*30 and B*13 in the SFTS patient group were lower than that in the control group (P = 0.0341 and 0.0085, Pc = 0.5115 and 0.252). The ORs of A*30 and B*13 in the SFTS patient group were 0.54 and 0.49, respectively. The frequency of two-locus haplotype A*30-B*13 was lower in the patient group than in the control group(5.59% versus 12.27%, P = 0.037,OR = 0.41, 95%CI = 0.18-0.96) without significance(Pc>0.05). A*30-B*13-DRB1*07 and A*02-B*15-DRB1*04 had strong associations with SFTS resistance and susceptibility respectively (Pc = 0.0412 and 0.0001,OR = 0.43 and 5.07). CONCLUSION: The host HLA class I polymorphism might play an important role with the occurrence of SFTS. Negative associations were observed with HLA-A*30, HLA-B*13 and Haplotype A*30-B*13, although the associations were not statistically significant. A*30-B*13-DRB1*07 had negative correlation with the occurrence of SFTS; in contrast, haplotype A*02-B*15-DRB1*04 was positively correlated with SFTS.

The platelet derived growth factor-B polymorphism is associated with risk of severe fever with thrombocytopenia syndrome in Chinese individuals.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus named SFTS virus (SFTSV). We hypothesize that host genetic variations may contribute to susceptibility to SFTS. RESULTS: Compared with the rs1800818 AA genotype, AG + GG genotypes were significantly associated with increased susceptibility to SFTS (odds ratio, 1.66, 95% confidence interval = 1.28-2.16; P < 0.001). By using the ELISA assay, we observed that PDGF-BB concentration was significantly reduced in acute phase of patients than in the controls (P < 0.001) and recovered patients at 6 month (P = 0.007) and 12 month (P = 0.003). A persistently reduced PDGF-BB was also revealed from the SFTSV-infected C57BL/6J mice (P < 0.001). The rs1800818 G allele was associated with decreased serum PDGF-BB levels in SFTS patients at their early infection (P = 0.015). In accordance, the relative mRNA levels of the at-risk G allele of 1800818 were lower than those of the A allele in heterozygous cell from acute phase of SFTS patients. PDGF-B rs1800818 conferred no susceptibility to severe or fatal outcome in SFTS patients. MATERIALS AND METHODS: An initially small-scale case-control association study guided the selection of platelet derived growth factor-B (PDGF-B) rs1800818 in 1020 SFTS patients and 1353 controls. Functional analyses were conducted to verify the biological significance of rs1800818 polymorphism. CONCLUSIONS: Our findings suggest that the PDGF-B rs1800818 polymorphism might play a role in mediating the susceptibility to SFTS.