Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus of significant public health concern. ZIKV shares a high degree of sequence and structural homology compared with other flaviviruses, including dengue virus (DENV), resulting in immunological cross-reactivity. Improving our current understanding of the extent and characteristics of this immunological cross-reactivity is important, as ZIKV is presently circulating in areas that are highly endemic for dengue. To assess the magnitude and functional quality of cross-reactive immune responses between these closely related viruses, we tested acute and convalescent sera from nine Thai patients with PCR-confirmed DENV infection against ZIKV. All of the sera tested were cross-reactive with ZIKV, both in binding and in neutralization. To deconstruct the observed serum cross-reactivity in depth, we also characterized a panel of DENV-specific plasmablast-derived monoclonal antibodies (mAbs) for activity against ZIKV. Nearly half of the 47 DENV-reactive mAbs studied bound to both whole ZIKV virion and ZIKV lysate, of which a subset also neutralized ZIKV. In addition, both sera and mAbs from the dengue-infected patients enhanced ZIKV infection of Fc gamma receptor (FcγR)-bearing cells in vitro. Taken together, these findings suggest that preexisting immunity to DENV may impact protective immune responses against ZIKV. In addition, the extensive cross-reactivity may have implications for ZIKV virulence and disease severity in DENV-experienced populations.Zika virus (ZIKV) is a mosquito-borne virus belonging to the Flaviviridae family of single-stranded positive-sense RNA viruses. First isolated in Uganda in 1947 (1), this virus remained largely dormant for the next six decades until it reemerged as the cause of an epidemic on Yap Islands, Micronesia in 2007 (2). ZIKV has since then been linked with several outbreaks in the Pacific and Americas, along with sporadic human cases in Africa and Asia (3, 4). Until its appearance in French Polynesia in 2013 and more recently in Brazil in 2015, ZIKV infection was primarily associated with mild self-limiting illness, with symptoms similar to and often milder than dengue virus (DENV) or Chikungunya virus (CHIKV) infections (2–4). However, the more recent outbreaks have caused severe neurological complications including Guillain–Barré Syndrome in adults and an increase in congenital microcephaly and other adverse birth outcomes in Brazil (5–7). The Pan American Health Organization has reported that as of May 2016, local transmission of ZIKV had spread to over 38 countries or territories in the Americas. In addition, a recent WHO report states that 44 new countries are experiencing their first ZIKV outbreak since 2015. Despite the improving surveillance of the virus, accurate diagnosis has been challenging given the similarities in the clinical presentation of ZIKV to other arboviral infections endemic in these regions, among other factors.During the viremic period, ZIKV can be found in patient blood, saliva, urine, and other bodily fluids early after symptom onset (8–10). During the Yap Islands epidemic in 2007, anti-ZIKV IgM ELISAs and ZIKV plaque reduction neutralization titer (PRNT) assays were performed to confirm infection in RT-PCR negative cases (2, 8). However, as these studies showed, the cross-reactivity between ZIKV and other flaviviruses makes confirmation of infection difficult, especially when patients may have had flavivirus exposures before their suspected ZIKV infection (2, 8). Given the overlapping presence of DENV and other flaviviruses in a majority of ZIKV epidemic regions (11), there are great challenges in serology-based testing of flavivirus-immune patients (12).The DENV envelope (E) protein, considered a major imunodominant target for antibody responses in dengue patients (13–15), bears greater than 50% homology to ZIKV E protein (16). In addition to complicating the serology-based diagnosis of ZIKV infection, this raises an interesting question about the biological implications of the cross-reactivity on protection, virulence, and immunopathology of ZIKV infections. At present, the effect of preexisting immunity to DENV or other flaviviruses on immune responses induced by ZIKV infection is unknown. To this end, we were interested in determining the degree to which dengue-induced antibodies cross-react with ZIKV in terms of binding, virus neutralization, and antibody-dependent enhancement (ADE) of ZIKV infection, both at the serum and single-cell level.In this study, we provide an analysis of the cross-reactivity of acute and convalescent dengue-immune sera against ZIKV. The sera were collected from nine patients admitted to Siriraj Hospital in Bangkok, Thailand with confirmed DENV infection. Both acute and convalescent sera showed high binding titers to ZIKV lysate and could also neutralize ZIKV in vitro. To understand the origin and characteristics of these cross-reactive serum responses, we also analyzed a panel of plasmablast-derived DENV-reactive monoclonal antibodies (mAbs). Of the 47 mAbs tested, nearly half (22/47) bound to ZIKV lysate and an additional four to the whole virus. Seven of these mAbs also neutralized ZIKV in vitro. Five sera and a subset of the mAbs were also tested for ADE activity using the FcγR-bearing monocytic U937 cell line. All sera and ZIKV-reactive mAbs tested enhanced infection in vitro, whereas two DENV-specific but ZIKV-nonreactive mAbs did not. The data presented here have important implications for clinical diagnosis given that the current ZIKV outbreak in the Americas and the Caribbean is largely ongoing in dengue-endemic areas. Equally important, these findings set the stage for more in-depth studies that explore how preexisting flavivirus immunity may shape immune responses to ZIKV infection.     

亚洲国家Zika病毒及其感染的流行状况

众所周知,2015年起南美洲地区发生Zika病毒(Zika virus)感染大流行,累积发现约200万人感染,成为近年来全世界最重要的公共卫生事件,引起世界轰动。虽然在亚洲国家未发现Zika病毒感染的大流行,但是在亚洲的印度,泰国,越南等地发现大量本土Zika病毒感染病例,并且在中国自然界采集的蚊虫标本中分离到Zika病毒,可见亚洲地区存在Zika病毒感染大流行的潜在风险,而一旦Zika病毒感染在亚洲发生大流行对中国公共卫生将造成巨大危害。为此关注Zika病毒及其感染在亚洲各国的流行状况对我国医疗及公共卫生相关人员具有十分重要的意义。     

寨卡病毒动物感染模型研究进展

寨卡病毒是一种经由蚊媒传播的重要的黄病毒属病毒,已导致全球数百万人感染,引发严峻的公共卫生危机。2015年以来,尤其是中南美洲地区暴发的寨卡疫情出现了新生儿小头畸形、大脑发育异常与格林巴列综合征等不同以往的严重症状,引发高度关注。合适的动物感染模型对于研究寨卡病毒的传播方式、致病机理及研发防控寨卡病毒感染的新药、疫苗及诊断试剂等都有十分重要的意义。本文就近年来建立的寨卡病毒动物感染模型进展进行综述。     

Temperature and development of Zika virus infection:an Indonesian case

Distribution of Zika virus has spread throughout the world.WHO has announced that Zika virus disease is a global health problem.As a tropical country,Indonesia has the potential to spread Zika virus.This letter is to report that there was a single case of zika in Jambi province published by the Eijkman Institute for Molecular Biology.This case was analyzed with the temperature in the scene,which is considered as an appropriate factor to development of Zika virus.     

Doubled dosage of sofosbuviris expected for inhibiting Zika virus infection

Sofosbuvir is a new antiviral drug that has been recommended for management of hepatitis C virus(HCV) for a few years. New researches support that sofosbuvir might be useful for the management of Zika virus infection. Based on the pharmacological activity, inhibiting the HCV RNA-dependent RNA polymerase(RdR p or NS5 protein), sofosbuvir is proposed for its effectiveness against Zika virus infection. Here, the authors used a mathematical modelling theoretical approach to predict the expected dosage of sofosbuvir for inhibiting Zika virus infection. Based on the modeling study, if sofosbuvir is assigned for management of Zika virus infection, doubled dosage of the present dosage for hepatitis C management is recommended.     

Zika virus infection and its emerging trends in Southeast Asia

Zika virus is a mosquito-borne flavivirus that represents a public health emergency at the ongoing epidemic.Previously,this rare virus was limited to sporadic cases in Africa and Asia until its emergence in Brazil,South America in 2015,where it rapidly spread throughout the world.Recently,a high number of cases were reported in Singapore and other Southeast Asia countries.A combination of factors explains the current Zika virus outbreak although it is highly likely that the changes in the climate and high frequency of travelling contribute to the spread of Aedes vector carrying the Zika virus mainly to the tropical climate countries such as the Southeast Asia.The Zika virus is known to cause mild clinical symptoms similar to those of dengue and chikungunya and transmitted by different species of Aedes mosquitoes.However,neurological complications such as Guillain-Barrésyndrome in adults,and congenital anomalies,including microcephaly in babies born to infected mothers,raised a serious concern.Currently,there is no specific antiviral treatment or vaccine available for Zika virus infection.Therefore,international public health response is primarily focused on preventing infection,particularly in pregnant women,and on providing up-to-date recommendations to reduce the risk of non-vector transmission of Zika virus.     

寨卡病毒病

寨卡病毒病是由寨卡病毒引起的急性传染病.人体因受携带病毒的雌性伊蚊叮咬而得病,为自限性疾病,隐性感染率高,症状轻,但有可能引起胎儿/婴儿小头畸形和格林-巴利综合征等严重并发症.实验室检测方法包括PCR检测病毒RNA和检测血清中的病毒抗体(IgM).该疾病目前无有效的抗病毒药物和疫苗,一般采用对症治疗的方法即可痊愈.寨卡病毒病的预防措施与其他虫媒病毒相同,即预防蚊虫叮咬和采取虫媒控制措施.该病上世纪中叶起源于非洲,2007年起传播范围不断扩大,速度不断加快.截止2015年3月,全球共有52个国家和地区有寨卡病毒本地传播.     

Afebrile,asymptomatic and non-thrombocytopenic Zika virus infection: don't miss it!

Zika virus infection is the present problematic arboviral disease. Classically, this disease cause febrile illness and can result in low platelet count. However, there are some new obervations on atypical clinical presentations of Zika virus infection that can make the diagnosis more difficult. The afebrile, asymptomatic and non-thrombocytopenic Zika virus infection can be seen in clinical practice and can lead to missed or delayed diagnosis.     

Cardiovascular manifestations associated with influenza virus infection

Influenza accounts for 3 to 5 million cases of severe illness and up to 300,000 deaths annually. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on the myocardium or through exacerbation of existing cardiovascular disease. Epidemiological studies have demonstrated an association between influenza epidemics and cardiovascular mortality and a decrease in cardiovascular mortality in high risk patients has been demonstrated following vaccination with influenza vaccine. Influenza is a recognised cause of myocarditis which can lead to significant impairment of cardiac function and mortality. With recent concerns regarding another potential global pandemic of influenza the huge potential for cardiovascular morbidity and mortality is discussed.     

Humidity that is appropriate for Zika virus infection:A summary from Thai cases

In the present day,Zika virus infection is a big problem in medicine.As a mosquito borne infectious disease,the climate parameters including humidity can affect the disease suitability.However,there is no previous data on the appropriate humidity level that can promote Zika virus infection.Here,the authors analyze the data on humidity where the Zika infections are detected in Thailand and found that the average humidity is equal to(66.14%±19.86%),which is the level that can be seen in several areas of the world including to non-tropical countries.This implies that there is a possible risk of Zika virus infection in the non-tropical country with appropriate humidity level.     

Healthcare workers' knowledge towards Zika virus infection in Indonesia:A survey in Aceh

Objective:To assess the knowledge on Zika virus(ZIKV) infection among healthcare providers(doctors) in Aceh province,Indonesia.Methods:A self-administered internet based survey was conducted from 3 May to 3 June 2016 among the members of doctor organizations in Aceh province.A set of validated,pre-tested questionnaire was used to measure knowledge regarding ZIKV infection and to collect a range of explanatory variables.A two-steps logistic regression analysis was employed to assess the association of participants' demographic,workplace characteristics and other explanatory variables with the knowledge.Results:A total of 442 participants included in the final analysis and 35.9% of them(159) had a good knowledge on ZIKV infection.Multivariate model revealed that type of occupation,type of workplace,availability of access to medical journals and experience made Zika disease as differential diagnose were associated with knowledge on ZIKV infection.In addition,three significant source of information regarding ZIKV were online media(60%),medical article or medical news(16.2%) and television(13.2%).Conclusion:The knowledge of the doctors in Aceh regarding ZIKV infection is relatively low.Doctors who have a good knowledge on ZIKV infection are more confident to established ZIKV disease as differential diagnosis in their clinical setting.Therefore,such program to increase healthcare providers' knowledge regarding ZIKV infection is needed to screen potential carriers of ZIKV infection.