Viral genome-based Zika virus transmission dynamics in a paediatric cohort during the 2016 Nicaragua epidemic.

BACKGROUND: Nicaragua experienced a large Zika epidemic in 2016, with up to 50% of the population in Managua infected. With the domesticated Aedes aegypti mosquito as its vector, it is widely assumed that Zika virus transmission occurs within the household and/or via human mobility. We investigated these assumptions by using viral genomes to trace Zika transmission spatially. METHODS: We analysed serum samples from 119 paediatric Zika cases participating in the long-standing Paediatric Dengue Cohort Study in Managua, which was expanded to include Zika in 2015. An optimal spanning directed tree was constructed by minimizing the differences in viral sequence diversity composition between patient nodes, where low-frequency variants were used to increase the resolution of the inferred Zika outbreak dynamics. FINDINGS: Out of the 18 houses where pairwise difference in sample collection dates among all the household members was within 30 days, we only found two where viruses from individuals within the same household were up to 10th-most closely linked to each other genetically. We also identified a substantial number of transmission events involving long geographical distances (n=30), as well as potential super-spreading events in the estimated transmission tree. INTERPRETATION: Our finding highlights that community transmission, often involving long geographical distances, played a much more important role in epidemic spread than within-household transmission. FUNDING: This study was supported by an NUS startup grant (OMS) and grants R01 AI099631 (AB), P01 AI106695 (EH), P01 AI106695-03S1 (FB), and U19 AI118610 (EH) from the US National Institutes of Health.

Positive epistasis between viral polymerase and the 3' untranslated region of its genome reveals the epidemiologic fitness of dengue virus.

Dengue virus (DENV) is a global health threat, causing repeated epidemics throughout the tropical world. While low herd immunity levels to any one of the four antigenic types of DENV predispose populations to outbreaks, viral genetic determinants that confer greater fitness for epidemic spread is an important but poorly understood contributor of dengue outbreaks. Here we report that positive epistasis between the coding and noncoding regions of the viral genome combined to elicit an epidemiologic fitness phenotype associated with the 1994 DENV2 outbreak in Puerto Rico. We found that five amino acid substitutions in the NS5 protein reduced viral genomic RNA (gRNA) replication rate to achieve a more favorable and relatively more abundant subgenomic flavivirus RNA (sfRNA), a byproduct of host 5'-3' exoribonuclease activity. The resulting increase in sfRNA relative to gRNA levels not only inhibited type I interferon (IFN) expression in infected cells through a previously described mechanism, but also enabled sfRNA to compete with gRNA for packaging into infectious particles. We suggest that delivery of sfRNA to new susceptible cells to inhibit type I IFN induction before gRNA replication and without the need for further de novo sfRNA synthesis could form a "preemptive strike" strategy against DENV.

Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness.

The global spread of dengue virus (DENV) infections has increased viral genetic diversity, some of which appears associated with greater epidemic potential. The mechanisms governing viral fitness in epidemiological settings, however, remain poorly defined. We identified a determinant of fitness in a foreign dominant (PR-2B) DENV serotype 2 (DENV-2) clade, which emerged during the 1994 epidemic in Puerto Rico and replaced an endemic (PR-1) DENV-2 clade. The PR-2B DENV-2 produced increased levels of subgenomic flavivirus RNA (sfRNA) relative to genomic RNA during replication. PR-2B sfRNA showed sequence-dependent binding to and prevention of tripartite motif 25 (TRIM25) deubiquitylation, which is critical for sustained and amplified retinoic acid-inducible gene 1 (RIG-I)-induced type I interferon expression. Our findings demonstrate a distinctive viral RNA-host protein interaction to evade the innate immune response for increased epidemiological fitness.

Dengue in Southeast Asia: epidemiological characteristics and strategic challenges in disease prevention.

Dengue emerged as a public health burden in Southeast Asia during and following the Second World War and has become increasingly important, with progressively longer and more frequent cyclical epidemics of dengue fever/dengue hemorrhagic fever. Despite this trend, surveillance for this vector-borne viral disease remains largely passive in most Southeast Asian countries, without adequate laboratory support. We review here the factors that may have contributed to the changing epidemiology of dengue in Southeast Asia as well as challenges of disease prevention. We also discuss a regional approach to active dengue virus surveillance, focusing on urban areas where the viruses are maintained, which may be a solution to limited financial resources since most of the countries in the region have developing economies. A regional approach would also result in a greater likelihood of success in disease prevention since the large volume of human travel is a major factor contributing to the geographical spread of dengue viruses.

Dengue in Southeast Asia: epidemiological characteristics and strategic challenges in disease prevention / Dengue no Sudeste Asiático: características epidemiológicas e desafios estratégicos na prevenção da doença

Dengue emerged as a public health burden in Southeast Asia during and following the Second World War and has become increasingly important, with progressively longer and more frequent cyclical epidemics of dengue fever/dengue hemorrhagic fever. Despite this trend, surveillance for this vector-borne viral disease remains largely passive in most Southeast Asian countries, without adequate laboratory support. We review here the factors that may have contributed to the changing epidemiology of dengue in Southeast Asia as well as challenges of disease prevention. We also discuss a regional approach to active dengue virus surveillance, focusing on urban areas where the viruses are maintained, which may be a solution to limited financial resources since most of the countries in the region have developing economies. A regional approach would also result in a greater likelihood of success in disease prevention since the large volume of human travel is a major factor contributing to the geographical spread of dengue viruses.

A dengue emergiu como problema de saúde pública no Sudeste Asiático durante e após a Segunda Guerra Mundial, e vem se agravando cada vez mais, com epidemias cíclicas progressivamente mais longas e freqüentes de dengue e de febre hemorrágica da dengue. Apesar dessa tendência, a vigilância dessa virose transmitida por vetores permanece basicamente passiva na maioria dos países do Sudeste Asiático, sem apoio laboratorial adequado. O artigo apresenta uma revisão dos fatores que podem ter contribuído para a mudança no perfil epidemiológico da dengue na região, além de discutir os desafios para a prevenção da doença. Analisa-se também uma abordagem regional para a vigilância ativa dos vírus da dengue, focando as áreas urbanas onde eles se mantêm, o que pode representar uma solução à limitação de recursos financeiros, uma vez que a maioria dos países da região tem economias em desenvolvimento. Uma abordagem regional também resultaria em maior probabilidade de sucesso na prevenção da doença, já que a grande circulação de viajantes na região é um fator importante na disseminação dos vírus da dengue.