Genomic Epidemiology and Active Surveillance to Investigate Outbreaks of Hantaviruses

Abstract

Emerging and re-emerging RNA viruses pose significant public health, economic, and societal burdens. Hantaviruses (genus Orthohantavirus, family Hantaviridae, order Bunyavirales) are enveloped, negative-sense, single-stranded, tripartite RNA viruses that are emerging zoonotic pathogens harbored by small mammals such as rodents, bats, moles, and shrews. Orthohantavirus infections cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome in humans (HCPS). Active targeted surveillance has elucidated high-resolution phylogeographic relationships between patient- and rodent-derived orthohantavirus genome sequences and identified the infection source by temporally and spatially tracking viral genomes. Active surveillance of patients with HFRS entails 1) recovering whole-genome sequences of Hantaan virus (HTNV) using amplicon (multiplex PCR-based) next-generation sequencing, 2) tracing the putative infection site of a patient by administering an epidemiological questionnaire, and 3) collecting HTNV-positive rodents using targeted rodent trapping. Moreover, viral genome tracking has been recently performed to rapidly and precisely characterize an outbreak from the emerging virus. Here, we reviewed genomic epidemiological and active surveillance data for determining the emergence of zoonotic RNA viruses based on viral genomic sequences obtained from patients and natural reservoirs. This review highlights the recent studies on tracking viral genomes for identifying and characterizing emerging viral outbreaks worldwide. We believe that active surveillance is an effective method for identifying rodent-borne orthohantavirus infection sites, and this report provides insights into disease mitigation and preparedness for managing emerging viral outbreaks.

Keywords: RNA viruses; epidemiological survey; next-generation sequencing; preventive strategies; rodent trapping; tracking hantaviral genomes.

Figure 1

Global geographic distribution of hantaviruses as etiological agents of hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. The representative hantaviral disease in each continent was marked as different color. Pink color indicates HFRS and blue color indicates HCPS. The gray circle represents the rodent-borne hantaviruses first characterized in nature.

Figure 2

Elaborate and accurate improvement of tracking orthohantavirus using targeted rodent trapping. (A) Phylogenetic analyses before surveillance. The whole-genome sequences of orthohantavirus from patients with hemorrhagic fever with renal syndrome (HFRS) did not cluster with a specific location. (B) Epidemiological surveys and active targeted rodent trapping in the suspected area. The epidemiological interviews were performed for precise virus tracking. Active targeted trapping was performed in the place predicted to be infected. (C) Phylogenetic analyses after active targeted surveillance. The whole-genome sequences of orthohantavirus from rodent samples trapped in the suspected site were clustered with the orthohantavirus from patients with HFRS.

Figure 3

Active targeted surveillance for the identification of infection sites of emerging orthohantavirus outbreaks. An infection location of a patient with hemorrhagic fever with renal syndrome (HFRS) was identified using active targeted surveillance. (A) The patient is hospitalized with suspected HFRS. (B) Laboratory diagnosis confirms orthohantavirus infection using serological and molecular tests. The epidemiological interview is conducted to identify a suspected site of emerging orthohantavirus. (C) A targeted rodent trapping is performed at the suspected infection site. (D) Using a target enrichment NGS method, whole-genome orthohantavirus sequences are recovered from patients with HFRS and orthohantavirus-infected rodents. (E) Bioinformatic analyses provide high-resolution phylogeographic links between patient- and rodent-derived orthohantavirus strains. “Patient A” is highly suggestive to be infected with orthohantavirus circulating in the green area. (F) Active surveillance provides follow-up measures for mitigating HFRS incidences by cleaning the sites, placing warning signs, rescheduling activities, and vaccinating the high-risk population in the endemic areas.