An integrated nationwide genomics study reveals transmission modes of typhoid fever in China

Typhoid fever, caused by Salmonella Typhi (S. Typhi), is a life-threatening disease, usually food-borne and commonly associated with international travel. The disease transmission remains endemic in many low- and middle-income countries, representing further hotspots for seeding new global outbreaks. China has historically been affected by typhoid fever, but the respective roles of local transmission and importation remain unknown. Here, we generated a nationwide map of the typhoid burden in China and investigated the associations between typhoid disease, climate and various socioeconomic parameters. To assess transmission dynamics, we sub-sampled S. Typhi isolated within China over five decades and sequenced their genomes. The resulting 705 new genomes, placed in context with 5,190 global isolates from 87 countries on six continents, led to the discovery of several predominant inland Chinese clones belonging to the clades 2.1/2.3/3.2/4.3. These clones were associated with multiple introductions from overseas, followed by local expansion. Notably, 4.3.1 isolates from eastern China were not genetically close to those from northwestern China but to the international isolates, indicating their association with international travel. Additional in vitro assays showed that 4.3.1 elaborated better intracellular survival, acid tolerance, and desiccation tolerance than other lineages, partially explaining its success. For the first time, we have probed typhoid transmission in China, finding local transmission and importation, which could guide the policy for typhoid control. IMPORTANCE: Typhoid fever is a life-threatening disease caused by Salmonella enterica serovar Typhi, resulting in a significant disease burden across developing countries. Historically, China was very much close to the global epicenter of typhoid, but the role of typhoid transmission within China and among epicenter remains overlooked in previous investigations. By using newly produced genomics on a national scale, we clarify the complex local and global transmission history of such a notorious disease agent in China spanning the most recent five decades, which largely undermines the global public health network.