Heterogeneous typhi transmission within a household: genomic insights from a chronic carrier.

Household outbreaks of serovar Typhi ( Typhi) typically involve genetically similar strains, often within a 0-5 single-nucleotide polymorphism (SNP) single linkage cluster. However, unusual genetic heterogeneity may indicate more complex transmission dynamics. This case represents an instance of household transmission facilitated by an asymptomatic carrier harbouring genetically diverse Typhi strains. A healthy adult developed severe typhoid requiring hospitalization, and two children required treatment. Public health epidemiological connections among the cases supported the findings of the phylogenetic analysis. We hypothesized that a household cluster of Typhi infections, displaying greater-than-expected genetic diversity, may have originated from a chronic carrier with a diverse in-host bacterial population - an under-recognized transmission route. To investigate the source and genomic diversity of a household cluster of Typhi cases with no recent travel history and to assess the role of asymptomatic carriage in transmission. We conducted detailed contact tracing, epidemiological investigations and whole-genome sequencing on isolates from four household cases. An asymptomatic contact, with a history of infection and recent travel to Pakistan, underwent enhanced sampling and genomic analysis of multiple Typhi isolates. The four household cases formed a 25-SNP single linkage cluster, inconsistent with typical isogenic clustering. Genomic analysis of multiple isolates from the asymptomatic carrier revealed a genetically diverse Typhi population with evidence of in-host evolution. Two case isolates were nested within the genomic diversity of the carrier's isolates. Epidemiological investigations identified no alternative sources of infection. This case series highlights the complexity of defining Typhi transmission using discrete SNP thresholds. While epidemiological links suggested a single source, phylogenetic analysis revealed notable genetic diversity among the strains. The findings underscore the public health risks posed by chronic carriers harbouring diverse Typhi populations and the complications associated with typhoid transmission and disease severity.