Integrating bacterial genomics and host transcriptomics links Burkholderia pseudomallei variation to melioidosis mortality and neutrophil responses

Bacterial genetic variation contributes to the outcome of infection, but its relationship with host immune responses is rarely investigated in the same patients, limiting the biological interpretation of pathogen-associated disease severity. Here, we integrated pathogen genomics, clinical outcomes and host transcriptomics to investigate host-pathogen interactions in melioidosis, a frequently fatal infection caused by Burkholderia pseudomallei. We analysed prospective clinical data from 2,142 patients, whole-genome sequences from 2,101 infecting isolates and 646 paired host blood transcriptomes across five cohorts collected between 2012 and 2023. Infections were typically dominated by a single strain, with limited within-host diversification, supporting the use of an infecting isolate genome to investigate pathogen-associated clinical outcomes. Bacterial genome-wide association studies identified one locus associated with binary mortality at genome-wide significance. Incorporating patient age, sex, body mass index and Charlson Comorbidity Index increased this to four, while modelling time to death as a continuous phenotype identified seven loci. Integration with paired host transcriptomes linked mortality-associated bacterial genetic variation to imputed signatures of increased immature neutrophils and reduced neutrophil degranulation. An intergenic region upstream of the polyketide synthesis locus BPSS1006-BPSS1011 was additionally associated with downregulation of host genes involved in myeloid-cell signalling and cell proliferation pathways. These findings connect naturally occurring B. pseudomallei genomic variation associated with mortality to distinct host immune signatures, providing insight into pathogen-host interactions underlying severe melioidosis and a framework for investigating the contribution of pathogen genetic diversity to clinical outcomes.