Genomic analysis unveils genome degradation events and gene flux in the emergence and persistence of S. Paratyphi A lineages

Paratyphoid fever caused by S. Paratyphi A is endemic in parts of South Asia and Southeast Asia. The proportion of enteric fever cases caused by S. Paratyphi A has substantially increased, yet only limited data is available on the population structure and genetic diversity of this serovar. We examined the phylogenetic distribution and evolutionary trajectory of S. Paratyphi A isolates collected as part of the Indian enteric fever surveillance study Surveillance of Enteric Fever in India (SEFI). In the study period (2017-2020), S. Paratyphi A comprised 17.6% (441/2503) of total enteric fever cases in India, with the isolates highly susceptible to all the major antibiotics used for treatment except fluoroquinolones. Phylogenetic analysis clustered the global S. Paratyphi A collection into seven lineages (A-G), and the present study isolates were distributed in lineages A, C and F. Our analysis highlights that the genome degradation events and gene acquisitions or losses are key molecular events in the evolution of new S. Paratyphi A lineages/sub-lineages. A total of 10 hypothetically disrupted coding sequences (HDCS) or pseudogenes-forming mutations possibly associated with the emergence of lineages were identified. The pan-genome analysis identified the insertion of P2/PSP3 phage and acquisition of IncX1 plasmid during the selection in 2.3.2/2.3.3 and 1.2.2 genotypes, respectively. We have identified six characteristic missense mutations associated with lipopolysaccharide (LPS) biosynthesis genes of S. Paratyphi A, however, these mutations confer only a low structural impact and possibly have minimal impact on vaccine effectiveness. Since S. Paratyphi A is human-restricted, high levels of genetic drift are not expected unless these bacteria transmit to naive hosts. However, public-health investigation and monitoring by means of genomic surveillance would be constantly needed to avoid S. Paratyphi A serovar becoming a public health threat similar to the S. Typhi of today. Author summarySalmonella enterica serovar Paratyphi A remains one of the most common causes of enteric fever in the endemic regions of Asia. Within-host evolution of this human-restricted pathogen has led to the emergence of multiple lineages and sub-lineages through significant genomic rearrangement and pseudogene formation. Our study provides a snapshot overview of the gene flux and genome degradation events that shaped the evolution of S. Paratyphi A over the last 300 years. We leveraged the ongoing enteric fever surveillance program in India to collect 441 S. Paratyphi A clinical isolates, of which 152 were whole-genome sequenced. We carefully screened every internal node and cataloged mutations and gene flux at every stage of divergence/lineages throughout the phylogeny, revealing the role of key genetic changes in the evolutionary adaptation of S. Paratyphi A. Though several studies have previously reported the evolutionary trajectory of S. Paratyphi A, our study provides additional signatures with the most plausible evidence to date, backed by a molecular basis of adaptive mutations. The data from this study would merit further attention and interest in validating vaccines and developing novel diagnostics against S. Paratyphi A infections.

Automated summary

This study investigates the evolutionary trajectory and population structure of S. Paratyphi A isolates collected in India. The study finds that S. Paratyphi A accounted for 17.6% of enteric fever cases in India during the study period, and the isolates were highly susceptible to major antibiotics except for fluoroquinolones. Phylogenetic analysis reveals that S. Paratyphi A isolates in India belong to lineages A, C, and F, and genome degradation events and gene acquisitions or losses are important molecular events in the evolution of new lineages.