World-wide, 20% of Salmonella Typhi (S. Typhi), the bacteria that causes typhoid fever, belong to types that had never been described by science before. Some of the bacterial strains have higher virulence, higher infectivity and high antibiotic resistance – possibly impacting the disease’s epidemiology and vaccine efficacy.

“By combining epidemiology, genomics, and molecular investigation, we were able to provide much-needed insights into the various types and consequences of the Vi capsule variants of S. Typhi,” said Dr. Jeongmin Song, associate professor in the department of Microbiology and Immunology at the Cornell University College of Veterinary Medicine, who led the study.

The discovery was published in the journal Nature Communications. Gi Young Lee, a postdoc in her lab, co-authored the paper.

“Vi” diversity

S. Typhi is transmitted through contaminated food and water, and causes 200,000 deaths per year. To thrive in a host, S. Typhi relies on a structure called the Vi capsule, a layer that covers the exterior of the bacteria and serves as a protective cloak against the host’s immune system. The molecules that form the Vi capsule, called capsular polysaccharides (CPS), are used to create typhoid vaccines. 

Despite the importance of the Vi capsule, its genetic diversity and how it may affect virulence had not been documented until now. “Before, we thought there was only one type,” said Song.  “We were curious to know whether there are Vi capsule variations among S. Typhi clinical strains found at various times and locations.”

To investigate the potential variability in Vi capsules, Lee and Song analyzed the whole genome of 5379 strains collected worldwide. Two particular enzymes involved in Vi capsule synthesis carried a lot of genetic variation. 

Hypo and hyper Vi variants

Focusing on 21 of the most common mutations found in these enzymes, Lee and Song established how this genetic variation affected the composition of the CPS forming the Vi capsule. “We made an intriguing finding,” said Song. “Each of these specific point mutations leads to a distinct variant form of Vi.”

Based on these structural properties, Lee and Song categorized S. Typhi variants into two main groups called hypo and hyper Vi capsule variants, referring to the amount, length, or chemical properties of the CPS.

Compared to the only known type of Vi capsules, S.Typhi with hypo Vi capsules have a higher ability to infect a host. S. Typhi with hyper Vi capsules, in turn, make infected mice sicker and have a higher mortality rate.

In addition, bacteria with hyper Vi capsules have an enhanced ability to colonize the gallbladder. Importantly, between 2% to 6% recovered patients with S. Typhi in the gallbladder become asymptomatic chronic carriers, and can shed S. Typhi for months or years, contributing to the persistence of the disease. “It’s like the story of Typhoid Mary,” said Song.

Also concerning is Lee and Song’s finding that hyper Vi strains are more geographically distributed than hypo Vi and show more antibiotic resistance. “It is alarming that all instances of a specific hyper Vi capsule variant have demonstrated resistance to ciprofloxacin, a commonly used treatment for typhoid patients in clinical settings,” said Song.

Scientific impacts

Song’s discovery has broad implications for epidemiology. For example, Song said it might be beneficial to update current detection methods to identify the circulating variants. Her findings also open possible clinical applications. We don’t know, she said, if the typhoid vaccine is equally effective against all types of Vi capsules.

As a next step, Song is expanding the correlation between genetic variation and capsule properties beyond the 21 described in her paper to all variants discovered. “We want to produce a reference chart for the scientific community,” she said. She is also working on other species of Salmonella that produce capsules similar to the hyper type, including the Salmonella Paratyphi C, which causes a disease similar to typhoid and Salmonella Dublin, that can infect humans and cattle.

“Overall, our study raises awareness of the existence of many Vi capsule types of S. Typhi, both within and outside the scientific community,” said Song. “It is a framework for future research on S. Typhi capsule variants and it provides strategies to combat [these types of] bacteria.”

A modified version of this story appears in the Cornell Chronicle.

Written by Elodie Smith