An Individual's Immune System May Dictate If They Become a “Typhoid Mary”

Modern understanding of bacterial carriers dates back to the infamous case of Typhoid Mary, who unintentionally infected the families she cooked for in early 20th-century New York with enteric fever, resulting in at least 51 cases and 3 deaths.

Over a century later, enteric fever—caused by typhoidal Salmonella, which includes Salmonella Typhi and Paratyphi A/B—remains a major global health issue that caused 107,500 deaths in 2021. Bacterial carriers who harbor bacteria for extended periods, often asymptomatically, are of particular concern as they are difficult to identify and can unknowingly spread the disease. Even today, the intricacies of typhoidal Salmonella carriage remain unknown. 

A study, published in the journal PLOS Neglected Tropical Diseases, has now provided insights into typhoidal Salmonella carriage. Researchers from the Quadram Institute in collaboration with the UK Health Security Agency (UKHSA) and Public Health Wales found that the risk of unknowingly spreading enteric fever appears to depend on the individuals themselves rather than the pathogen.

The researchers identified demographic factors significantly linked to bacterial carriage. Data that will enable public health bodies to target higher-risk individuals to find modern-day “Typhoid Marys”.

Identifying modern “Typhoid Marys”

Detecting modern-day carriers is challenging as it relies on patients submitting multiple samples over the course of their infection. “Following treatment and symptom cessation, many patients will understandably stop submitting samples,” Alice Nisbet, a postgraduate student at the Quadram Institute, honorary UKHSA contract holder, and first author of the study, told Technology Networks.

When carriage remains asymptomatic, or where there are no symptoms during initial infection, the condition may never be identified.

“Additionally, even when repeated samples are given, the intermittent nature of shedding (when bacteria are released from the host into the environment) during carriage means bacteria could appear to have cleared from an individual when actually they continue to persist,” said Nisbet.

To determine the factors that contribute to carriage, researchers examined surveillance data on enteric fever from the UKHSA and Public Health Wales collected between 2004 and 2023. The last carriage estimates for the UK date back to the 1900s when enteric fever was much more prevalent.

Isolates from 8,335 patients were included in the dataset. In total, 224 carriers were identified over the study period (2.7% of cases); carriers were defined as cases that failed to clear after three weeks. Only 0.1% of cases persisted over a year.

Analysis of enteric fever trends revealed that cases are rising in England and Wales. A mean of 415 enteric fever cases were recorded per year across the study period, dropping substantially during the COVID-19 pandemic, before increasing and subsequently peaking at 652 cases in 2023.

Specific demographic groups were identified as at higher risk of typhoidal Salmonella infection, including patients associated with lower Index of Multiple Deprivation deciles and specific ethnic groups travelling to Asia, Africa, and South America.

“The exact reason for rising enteric fever cases in England and Wales remains unclear, but continued surveillance by UKHSA and Public Health Wales is ensuring appropriate public health action is limiting the impact of this disease,” stated Nisbet.

Genomic analysis was undertaken on available isolate genomes to identify possible genetic signatures associated with carriage. The findings suggest there is no genetic signature for carriage of typhoidal Salmonella that could be determined using single nucleotide polymorphisms—one-letter changes in the genetic code—outside of a small number of S. Paratyphi B isolates that require further investigation. Based on these findings, the researchers concluded it's not possible to determine which bacteria are more likely to cause carriage based on DNA sequence alone.

Elderly patients and non-travelers are at higher risk of carriage

The lack of a genetic signature further complicates the ability to track potential carriers and reduce transmission. Instead, patient features associated with carriage could be used to help guide future public health action.

“In terms of typhoidal Salmonella carriage, our findings suggest that the patient’s immune system may play a key role in susceptibility, with more carriage typically seen in young children and elderly patients.” — Alice Nisbet.

Odds of carriage were significantly increased in patients aged 81–90 (447%) and in non-travel-associated cases (64%), while odds were significantly decreased in patients aged 21–30 (35%).

Risk of carriage may be heightened among non-travel-associated cases as a result of immune “naivety”, Nisbet explained: “As both England and Wales are non-endemic regions for enteric fever, meaning the disease is not commonly found here in its acute (symptomatic) form, people are unlikely to encounter typhoidal Salmonella in their day-to-day lives and levels of background immunity will be low.”

Implications for slowing the spread of Salmonella

The disease patterns identified in the study could help further tailor current public health guidance as well as adapt future public health intervention campaigns to ensure interventions reach the more vulnerable populations.

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“Additionally, the identification of demographic factors significantly linked to bacterial carriage, including age and travel history, has led to the recommendation for patients within such groups to continue submitting samples,” said Nisbet. “This could help us identify carriage as early as possible and ensure appropriate interventions can be undertaken.”

“The scale and efficacy of modern routine surveillance by UKHSA and Public Health Wales means we are now in a better position than ever before to identify and study bacterial carriage,” Nisbet suggested.

Future work could see this method applied to other pathogens to investigate asymptomatic carriage of other infectious diseases. For example, carriage is also an issue for non-typhoidal Salmonella, which can cause acute gastroenteritis.

Non-typhoidal serovar Salmonella Agona has previously been studied using data collected by the Gastrointestinal Bacteria Reference Unit at the UKHSA. The study also found no specific lineages that were responsible for persistent infection. However, the authors noted increases in single nucleotide polymorphisms and genomic structure variation during the early stages of persistent infection.

“Future studies are underway for other non-typhoidal Salmonella, which can increase our understanding of the condition and pave the way for both improved public health action and characterization of the bacterial processes underpinning long-term persistence,” Nisbet concluded.

Reference: Nisbet AM, Mohamed I, Verlander NQ, et al. The typhoid Mary legacy: Genomic epidemiology uncovers contemporary carriage dynamics across two decades of enteric fever surveillance in England and Wales. PLOS Negl Trop Dis. 2026;20(4):e0014177. doi: 10.1371/journal.pntd.0014177

About the interviewee:

Credit: Ruby O’Grady—Quadram Institute.

Alice Nisbet’s research interests lie in investigating the impact of infectious diseases on the modern world, and the genomics and phenotypic traits underlying the virulence of bacterial pathogens. Her work incorporates both time in the lab and bioinformatics in attempts to understand how we can combat disease.

Nisbet graduated from the University of Sheffield with a masters of biological science in microbiology and biochemistry after undertaking research projects on both Saccharomyces cerevisiae and Streptococcus pyogenes. She currently works at the Quadram Institute on the Microbes, Microbiomes, and Bioinformatics Doctoral Training Program as part of Dr. Gemma Langridge’s group, exploring carriage of typhoidal salmonellae—especially carriage of Salmonella Paratyphi A—in collaboration with UKHSA and Public Health Wales. As part of the collaboration, she holds an honorary contract with UKHSA.