Typhoid or enteric fever is caused primarily by Salmonella enterica
serovar Typhi and is a human-specific disease for which there are an estimated 21 million new infections every year, resulting in approximately 200,000 deaths1
. Typhoid is an acute illness often characterized by high fever, malaise and abdominal pain2
. Globally, children are disproportionately affected, especially in south central Asia, Southeast Asia, Latin America and Southern Africa, where the incidence of antibiotic resistance exacerbates the morbidity and mortality associated with the disease1,3
. Serious complications include intestinal perforation, septicaemia and meningitis, with the highest incidence of these being found in paediatric and immunocompromised patients. These complications are life threatening and require advanced medical care that is often not available in typhoid-endemic regions4–6
Typhoid is most commonly spread by ingestion of contaminated water or food. Following entry into the small intestine, the bacteria cross the intestinal epithelial barrier (probably by invasion of microfold (M) cells in the Peyer’s patches and lymphoid-associated tissues), are phagocytosed by macrophages and spread systemically, producing acute disease7–10
. The most common sites of infection are the ileum, liver, spleen, bone marrow and gall bladder. The bacteria reach the gall bladder through the vasculature or the ducts that emanate from the liver2,11
. Over the past decade, the incidence of antibiotic resistance among S.
Typhi isolates has risen dramatically in endemic regions. Strains that are refractory to almost every available first-line antibiotic have been recovered, and up to 60% of all strains isolated exhibit multidrug resistance12,13
. Fortunately, with adequate treatment, most patients recover from the acute phase of typhoid; however, 3–5% of individuals who are infected with S.
Typhi develop a chronic infection in the gall bladder14,15
. Because S.
Typhi is a human-restricted pathogen, these chronic carriers form a crucial reservoir for the further spread of the disease through bacterial shedding in faeces and urine16–18
. Chronic S.
Typhi infections can persist for decades, and although infected individuals are highly contagious, they are typically asymptomatic, making the identification of carriers difficult19,20
. The situation is further complicated by the fact that approximately 25% of carriers experience no clinical manifestations during the acute phase of the disease2
Epidemiological studies conducted in endemic regions have indicated that there is a strong link between the development of the chronic carrier state and the presence of gallstones; in fact, approximately 90% of chronically infected carriers have gallstones21,22
. In addition, the typhoid carrier state, both with and without the occurence of gallstones, has been implicated as the crucial predisposing factor for the development of gall bladder cancer23–26
. It has been proposed that bacterial degradation of bile salts and chronic cholecystitis (gall bladder inflammation) related to gallstones could promote the development of gall bladder carcinomas27
. This impact on human health, combined with the high incidence of typhoid fever in many parts of the world, highlights the importance of understanding the mechanisms involved in S.
Typhi carriage. In this Progress article, we summarize recent findings on the mechanisms of gall bladder infection by Salmonella
spp., with an emphasis on biofilm formation on gallstones as a hallmark of typhoid carriage. For a historical perspective of typhoid carriers, see BOX 1
Box 1 | Typhoid Mary Salmonella enterica
serovar Typhi is a human-restricted pathogen, making healthy carriers crucial in the infectious cycle. This role was famously illustrated by Mary Mallon, or Typhoid Mary, a cook in New York City (USA) in the early twentieth century. She is reported to have infected at least 54 people. Other carriers were also identified in New York City around this time, many of who spread the infection to more people than Mary Mallon did. Around the same time, in Folkstone (UK), another chronic carrier referred to as ‘Mr N. the milker’ infected more than 200 people over the course of 14 years. In these cases, public health officials ultimately stepped in and requested that the carriers remove themselves from food service, and although Mr N. and others agreed, Typhoid Mary refused, ultimately leading to her arrest and involuntary lifelong quarantine on North Brother Island in New York. Typhoid Mary was the first identified healthy carrier of an infectious disease in the United States, as she was symptom free and was not documented as experiencing a bout of typhoid fever72–74
This confinement practice continued even after Mary’s death. In 2008, it emerged that 43 female typhoid carriers were quarantined in the Long Grove Asylum in Epsom (Surrey, UK) between 1907 and 1992 and some were held for more than 40 years until the asylum closed in 1992 (REF. 75
), well after the widespread use of antibiotics had begun and increased medical knowledge of the typhoid fever carrier state was gained.