Salmonella enterica serovar Typhi

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University of Oklahoma Study Abroad Microbiology in Arezzo, Italy[1]

Image of Salmonella enterica serovar Typhi. [2]

Etiology/Bacteriology

Taxonomy

Description

Salmonella enterica serovar Typhi is a gram-negative facultative anaerobe. While this bacterium strictly infects humans, scientists remain uncertain regarding the reason behind this pathogen’s selective host behavior. This rod shaped invasive pathogen initially propagates inside the intestinal tract and spreads throughout the peripheral lymphatic system, such as the bone marrow and the Peyer’s patch, to cause typhoid fever [3]. Typhoid fever generally occurs in four stages throughout a four-week period with an incubation period of 1 to 2 weeks before the onset of initial symptoms. The incubation period may vary depending on the host immune system and severity of infection [4]. Beginning with a fever between 103-104°F, the patient's condition will continue to deteriorate due to symptoms including diarrhea, rashes, and delirium. Patient death is largely the result of complications from the illness including myocarditis, intestinal bleeding or perforations [5].
This human pathogen has existed for thousands of years by thriving in poor sanitary conditions, especially in crowded areas. Salmonella Typhi is originally derived from the ancient Greek word typhos, defining an ethereal smoke or cloud believed to cause madness and disease. Some scientists and historians have suggested that this bacterium may have been responsible for the Plague of Athens in the final stages of the Pelopennesian War. Antibiotics have reduced the frequency of typhoid fever, yet it still remains prevalent in developing countries. The relatively new subspecies, S. paratyphi causes similar, albeit milder symptoms with a more abrupt onset and a shorter course of infection. Both S. Typhi and S. Paratyphi serovars are referred to collectively as typhoidal Salmonella. [6]
Typhoid fever is usually treated with antibiotics such as Ciprofloxacin. Due to the use of fluoroquinolones, over 10 years the clonal expansion of the haplotype H58 has increased in Asia and Africa where the invasive Salmonella Typhi continues to constitute a severe risk. However, other strains and halotypes of typhoid fever remain sensitive to antibiotics despite the growing selection for antibiotic resistant strains [7]. Additional experimentation and research regarding Salmonella Typhi is difficult due to its preference for human hosts. Mouse models infected with S. enterica serovar Typhimurium have been the main source to observe pathogenic effects due to its similar genome, which only differs by 11%. [8] [9]

Pathogenesis

Transmission

The transmission of Salmonella enterica serovar Typhi, like most Samonella serovars, occurs through the fecal-oral method. The pathogen is human host-adapted and generally spreads through contaminated food and water sources. Some hosts of Salmonella Typhi become asymptomatic carriers and can unknowingly transmit the pathogen to others. Because they are unaware of their condition, these carriers often lack proper preventative measures for slowing the spread of bacteria. Without proper prevention, the bacteria are able to attain a high transmission rate. While lacking symptoms themselves, these carriers excrete large amounts of the bacteria in their feces and pass on the pathogen by contaminating food and water sources. [10] A primary example of an asymptomatic carrier who caused high transmission rates is "Typhoid Mary." Mary Mallon, an Irish cook in the New York City area, was the first known typhoid carrier in the United States. Despite her complete lack of symptoms, it is believed that Mallon caused a minimum of seven outbreaks of typhoid fever, resulting in 57 cases of the disease and 3 deaths. [11]

Infectious dose, incubation, and colonization

The infectious dose is 10^3-10^6 bacilli, and the incubation period is between 7-14 days.

A high infectious dose of Salmonella Typhi is needed for infection, because it lacks acid tolerance. As a result much of the bacteria is destroyed as it passes through the highly acidic environment of the stomach. The bacteria must be abundant enough to overcome conditions of the stomach to successfully infiltrate the host. [6]
To colonize, S. Typhi adheres to the mucosal lining of the small intestine and penetrates the epithelial cells. The bacteria spread to the peripheral lymphoid organs during secondary infection. The gallbladder serves as the primary reservoir of chronic infection. The formation of biofilms in the gut and on gallstones is a critical factor in the carriage and shedding of S. Typhi. [12]

Epidemiology

Typhoid fever has continued to be a persistent threat in developing countries such as India, South American, Southeast Asia, and Africa due to poor sanitation conditions and lack of access to clean water [13]. 80% of typhoid cases are believed to have originated from Bangladesh, India, China, Indonesia, Nepal, Laos, Vietnam, or Pakistan [14]. The CDC reported that 22 million people are affected by Salmonella enterica serovar Typhi yearly, which resulted in approximately 200,000 deaths [15]. The United States specifically reports between 200 and 300 of these cases yearly, however approximately 80% of these cases are a consequence of traveling to countries with a high occurrence of typhoid fever [16]. Before the use of antibiotics in the United States, the fatality rate was between 9-13%. Modern day medicine has decreased the mortality rate for patients that have access to treatment to just below one percent while mortality rates for patients that receive no treatment are greater than 10 percent [3].

The World Health organization claims that statistics are difficult to verify due to lack of proper supplies and measuring techniques in regions throughout Africa. However, they believe that the rate of typhoid fever infections has been gradually declining over the past several years in countries such as India and Chile. These results are attributed to increased attention towards health and sanitation methods [17].

Virulence Factors

Most of the bacterium's virulence arises from Salmonella pathogenicity islands, also known as SPI. These islands encode for the majority of effector molecules associated with pathogen virulence. For example, after entering a host cell, Salmonella Typhi will secrete effector proteins including SIPA and SptP. These proteins will alter the actin cytoskeleton of the host cell, which is responsible for cell migration.

SPI7 is considered the most important pathogenicity island because it codes for the Vi antigen which is expressed on the surface. This antigen resides within a polysaccharide capsule which is essential for increased virulence and severity of symptoms. It is believed that this capsule also prevents lipopolysaccharide recognition by Pattern Recognition Receptors (PRRs) in order to prevent immune response, however further research is required. Secretion of the protein invasin will allow non-phagocytic cells to ingest the bacterium in order to allow for intracellular access leading to the inhibition of oxidative leukocytes and rendering the innate immune response ineffective. Other possible factors include ion transporters, fimbrae, and flagella required for attachment and colonization. [6]

Recently, the typhoid toxin has been discovered. This toxin is known as chimaeric A2B5 typhoid toxin and is made up of two subunits including the PltA and CdtB. These two subunits are comparable to pertussis and cytolethal and pertussis toxins. It is believed that this toxin is the cause of the high fevers present during the first and second week of infection. [18]

Clinical Features

Symptoms of the infection can be classified according to a time frame after exposure. During the incubation period of 7 to 14 days, the patient is asymptomatic as the bacteria colonizes and breaches the intestinal wall. Within 72 hours after the onset of the illness, the patient may experience a high fever between 103-104°F. A rash on the abdomen or chest, fatigue, dry cough, and diarrhea also characterizes this first week of infection. If the patient has not received treatment by the second week, symptoms will increasingly worsen including the fever and continuation of diarrhea or constipation that can lead to extreme weight loss. By the third week with no medical attention, the patient will become delirious and experience severe exhaustion known as the typhoid state. During this week severe complications may occur in association with prolonged infection of typhoid fever [19]. Approximately three percent of people with typhoid fever develop a perforated intestine causing internal bleeding, which could cause blood to appear in the stool [4]. This results in a hole in the small or large intestine triggering possible symptoms of abdominal pain, nausea, vomiting, and blood sepsis. Other complications associated with typhoid fever include myocarditis, intravascular coagulation, kidney or bladder infections, and meningitis. Psychiatric problems for example, delirium, hallucinations, and paranoid psychosis can also occur as a result of infection [19]. If the patient is able to survive to the fourth week, they will gradually improve and are able to regain their mental state, however this recovery period may last up to several weeks or months [5]. Statistically, around 10 percent of patients will experience a relapse of symptoms after they have recovered. The probability of relapse is shown to increases with antibiotic usage. Three to five percent of survivors may also become long-term asymptomatic carriers with the potential to trigger new outbreaks [20].

These effects can be more severe or prolonged in children and the elderly. Bacteremia, or the spread of the pathogen into the blood stream, generally occurs in 5-10% of cases and can lead to more severe symptoms such as meningitis and infections of the bones and joints. This can be especially dangerous in immunocompromised patients such as those suffering from HIV or Malaria [6].

Diagnosis

Stool cultures are used to diagnose the disease, but in many cases, blood cultures must also be used to reach a confident diagnosis due to the sensitivity of stool cultures in the early and late stages of illness. The blood cultures from the infected host can be tested on MacConkey agar and EMB agar. [18] [21]

Salmonella Typhi enters the bloodstream upon infection and is carried by white blood cells to the liver, spleen, and bone marrow where multiplication occurs, after which the bacteria enter back into the bloodstream. As the bacteria invade the lymphatic tissue of the bowel, they continue to proliferate. The bacteria then enter the intestinal tract and can be used in the diagnosis of stool cultures from the laboratory. In early and late stages of the disease, stool cultures are more sensitive to culturing but should be tested simultaneously with blood culture to make a definitive diagnosis. Additional testing may be done to differentiate between the different serovars of S. enterica species. These molecular biological tests are based on different antigens on the bacteria's surfaces, such as O, K, and H. [3]

Treatment

Antibiotic therapy, specifically ciprofloxacin and ampicillin, is the only effective treatment. For pregnant women, ceftriaxone is used. Recently, antibiotic resistance by S. Typhi has increased and developed into a more serious issue concerning the effectiveness and use of antibiotics. To stimulate recovery, fluids and a healthy diet can be administered in addition to antibiotics [21]. Previously, antibiotic treatment for typhoid fever included regimens of ampicillin, trimthoproim-sulfamethoxazole, and chloramphenicol. Because of developing drug resistance over the past twenty years, the usage of these drugs is now limited. Strains specific to South America have shown significant resistant to antibiotic therapy. Currently quinolone, macrolide, and third-generation cephalosporin antibiotics are used to treat resistant strains. Quinolone sensitivity has steadily declined in different parts of the world, but it remains significant in the United States [13]. To treat the carrier state, prolonged antibiotics are prescribed. Additionally, the direct site of chronic infection can be removed, such as gall bladder removal [22].

Prevention

To avoid infection, hygiene such as clean hands and treated water is encouraged. Boiling water and correct procedure when handling raw fruits and vegetables decrease the risk of infection. [22] In association, two vaccines are available: inactivated typhoid vaccine administered via injection and live typhoid vaccine administered orally. Neither vaccine is 100% effective, and both require repeated immunizations. [15]
To prevent the infection while recovering from typhoid, one should avoid handling food, isolate personal items, wash hands as often as possible, and clean toilets, door handles, and telephone receivers daily [22].

Host Immune Response

Salmonella enterica serovar Typhi can cause life-threatening bacterial infections called typhoid fever. The uncontrolled activation of the host innate immune response can potentially lead to systematic inflammation, tissue injury, intravascular coagulation, and even death [12].

Salmonella enterica serovar Typhi is an invasive pathogen. It is recognized by the host’s immune system using toll-like receptors (TLRs) which initiate the innate immune response. The TLRs recognize pathogen-associated molecular patterns (PAMPS) located on the surface of the pathogen. This recognition allows for the innate immune system to initiate its response, causing the activation and recruitment of macrophages, neutrophils, and cytokines. For example, IFN-γ is a significant cytokine for macrophage activation and early host resistance of S. Typhi [12].

Victims of typhoid fever are susceptible to reinfection because of the initial severe disruption of the gut microbiome. A typical host contains a microbiome of 1x10^14 bacteria with an average of 500 to 1,000 different species. A healthy microbiome can protect the host’s epithelial cells from infection. The gut microbiome produces toxic metabolites that can suppress the virulence of S. Typhi’s gene expression, boost the host’s immune response, and help clear the intestinal lumen after non-typhoidal diarrhea. Additionally, apoptosis can strengthen the host’s defense by allowing the body to prevent further release of pro-inflammatory cell mediators. The ability of S. Typhi to use a microbiome nutrient called ethanolamine allows it to colonize in the intestinal tract. This rich nutrient often allows S. Typhi to outcompete other pathogens. Antimicrobial treatment for S. Typhi may cause depletion of the host’s gut microbiome. This depletion can lead to prolonged effects of intestinal colonization and an increase in carrier status and fecal shedding [12].

References

1 University of Oklahoma Faculty and Staff.
2 Kenyan Waterborne Disease Center
3 "Salmonella Typhi" Salmonella Typhi.
4 "Salmonella enterica SPP" Public Health Agency of Canada.
5 "Typhoid fever- symptoms." NHS.
6 Brusch, J.L. "Typhoid Fever" Medscape.
7 Roumagnac, P., Weill, F.X., Dolecek, C., et al. "Evolutionary history of Salmonella typhi." Science.
8 Garai, P., Gnanadhas, D.P., Chakravortty, D. "Salmonella enterica serovars Typhimurium and Typhi as model organisms." US National Library of Medicine.
9 Deng, W., Liou, S., Plunkett, G., et al. "Comparative Genomics of Salmonella enterica Serovar Typhi Strains Ty2 and CT18." US National Library of Medicine.
10 Gopinath, S., Carden, S., Monach, D. "Shedding light on Salmonella carriers." Trends Microbiology.
11 "Mary Mallon (Typhoid Mary)." American Journal of Public Health.
12 de Jong, H.K., Parry, C.M., van der Pol, T. "Host-Pathogen Interaction in Invasive Salmonellosis" PLOS Pathogens.
13 Klochko, A. "Salmonellosis Treatment and Management." Medscape.
14 Chau, T.T., Campbell, I.J. "Antimicrobial Drug Resistance of Salmonella enterica Serovar Typhi in Asia and Molecular Mechanism of Reduced Susceptibility to the Fluoroquinolones." NCBI.
15 "Typhoid Fever" Center for Disease Control and Prevention.
16 Hohmann, E.L., "Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever" UpToDate
17 Crump, J.A., Luby, S.P., Mintz, E.D., "The global burden of typhoid fever" WHO
18 Song, J., Gao, X., Galan J.E. "Structure and Function of the Salmonella Typhi chimaeric A2B5 typhoid toxin" Nature: International weekly journal of science.
19 "Diseases and Conditions: Typhoid Fever" Mayo Clinic.
20 "Typhoid Fever." WebMD.
21 Pollack, D.V. "Salmonella enterica Typhi." University of Connecticut.
22 Balentine, J.R. "Typhoid Fever." Medicine Net.
23 "Typhoid Fever." Medline Plus.

Created by Taylor Caswell, Sarah Grebennikov, Mary Kate Lowe, and Paige Whitson
Students of Dr. Tyrrell Conway, University of Oklahoma