A Microbial Biorealm page on the genus Salmonella typhi
Higher order taxa
Bacteria; Proteobacteria; Gammaproteobacteria; Enteriobacteriales; Enterobacteriaceae
Description and significance
There are over 2,000 various groupings (serovars) that comprise S. enterica, each very closely related to each other making Salmonella typhi a prime example of a serovar. Salmonella typhi is a gram negative bacterium that causes systemic infections and typhoid fever in humans. This rod-shaped, flagellated organism’s sole reservoir is humans. It has caused many deaths in developing countries where sanitation is poor and is spread through contamination of water and undercooked food. Eradication seems highly unlikely due to recent emergence of multi drug resistance strains. Salmonella Typhi strain Ct18 was originally isolated from a patient in a hospital in Vietnam. The chromosome sequence is 4,809,037 bp in length with a G+C content of 52.09%. The chromosome was sequenced though the method of shotgun sequencing with 97,000 shotgun reads. Since then, Salmonella typhi has undergone evolutionary change and has become resistant to antibiotics (1).
The genome for Salmonella typhi has been completely sequenced. There are about 204 pseudogenes encoded in Salmonella typhi. A majority of these genes have been inactivated by a stop codon, which shows that the genes were recently modified due to evolutionary changes. Of the 204 genes, twenty seven are remnants of insert sequences and genes of bacteriophage origin. Seventy five are involved in house keeping functions and 46 of the gene mutations have to do with host interaction.
There are two commonly used strains of Salmonella typhi, CT18 and Ty2. Salmonella typhi CT18 has a large circular chromosome consisting of 4.8 Mb and two plasmids, pHCM1 and pHCM2, one of which has multiple drug resistance (pHCM1). Salmonella typhi Ty2 has one large chromosome that is 4.7 Mb and unlike CT18, it does not have plasmids and can be affected by antibiotics. In fact, the current vaccine was developed using S. typhi Ty2. Out of the 204 pseudogenes in Salmonella, 195 genes are the same in both strains CT18 and Ty2, making them 98% identical (1,5).
Cell structure and metabolism
Salmonella typhi is a rod-shaped, gram negative bacteria that contain features that separates itself from other types of bacteria which include: having 2 membranes ( and outer and an inner), periplasm, and a Lipopollysaccharide chain that consists of α-d-galactosyl-(1 → 2)-α-d-mannosyl-(1 → 4)-l-rhamnosyl-(1 → 3)-repeating units, and has short branches of single 3,6-dideoxyhexose residues (3).
Salmonella typhi has a complex regulatory system, which mediates its response to the changes in its external environment. Sigma factors, which are global regulators that alter the specificity of RNA polymerase, are examples of such regulation. Some sigma factors direct transcription to produce stress proteins, which increases the chances of the bacteria surviving environmental changes. RNA polymerase S is produced in response to starvation and changes in pH and temperature. It also regulates the expression of up to 50 other proteins and is also involved in the regulation of virulence plasmids.
In order to survive in the intestinal organs of its hosts where there are low levels of oxygen, Salmonella typhi has to be able to learn to use other sources other than oxygen as an electron acceptor. Therefore, Salmonella has adapted to grow under both an aerobic and anaerobic conditions. Salmonella’s most common source of electron acceptors is nitrogen. Examples of other electron acceptors are: nitrate, nitrite, fumarate, and dimethlysulphoxide. Global and specific regulatory systems of anaerobic gene expression, like the ones mentioned above, are implemented to make sure that the most energetically favorable metabolic process is used. Evidence shows that the availability of oxygen is an environmental signal that controls Salmonella’s virulence (11).
Salmonella typhi is a food born pathogen and that is increasingly difficult to control. Salmonella’s ability to change its phenotype and genotype in response to environmental changes make it almost impossible to eradicate from the food chain. When a culture of Salmonella was transferred to higher temperatures (60 C), it took 60 minutes to maximize heat resistance. When the pH was lowered, acid resistance increased. The time taken to kill 90% was 4-14 minutes. Salmonella cells experience gradual changes which is why Salmonella thrives in undercooked meat. It is able to adapt to survive the cooking process and also has the ability to cross the gastric acid barrier (this is how they enter the human intestine). A high-fat matrix is protects Salmonella against these stressful environments (2).
Salmonella typhi has killed over 600,000 people annually all over the world. It is a deadly bacterial disease that causes typhoid fever and is transmitted through food and water. It has become an epidemic in South Asian countries where sanitation is lacking. S. typhi usually invades the surface of the intestine in humans, but have developed and adapted to grow into the deeper tissues of the spleen, liver, and the bone marrow. Symptoms most characterized by this disease often include a sudden onset of a high fever, a headache, and nausea. Other common symptoms include loss of appetite, diarrhea, and enlargement of the spleen (depending on where it is located).
Salmonella typhi involves colonization of the Reticuloendothelial system. Some individuals who are infected with S. typhi become life-long carriers that serve as the reservoir for these pathogens. S typhi has an endotoxin (which is typical of Gram negative organisms), as well as the Vi antigen, which increases virulence. It also produces a protein called invasin that allows non-phagocytic cells to take up the bacterium and allows it to live intracellularly. Salmonella typhi is a strong pathogen for humans due to its resistance to the innate immune response system (6).
Recently, strains of MDR (multi-drug resistant) Salmonella have been identified and grouped together in a single haplotype named H58. It has been found that these strains are now resistant to nalidixic acid and have reduced susceptibility to fluoroquinolones. This strain has been recently found in Morocco, which shows that the MDR strain has reached as far as Africa (4).
Much research is going on since the global emergence of multi drug resistant strains. In India, samples of 21 Salmonella typhi strains were tested for their vulnerability to antimicrobial agents. Three different antibiotics were tested: chloramphenicol (256 mg/liter), trimethoprim (64 mg/liter), and amoxicillin (>128 mg/liter). Eleven of the S. typhi strains were resistance to chloramphenicol, trimethoprim , and amoxicillin. Four of the isolates were resistant to all of them except for amoxicillin. Other antimicrobial agents were also tested. All the S. typhi isolates were susceptible to cephalosporin agents, gentamicin, amoxicillin plus clavulanic acid, and imipenem. One of four plasmids encoded each S. typhi isolate. The genes responsible for the resistance of the antibiotics listed above (chloaramphenical and etc.) are: chloramphenicol acetyltransferase type I, dihydrofolate reductase type VII, and TEM-1 β-lactamase. Pulsed-field gel electrophoresis analysis of XbaI-generated genomic restriction fragments identified a single distinct profile (18 DNA fragments) for all of the resistant isolates. After comparing this, six different profiles were recognized among the sensitive isolates. It was found that a single strain containing a plasmid having multi drug-resistance has emerged in the S. typhi population and has been able to adapt and survive the antibiotics as they are introduced into clinical medicine (10).
With the current spread of Salmonella, researchers are looking for easier ways to detect typhoid fever in order to better treat patients. Another project has to do with dipstick assay which detects antibodies and analyzes the effect of typhoid fever in patients. It found specific IgM antibodies on patients in 43.5%, 92.9%, and 100% for samples collected 4-6 days, 6-9 days, and greater than 9 days after the onset of fever, respectively, the number of antibodies increasing during the length of the duration. Testing of serum samples from culture negative patients with a clinical diagnosis of typhoid fever resulted in staining of the dipstick in 4.3% of the samples collected on the day of admission and in 76.6% one week later. This shows the late development of antibodies in the blood for a large number of patients. The advantages of the dipstick assay are that the result can be obtained on the same day allowing a prompt treatment. No special laboratory equipment is really needed to perform the assay and one would only need a small amount of serum. What makes it even better is that the simplicity of the assay would allow it to be used in places that lack laboratory facilities, such as third world countries that lack modern facilities and where disease is running high (9).
More people have taken a greater interest in Salmonella typhi since the decreasing effects of antibiotics. In 2006, more research was done in order to find the global gene expression by Salmonella typhi during infection. Global expression profiles of typhi grown in vitro and within macrophages at different time points were obtained and studied. Virulence factors, such as the SPI-1- and SPI-2-encoded type III secretion systems, were found as expected during infection by Salmonella. The results concluded that Salmonella typhi had an increased expression of genes encoding resistance to antimicrobial peptides, which used the glyoxylate bypass for fatty acid utilization, and did not induce the SOS response or the oxidative stress response. It was also found that genes coding for the flagellar apparatus, chemotaxis, and iron transport systems were down-regulated in vivo. This experiment allowed a better understanding of Salmonella and found a safer and more effective way to determine the bacterial transcriptome in vivo. This could possibly lead to the investigation of transcriptional profiles of other bacterial pathogens without the need to recover much bacterial mRNA from the host (7).
1. Den, Weng, Shian-Ren Liou, Plunkett, Guy, Mayhew, George F., Rose Debra J., Burland,Valerie, Voula Kodoyianni, Schwartz, David C., and Blattner,Frederick R., “Comparative Genomics of Salmonella enterica Serovar Typhi Strains Ty2 and CT18”. Journal of Bacteriology.2003. Volume 185. p. 2330-2337.
2. Humphrey,Tom. “SALMONELLA, STRESS RESPONSES AND FOOD SAFETY”. Nature Reviews Micriobiology.2004. Volume 2. p. 504-509.
3. Kita, Hiroshi, and Nikaido Hiroshi. “Structure of Cell Wall Lipopolysaccharide from Salmonella typhimurium IV. Anomeric Configuration of l-Rhamnose Residues and Its Taxonomic Implications”. Journal of Bacteriology. 1973. Volume 113. p. 672-679
4. Ojcius, David. “In the News”. Nature Reviews Microbiology. 2007. Volume 5. p. 10-11.
5. Parkhill J, Dougan G, James KD, Thomson NR, Pickard D, Wain J, Churcher C, Mungall KL, Bentley SD, Holden MT, Sebaihia M, “Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18”. Nature. 2001. Volume 413. p. 848-852
6. Falkow, Stanley, Monack, Denise M., Mueller, Anne. “PERSISTENT BACTERIAL INFECTIONS: THE INTERFACE OF THE PATHOGEN AND THE HOST IMMUNE SYSTEM”. Nature Review of Micribiology.2004. Volume 2. p.747-765.
7. Faucher,Sébastien P., Porwollik,Steffen, Dozois,Charles, McClelland,Michael, and Daigle, France. “Transcriptome of Salmonella enterica serovar Typhi within macrophages revealed through the selective capture of transcribed sequences”. The National Academy of Sciences of the USA. 2006. Volume103. p. 1906-1911.
8. Salmonella Typhi. GlaxoSmithKline Biologicals, Belgium. Sanger Institution. 25 Aug. 2007 <http://www.sanger.ac.uk/Projects/S_typhi/>.
9. Hatta, M., Gorris, M.G., Heerkens,E., Gooskens J., and Smits, HL. “Simple dipstick assay for the detection of Salmonella typhi-specific IgM antibodies and the evolution of the immune response in patients with typhoid fever”. American Journal of Tropical Medicine and Hygiene. 2002. Volume 66. p. 416-421.
10. Philippa, M.A., Shanahan, Jesudason, Mary V., Thomson, Christopher J., and Sebastian, G. B. “Molecular Analysis of and Identification of Antibiotic Resistance Genes in Clinical Isolates of Salmonella typhi from India”. American Society for Microbiology. 1998. Volume 36. p. 1595–1600.
11. Contreras, Ines, Toro, Cecilia, Troncoso, Gonzalo, Mora, Guido. “Salmonella typhi mutants defective in anaerobic respiration are impaired in their ability to replicate within epithelial cells”. Microbiology. 1997. Volume 143. p. 2665-2672.
Edited by Rupal Shah a student of Rachel Larsen