YfdX

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Introduction

is a family protein that is encoded by several pathogenic bacteria such as Salmonella and E. coli. Particularly YfdX is encoded in Salmonella enterica serovar Typhi that causes a fatal disease called Typhoid Fever. Salmonella is a gram-negative bacterium that is excellent at infecting living organisms. They are fast replicating, mobile, and are armed with needle completes that can penetrate cells in the human digestive tract (“Salmonella Are Armed, Agile and Primed for Invasion.”). When Salmonella invade the epithelial cells lining the intestines it can survive and replicate inside membrane bond compartments called vacuoles (“Salmonella Are Armed, Agile and Primed for Invasion.”) The salmonella moves from cells to cell with a flagellum with in the intestine (“Salmonella Are Armed, Agile and Primed for Invasion.”).

Disease

Typhoid fever is a disease that can be spread by contaminated food or water and causes symptoms of lasting fever, weakness, stomach pains, headache, loss of appetite, constipation and sometimes internal bleeding ^[3]. S. Typhi it is an etiologic agent, the microbial toxin that causes disease in humans. S Typhi is a human restricted disease however, some higher primates can be infected experimentally ^[3]. S. Typhi is 90% homologous to S Typhimurium but S. Typhimurium can infect both humans and primates ^[3]. S. Typhi is unique for a couple of small reasons. First S. Typhi has a large region specific to it, Salmonella pathogenicity island 7 that encodes the viaB locus ^[3]. This locus consists of ten genes related to the biosynthesis and export of Vi polysaccharides capsule ^[3]. This involves circumventing Toll-Like Receptors mediated immune surveillance ^[3]. Another area that is specific to S. Typhi is a small island with a locus encoding five genes ^[3]. These genes include three typhoid toxins components, a bacteriophage muramidase homolog controlling typhoid toxin secretions and a small gene of unknown function ^[3].

Toxicity of Typhoid Toxin

When a person is infected with typhoid it is spread through the intestinal tract the bloodstream. The reason this disease is so toxic is from , a unique factor produced by S. typhi ^[3]. The toxin is a different type which means it is made up of one A subunit and 1 B subunit ^[3]. Typhoid toxin has 2 types of A subunits and 1 B subunit. The A subunits are and , and the B subunit is ^[3]. Research has shown that the toxin is made up of 1 molecule of each PltA and CdtB with ^[3]. The combination of Typhoid toxin subunits is what leads it to be very toxic. The typhoid toxin can bind to a wide variety of cells by attaching to certain types of proteins presents on the surface of many cells ^[3]. These proteins have a specific carbohydrate called glycan and typhoid toxin binds very well to this. Research has shown if there is a reduction in glycans leads to a reduction in typhoid toxin binding ^[3]. The PltB is thought to be responsible to the binding of the glycans because it has a pocket for the binding of glycans. Typhoid toxin primarily targets immune cells and the central nervous system, leading to the reason why the symptoms are so severe ^[3].

Structural highlights of Typhoid Toxin

The two A subunits are enzymatic, and this is important because it shows molecular evolution and how these two separate toxins fused together and became one ^[3]. Thus, leading to its incredible virulence because it’s becoming more complex and harder for organisms to deal with the infection. A similar toxin that has the similar structure of the two A enzymatic subunits is Anthrax toxin however, it has A subunits from two individual toxin complexes that have one A subunit ^[3]. This means that the typhoid toxin is the first to be discovered of its kind. Along with the two enzymatic subunits becoming one it’s trafficking mechanism is also different from typical AB toxin ^[3]. Typhoid toxin is exclusively produced in the intracellular infected cells, which in most cases is a vacuole in the epithelial lining of the intestines, leads to believe that the infected cells are apart of the export trafficking of typhoid toxin to extracellular milieu ^[3].This type of mechanism allows the typhoid toxin to be extremely virulent and spread so quickly.

Where YfdX Comes From

YfdX is a product of yfdXWUVE operon and is said to be under the control of . EvgA come from the EvgAS. EvgAS is a two-component system that modulates drug resistance of E. coli by regulating the expression of the drug transporters ^[4]. EvgA research has shown that the toxin is made up of 1 molecule of each PltA and CdtB with 5 molecules of PltB ^[4]. EvgA is the response regulator and modulates the expression of emrKY, which encodes a bile salt specific exporter and yhiUV which encodes a multidrug exporter ^[4] However, over expression of EvgA gives potential an acid resistant phenotype ^[4]. The acid resistance is somewhat got in rid of by the deletion of ydeP, yhiE, or ydeO, genes induced by EvgA overexpression ^[4]. Along with EvgA most likely planning major role in tolerance to outside forces the yfdXWUVE operon does as well. The yfdXWUVE operon appears to encode proteins that enhance the ability of Salmonella to survive under acidic conditions ^[5].

Structural highlights of YfdX

YfdX weighs around 42kDa and is suggested to be a dimer in solution ^[6]. It has 10-186 residues from its total 199 amino acids ^[6]. It is composed of six α-helices, one 310-helix, and three β-strands. These arrange into three subdomains: a four helical bundle, and antiparallel β-sheet, and two helical bundles ^[6]. The importance of YfdX is that it plays a major role in Salmonella susceptibility to two β-lactam antibiotics, penicillin G and carbenicillin ^[6]). Without the YfdX protein the Salmonella virulence was enhanced. One specific type of YfdX protein is . This comes from a multidrug resistant strain of Salmonella Typhi (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). The multidrug resistant strains of S. Typhi. have been reported to be resistant to antibiotics such as ciprofloxacin, rifampin, ampicillin, etc. (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). The structure of STY3178 was found in a study to be a well folded and predominately α-helical protein containing β-sheets elements (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). STY3178 is existing in a trimetric oligomerization state in solution. (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). Its ability to bind to antibiotics was found to demonstrate that different small antibiotics are capable of binding to STY3178 such as ciprofloxacin, rifampin, and ampicillin (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). Studies show that the binding of ciprofloxacin binding is stronger than rifampin flowed by ampicillin (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). This is important to note because if a patient were to come down with typhoid fever and had the STY3178 protein it would be best to see which antibiotic would bind best to the STY3178 protein.

Summary

Typhoid Fever is one of the worst infections to get for it is fatal and is damaging to the body. It is not like most bacterial infections for it as some unique features to it that make it special. It is human- restricted and has a unique Typhoid Toxin with an atypical AB toxin structure, one that has been yet to be seen by any other bacteria. Its two enzymatic A subunits most likely contribute to why it is so virulent. Along with what makes typhoid fever such a harsh disease the protein YfdX is the protein that makes that makes a strain of Salmonella, S. Typhi. YfdX is a product of yfdXWUVE operon which helps the S. Typhi resists acidic conditions. Along with EvgA that controls the YfdX protein. Evg is the response regulator and modulates which encodes a bile salt specific exporter and encodes a multidrug exporter. Lastly the YfdX specific protein STY3178 is present in some multidrug resistant strains of S. Typhi. This gene was specifically looked at to show that it does allow binding of antibiotics. This is important because a multidrug resistant S. Typhi is potentially dangerous and medical professionals need to know what antibiotic to use in a case of Typhoid Fever.

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