Trichomonas interacts specifically with the mucin, the predominant component of the mucus. Then the organism comes in contact with the vaginal epithelium cells VECs which are under the influence of various hormonal changes induced by the menstrual cycle.
So, to colonize the vaginal epithelium T. These APs have sequence homology to metabolic enzymes and the majority are positively regulated by iron at the level of transcription and translation. The transcription of this gene is critically regulated by its promoter region where presence of multiple closely spaced DNA regulatory elements regulate iron-induced transcription [ 44 ].
The main function of the hydrogenosome, an organelle typical of trichomonads, and converting malate or pyruvate to H 2 , CO 2 , and acetate by a pathway associated with ATP synthesis. This pathway relies on activity of iron-sulphur proteins such as pyruvate: ferredoxin oxidoreductase PFOR , hydrogenase, and ferredoxin.
Studies have shown that like AP, PFO is localized to the parasite surface and participates in cytoadherence [ 46 ]. Thus, T. These adhesion proteins help parasite attachment and their role in pathogenesis has been confirmed by coculture experiments. It has been shown in these experiments that antibodies to adhesion proteins APs reduce the parasite adhesion and subsequent cytopathic effects CE on host cells.
During these processes, iron along with calcium and phosphatase is essentially required for differential gene expression which helps in survival, growth, and colonization of parasite in the vaginal hostile environment [ 42 , 47 ]. However, the mechanisms by which these enzymes are localized at the Trichomonas surface and the pathways in which they act are poorly understood. The responses of T. These parasites also exhibit generation times of approximately 10 hours, 2.
Iron is an essential element which has a significant effect on the virulence of T. Ryu et al. Iron also affects the level of adherence and the cytotoxicity of trichomonads to HeLa cells, which are significantly reduced when trophozoites were cultivated in iron-deficient media. It has been seen that T. However, parasites become resistant to complement when grown in iron-rich media. The resistance to complement has been shown to be dependent on iron concentration, and other divalent ions other than iron do not modulate the complement activity.
Lactoferrin is known to provide the iron source to the trophozoites and it also renders the low-iron parasites resistant to complement lysis. Pretreatment of high-iron, complement-resistant parasites with proteinase inhibitors prevented the degradation of C3 on the trichomonal surface and results in degradation of parasite by complement activity. Thus, proteinases are the enzymes which provide resistance to complement degradation when iron sources are available [ 51 ].
The vaginal micro-environment undergoes dramatic change during menstruation as it is flooded with serum proteins, erythrocytes, and other macromolecules. During this stage, T. Activation of alternative complement system does not require antibodies and it can be activated by magnesium ions, factors B and D, properdin, and C3 for activation.
It has been observed that menstrual blood complement is trichomonacidal, mediated by activation of alternative pathway. However, trichomonads are known to undergo adaptive changes in vivo , which enable the parasites to avoid lysis by complement as a survival strategy [ 51 ].
Most important being the iron which regulates the gene expression of surface immunogens and adhesions as described above. Even after menstruation, infection persists as some parasites evade the immune mechanism of alternative complement pathway by secreting various proteinases. These proteinases not only help the parasites acquire the nutrients through lysis of erythrocytes but also help in recognition and binding to host cells.
Thus, trichomonad proteinases have dual role in host pathology and parasite survival. P is an immunogenic protein which causes phenotypic variation of T.
Two types of isolates have been documented during infection with T. Type I isolates comprise homogeneous nonfluorescent negative phenotype trichomonads which synthesize and express P in the cytoplasm. In contrast, type II isolates comprise both fluorescent and nonfluorescent subpopulations positive and negative phenotypes. Growth of virus-positive organisms in high-iron medium induces expression of trichomonad adhesins but yields parasites without surface P P has been found to be highly phosphorylated in high-iron parasites and modulating the low surface expression of P Thus, iron plays a role in modulating surface localization of P in virus-harbouring parasites [ 54 ].
It has been seen that iron is essential for the virulence of the parasite and Trichomonas has evolved different strategies for acquiring iron.
Iron also up-regulates the cysteine proteinases CPs involved in complement resistance and several parasite functions as described above. A similar effect has also been observed with CP39, involved in cytotoxicity [ 58 ]. Similarly, iron also downregulates the other genes such as tvcp12 and flp-1,2 which encodes for papain-like CP and fibronectin-like proteins, respectively [ 59 , 60 ].
Thus, it is very surprising that similar iron concentrations exert opposite effects on expression of adhesions and some CPs. This irony has been explained by the fact that iron concentration fluctuates in the vagina during menstrual cycle. Lactoferrin concentration is also known to vary during the different phases of menstrual cycle; that is, it is present in highest concentration after the menstruation and decreases progressively during the cycle with minimum levels present immediately before menstruation.
Trichomonas has evolved the two different mechanisms to maintain its pathogenicity at different phases of menstrual cycle which helps in its survival. It has been postulated that just before the menstruation when iron concentration is lowest, T. Simultaneously, low iron levels may reduce the expression of adhesions leading to decreased level of cytoadherence, allowing the parasite to move around in search for new iron sources.
The opposite effect might be occurring during the highest level of iron concentrations during and after menstruation ; there occurs an up-regulation of adhesin expression, providing an opportunity for the parasites to adhere firmly to prevent the flushing by menstrual blood flow [ 57 ]. Drug resistance among the protozoa is increasing at an alarming rate, with relatively few options left for the treatment. In , resistance among T. The 5-nitroimidazole family of drugs metronidazole and tinidazole are the only class of drugs approved for the treatment of trichomoniasis [ 62 ] and P.
Upcroft and J. Resistant organisms are cosmopolitan in distribution and are of considerable concern as Trichomonas infections are linked to human immunodeficiency virus HIV transmission. Further scientific research is required to fill the gaps in knowledge about understanding the pathogenesis, so that newer drug targets can be evaluated in order to overcome the increasing burden of drug resistance. Lehker and Alderete [ 38 ] examined the sera of patients by immunoblotting to detect the proteins from parasites grown in low- and high-iron media, recognized by antibodies.
Twelve trichomonad immunogens from parasites grown in iron-rich medium and 7 from those grown in low-iron medium were found. Sera from patients with vaginitis recognized the purified Lf receptor protein. Lf may be used as a carrier for drug delivery as it specifically binds to receptor at the surface of Trichomonas. Moreover, it is concentrated at places where infection is present at the mucosal surface. Inhibition of Lf binding sites at Trichomonas surface may deprive the parasites from iron availability and can be used as an attractive therapeutic strategy.
Thus, search for newer drug targets and vaccine candidates in relation to lactoferrin, its receptors, and Trichomonas is required in coming years to win the fight against this parasite. Iron is an essential nutrient required by T. Trichomonas has evolved the receptor-mediated uptake of iron through holo-Lf and its concentration and affinity vary according to the availability of iron in the external environment. Usually, iron is known to upregulate various adhesins and other factors which increase which help in maintaining the virulence.
However, it has been seen that cystein proteinases CP65 and CP39 are downregulated when the external iron concentration is high. It is important for the survival of parasite as when abundant iron is available, that is, during menstrual flow, there is an increase in cytoadherence, preventing flushing of parasites during blood flow of menstruation.
On the other hand, just before menstruation, iron concentration is low; thus cytoadhesion is also decreased and CP65 and CP39 are activated which help moving the parasite in search of iron and maintain its virulence. Furthermore, drugs can be formulated which can target the holo-Lf receptor or various immunogens can be tested which can provide immunity or holo-Lf can be used a carrier for drug delivery.
However, studies are required in animal models to check the efficacy and adverse effects of new drugs, targeting Lf or its receptor. At present there is no drug available which targets the Lf or its receptor for the treatment of trichomoniasis. Finally to conclude apo-Lf is lethal to parasite, but when it acquires iron holo-Lf , it is used as a iron source by the parasite. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Academic Editor: Bryan Larsen. Received 22 Mar Revised 05 Jul Accepted 18 Aug Published 04 Sep Abstract Trichomonas vaginalis is a parasitic protozoan which infects the urogenital tract and requires iron as an essential nutrient. Introduction Trichomonas vaginalis is a flagellated, parasitic protozoan which causes trichomoniasis by infecting urogenital tract.
Brief Description of the Parasite T. Transmission and Clinical Features Trophozoites of Trichomonas are transmitted from person to person through sexual contact. Iron an Essential Nutrient Iron is an essential nutrient required for the survival of both humans and pathogenic protozoa. Lactoferrin Lf Lactoferrin Lf is a mammalian non-heme iron-binding glycoprotein which can bind two ferric ions with very high affinity even at an acidic pH of 2.
Functions of Lactoferrin Lf Lf is a multifunctional protein with a wide range of biological activities including regulation of iron absorption, immune response, antioxidant, anticarcinogenic, anti-inflammatory properties, and antimicrobial activity [ 12 , 19 — 21 ]. Microbiostatic and Microbicidal Effects Apo-Lf is secreted as microbicidal product by secondary granules of neutrophils. Lactoferrin Friend or Foe When apo-Lf acquires iron, it becomes saturated with iron and forms holo-Lf which is an important source of iron for microbes.
Mechanisms Adopted by Parasites to Acquire Iron from Holo-Lf Basically there are four different mechanisms by which parasites acquire iron as a source of nutrient from holo-Lf and these are as follows [ 33 ]. Role of Iron on Growth of T. Role of Iron in Cytoadherence Levels of cytoadherence to HeLa cells have been found to be modulated by different iron levels.
Effect of Iron on the Virulence of T. Irony about Iron Regulation of CP65 Cysteine Proteinase It has been seen that iron is essential for the virulence of the parasite and Trichomonas has evolved different strategies for acquiring iron. Future Prospects Drug resistance among the protozoa is increasing at an alarming rate, with relatively few options left for the treatment.
Drug Delivery Lf may be used as a carrier for drug delivery as it specifically binds to receptor at the surface of Trichomonas. Inhibition of Lf and Receptor Binding Inhibition of Lf binding sites at Trichomonas surface may deprive the parasites from iron availability and can be used as an attractive therapeutic strategy. Conclusion Iron is an essential nutrient required by T. References R. Petrin, K. PubMedCentral Google Scholar.
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Trichomonas vaginalis is typically a pear-shaped organism. When it sticks to the vaginal wall, the parasite flattens, looking almost squashed. That flattening dramatically increases its surface area. The scientists hypothesize that this trait brought the microbe a selective advantage during its evolution: A bug with a big surface area, enabled by a big genome, is better at colonizing the area it is infecting.
Trichomonas also shows predatory behavior. It phagocytoses, or eats up, good bacteria in the vagina. That makes the vagina more alkaline and more hospitable toward Trichomonas and other pathogens.
When infecting women, the pathogen latches onto vaginal tissue and forms tendrils that project into the vaginal tissue. The parasite also secretes a series of proteins, which destroy the vaginal epithelial cells, the cells that make up the vaginal tissue surface. For the first time, the genome project managed to identify these pathogenic virulence factors, called trichopores, she says.
Mariner elements are another novelty of the T. They are transposons or jumping genes, which previously had only been found in animals and plants but never in protists, which are the single-celled organisms that are not plants, animals or fungi.
The genomics headache The little bug served a sizable genomics challenge. The sequencing technology and the computer algorithms used to assemble and align sequenced gene fragments with computers are not available to deal with this parasite. The cause of the headache for researchers: the repeats in the genome. As Dr. Carlton explains, to sequence a genome, it is broken down into reads. These reads are snippets of DNA with units or bases.
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