Tuesday, February 9, 2016

Overly Attached Parasite

by KP

Trichomonas vaginalis is an extremely common human parasite that primarily infects vaginal cells as well as other cells of the urinary tract and the cervix, particularly in older women. It is estimated that T. vaginalis infects between 5 and 8 million in the United States and over 100 million worldwide each year. This makes trichomoniasis the most transmitted non-viral STD in the world. These staggering numbers are likely because T. vaginalis is easily transmitted and can be transmitted through non-penetrative sex and the sharing of clothing. Trichomoniasis is very treatable, with the normal treatment being a single dose of antiprotozoan drugs (1). Despite the fact that T. vaginalis often is present without symptoms, it is still a very important human pathogen because it has been shown to increase the risk of HIV infection, cervical cancer, and preterm delivery in pregnancy (2).
As a parasite that grows on the outside of host cells, the adhesion of T. vaginalis to host cells is key for it to cause symptoms and increase risk (3). The pathogen primarily causes damage to cells of the epithelium, the cells that line the outside of hollow structures and glands in the body. This adhesion to host cells is hugely important to T. vaginalis infection as it is actually unable to kill or damage host cells without adhering to them.
Transmission of trichomoniasis only occurs when it’s in trophozoite form. The trophozoite form is how the parasite lives for most of its life cycle. When it adheres to vaginal cells, the structure of the parasite changes from its trophozoite form to its flatter amoeboid form and has more contact area with host cells (Figure 1). The amoeboid form has increased adhesion between the parasite and host cells because of the increased area over which the parasite and host cell interact. After adhesion, T. vaginalis lyses, or in other words kills, infected cells. The parasite is then able to migrate across the epithelium causing the characteristic inflammation associated with trichomoniasis (5). People will experience inflammation of the vagina and the urethra.
Figure 1: Scanning electron microscopic images of T. vaginalis. A is the trophozoite form in a broth culture. B is the trophozoite form adhering to a vaginal epithelial cell before transformation to its amoeboid form. C is the amoeboid form adhering to a vaginal epithelial cell. (4)    
This essential cell to cell attachment can be mediated by many different types of proteins, lipids, or sugars. The adhesion molecules are a part of a broader category of molecules called virulence factors. These are important to understanding T. vaginalis infection because they are responsible for the parasite’s ability to infect and cause symptoms. Host cells also have surface molecules, which are referred to as receptors, and will attach to molecules on the surface of parasites. These molecules do not intentionally allow attachment by T. vaginalis and other parasites. Generally the host cell surface molecules play important roles in the healthy lifecycle of the cell. Parasites like T. vaginalis have evolved to exploit the fact that the molecules are necessary.
There are also many environmental conditions on which successful infection of vaginal epithelial cells by T. vaginalis depends. Temperature, pH, zinc levels, iron levels, and host immune response are all environmental factors to which make T. vaginalis infection more or less likely (6). These environmental factors can also make symptoms more severe. The adhesion step alone is impacted by several of these environmental characteristics such as iron levels and host immune response.
Lipophosphoglycan (LPG) is one adhesion molecule that regulates the surrounding environment to make infection worse. It has been shown that when LPG contacts host cell this causes the host cell to produce more signals that recruit immune cells to the site of infection. While immune cells are important for protecting our bodies from infection, the immune cells themselves can cause inflammation and damage to tissues in an effort to get rid of infections by any means necessary. The immune signals also exacerbate the infection by recruiting additional T. vaginalis cells to the site of infection (7).
LPG is a molecule made up of a lipid part and a sugar part found on the surface of T. vaginalis cells. As stated earlier, LPG is important to the adhesion of parasites to host cells. LPG in T. vaginalis has parts made of a type of sugar called galactose that are bound by the host cell surface protein Galectin-1. This host cell receptor not only plays a significant role in vaginal infections, as it can be found on just about any type of cell (8). This is one of the main reasons trichomoniasis can occur in the urethra in addition to the vagina.
Like LPG, proteins called cysteine proteases help to mediate adhesion of the parasite to host cells while causing damage to infected cells (9). Unlike LPG, cysteine proteases on the parasites do not manipulate the host immune system to cause inflammation. Cysteine proteases on the surface of T. vaginalis cells were found to damage anti-microbial and anti-inflammatory proteins found on the surface of vaginal epithelial cells (10). The cleavage of the anti-microbial and anti-inflammatory proteins by cysteine proteases is thought to be the main cause of the increased risk of developing HIV in individuals infected with trichomoniasis. Secretory leukocyte protease inhibitors (SLPI), which are specifically targeted by cysteine proteases, were shown to inhibit HIV infection of mucous membranes.
Cleaving proteins like SLPI is not the only strategy cysteine proteases use to cause symptoms. The cysteine protease CP30 was also shown to turn on a pathway that leads to apoptosis, or programmed cell death, in host cells (11). The process of CP30 causing apoptosis appeared to be somewhat dependent on the amount of available iron during infection. In high iron environments, CP30 activity was lower overall and in lower iron environments, CP30 levels were increased (12). This finding and the existence of other virulence factors regulated by iron implicates the menstrual cycle as some sort of factor that allows trichomoniasis to persist if untreated (13, 14). It should be stated that an exact relationship between menstruation and the persistence of untreated Trichomonas infection is not currently known.
                  Without adhesion, T. vaginalis would not be able to parasitize other cells or cause any of the characteristic symptoms of trichomoniasis. Attachment is not only important to the health of host cells, it also causes important changes in the structure of the parasite. LPG on the parasite attaches to Galectin-1 on host cell. This causes the host cell to release immune signals. These immune signals worsen the infection by recruiting immune cells and additional parasitic cells to the site of infection. T. vaginalis also causes inflammation using the protein CP30, which destroys anti-microbial and anti-inflammatory proteins found on the surface of host cells. Iron levels regulate CP30 levels, which suggests a possible relationship between trichomoniasis and the menstrual cycle. The ways that T. vaginalis adheres is also a big part of the reason why trichomoniasis increases the risk of HIV and cervical cancer and why this organism can impact human health so greatly despite being a relatively minor illness.

References
1)     Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. Morbidity and Mortality Report. 64(3), 72 – 75 (2015).
2)     Schwebke JR, Burgess D. Trichomoniasis. Clinical Microbiology Reviews. 17(4), 794 – 803 (2004).
3)     Alderete JF, Lehker MW, Arroyo R. The mechanisms and molecules involved in cytoadherence and pathogenesis of Trichomonas vaginalis. Parisitology Today. 11(2), 70 – 74 (1995).
4)     Arroyo R, Gonzalez-Robles A, Martinez-Palomo A, Alderete JF. Signalling of Trichomonas vaginalis for amoeboid transformation and adhesion synthesis follows cytoadherence. Molecular Microbiology. 7, 299 – 309 (1993).
5)     De Miguel N, Riestra A, Johnson PJ. Reversible association of tetraspanin with Trichomonas vaginalis flagella upon adherence to host cells. Cellular Microbiology. 14(12), 1797 – 1807 (2012).
6)     Figueroa-Angulo EE, Rendon-Gandarilla FJ, Puente-Rivera J, Calla-Choque JS, Cardenas-Guerra RE, Ortega-Lopez J, Quintas-Granados LI, Alvarez-Sanchez ME, Arroyo R. The effects of environmental factors on the virulence of Trichomonas vaginalis. Microbes and Infection. 14, 1411 – 1427 (2012).
7)     Fichorova RN, Trifonova RT, Gilbert RO, Costello CE, Hayes GR, Lucas JJ, Singh BN. Trichomonas vaginalis lipophosphoglycan triggers a selective upregulation of cytokines by human female reproductive tract epithelial cells. Infection and Immunity. 74(10), 5773 – 5779 (2006).
8)     Okumura CYM, Baum LG, Johnson PJ. Galectin-1 on cervical epithelial cells is a receptor for the sexually transmitted human parasite Trichomonas vaginalis. Cellular Microbiology. 10(10), 2078 – 2090 (2008).
9)     Arroyo R, Alderete JF. Trichomonas vaginalis surface proteinase activity is necessary for parasite adherence to epithelial. Infection and Immunity. 57(10), 2991 – 2997 (1989).
10)  Draper D, Donohoe W, Mortimer L, Heine RP. Cysteine proteases of Trichomonas vaginalis degrade secretory leukocyte protease inhibitor. Journal of Infectious Disease. 178(3), 815 – 819 (1998).
11)  Sommer U, Costello CE, Hayes GR, Beach DH, Gilbert RO, Lucas JJ, Singh BN. Identification of Trichomonas vaginalis cysteine proteases that induce apoptosis in human vaginal epithelial cells. Journal of Biological Chemistry. 280(25), 23853 – 23860 (2005).
12)  Kummer S, Hayes GR, Gilbert RO, Beach DH, Lucas JJ, Singh BN. Induction of human host cell apoptosis by Trichomonas vaginalis cysteine proteases is modulated by parasite exposure to iron. Microbial Pathogenesis. 44, 197 – 203 (2008).
13)  Garcia AF, Chang TH, Benchimol M, Klumpp DJ, Lehker MW, Alderete JF. Iron and contact with host cells induce expression of adhesins on surface of Trichomonas vaginalis. Molecular Microbiology. 47(5), 1207 – 1224 (2003).
14)  Hsu HM, Lee Y, Hsu PH, Liu HW, Chu CH, Chou YW, Chen YR, Chen SH, Tai JH. Signal transduction triggered by iron to induce the nuclear importation of a Myb3 transcription factor in the parasitic protozoan Trichomonas vaginalis. Journal of Biological Chemistry. 289(42), 29334 – 29349 (2014).

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