Team:Goettingen/project overview/therapeutics

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        <h3>Project</h3>
 
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        <ul>
 
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        <li><a href="project_overview">Background</a></li>
 
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<ul>
 
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<li><a href="https://2014.igem.org/Team:Goettingen/project_overview">The global burden of fungal infections</a></li>
 
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<li><a href="https://2014.igem.org/Team:Goettingen/project_overview/fungal_infections">Fungal infections</a></li>
 
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<li><a href="https://2014.igem.org/Team:Goettingen/project_overview/current_tools">Current diagnostic tools</a></li></ul>
 
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<li><a href="https://2014.igem.org/Team:Goettingen/project_overview/project">Our project!</a></li>
 
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<li><a href="https://2014.igem.org/Team:Goettingen/project_overview/perspectives">Further perspectives</a></li>
 
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<ul>
 
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<li><a href="https://2014.igem.org/Team:Goettingen/project_overview/diganosis">Diagnosis</a></li>
 
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<li><a href="https://2014.igem.org/Team:Goettingen/project_overview/therapeutics">Therapeutics</a></li></ul>
 
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        <li><a href="https://2014.igem.org/Team:Goettingen/project_overview/project_gallery">Gallery</a></li>
 
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<li><a href="https://2014.igem.org/Team:Goettingen/project_overview/project_drylab">Dry lab</a></li>
 
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<li><a href="https://2014.igem.org/Team:Goettingen/project_overview/project_wetlab">Wet lab</a></li>
 
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      <h1 >Background</h1>
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      <h2 id="global_burden">The global burden of fungal infections</h2>       <br />
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<div id="goenext"><a id="prev"><img id="pButton"></a> 14/15 <a id="next"><img id="nButton"></a></div>
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    <p>Fungal pathogens are a major public health threat with significant global effects which, surprisingly, is not being addressed as it should. Globally, around 1.5 million people die each year of invasive fungal infections and the number of people who die each year from the top 10 invasive fungal diseases is at least equal to those dying from tuberculosis or malaria. Moreover, the mortality rate of invasive fungal infections is usually greater than 50%.</p><br><p>In contrast, funding for medical mycology is highly underrepresented, accounting for 1.4-2.5% of the total of what the Wellcome Trust, the U.K. Medical Research Council and the U.S. National Institutes of Health spent in 5 years during the late 2010s. This underrepresentation could be just an effect of the number of applications for funding in the area, but even so, the need for an increased awareness and engagement by funding institutions and researchers is no less urgent: the development of new diagnostic and therapeutic tools is critical to improve the situation of high-risk patients.</p>
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<br />
<br />
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<h2 id="fungal_inf">Fungal infections and current diagnostic tools</h2>
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          <br /><br />
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      <h1>Therapeutic Applications</h1><br />  
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<p>The most common fungal infections are superficial skin, nails and mucosal infections, which are caused in most cases by fungi of the genus <i>Candida</i>. These infections are usually not life threatening and have such common manifestations as athlete's foot and vulvovaginal candidiasis.</p>
+
<h2>Fungal Infections and the branches of the immune system that deal with them</h2><br />
-
<br /><p>Invasive fungal infections, on the other hand, have unacceptably high mortality rates. Patients with a compromised immune system -such as AIDS patients and post-transplantation patients taking immunosupresants- are at special risk as they don't have the usual barriers that prevent invasive infections in healthy individuals.</p><br />
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<p>
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<p>According to Brown, <i>et al</i>., (2012), more than 90% of the reported deaths caused by fungi are associated with species from four genera: <i>Cryptococcus</i>, <i>Candida</i>, <i>Aspergillus</i> and <i>Pneumocystis</i>, but epidemiological data for fungal infections is poor, as these infections are often misdiagnosed and there is a lack of accurate data from the developing world.</p><br />
+
The peptides we developed have significant applications from a clinical standpoint. It has been observed in that individuals suffering from deficiencies in antibody and complement mediated cytotoxicity are less vulnerable to fungal infections than the ones suffering from phagocytic defects. Moreover studies have shown that neutrophils are pivotal in fending off fungal infections.  This is further supported by the fact that many cases of fungal infections were following a period of neutropenia (low neutrophil count in blood).</p> <br />
 +
<p>Two vital principles can be gathered from the aforementioned information:</p> <br />  
 +
<ul>
 +
<li>- Phagocytes (especially neutrophils) play a very important role in the resolution (clearance) of the fungal infection.</li> <br />
 +
<li>- Antibodies and the complement system are not that effective against fungal pathogens due to the surface of these pathogens being unfriendly to binding.</li><br />
-
<h3>Endemic dimorphic fungosis</h3><br />
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<p>As such, the modulation of these branches of the immune system should aid in the resolution of the disease.  It's important to mention that since most patients suffering from invasive mycoses are immuno-compromised and that there are different types of immunodeficiencies. Depending upon which branch is dysfunctional, an appropriate strategy of immunomodulation can be adopted.</p> <br />
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<p> The following map is an adaptiation of the information presented in Brown, <i>et al</i>., (2012), where the authors make some comments regarding the quality of that information: 1) the data is extrapolated from a few and geographically localized studies and 2) accurate data is lacking from the developing world and the calculations may underestimate the true values of the presented statistics.</p><br />
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<h2>Modifications to the peptide so that it  can emulate an antibody's stimulatory function</h2><br />
 +
<p>
 +
The novelty in our peptides is that it CAN bind to the fungal surface and it can be further modified using the Fc(constant) region of the IgG1 or IgG3 antibody subtype (IgG2a in mice). This region is important as it is recognized by the effector cells (neutrophils and macrophages) of the immune system and thereafter, leads to the death of the target cell. This way, not only can it bind to fungal pathogens but can also “draw attention” towards itself from the immune system. In addition to this, the constant region can also activate the compliment cascade via the "classical" pathway. Essentially, this set-up functions as a modified antibody with an added bonus of greater affinity. </p> <br />
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      {name: '<b>Disease:</b> Penicilliosis<br><b>Pathogen:</b><i> Penicillium marneffei</i><br><b>Region:</b> Southeast Asia<br><b>Est. life-threatening infections per year</b>: >8,000', latitude: 10.1333, longitude: 102.7000, radius: 8, fillKey: 'gt50'},
 
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      {name: '<b>Disease: </b>Histoplasmosis<br><b>Pathogen:</b><i> Histoplasma capsulatum</i><br><b>Region:</b> Midwestern United States<br><b>Est. life-threatening infections per year</b>: ~25,000', latitude: 40.5, longitude: -85, radius: 25, fillKey: 'gt50'},
 
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      {name: '<b>Disease:</b> Coccidioidomycosis<br><b>Pathogen:</b><i> Coccidioides immitis</i><br><b>Region:</b> Southwestern United States<br><b>Est. life-threatening infections per year</b>: ~25,000', latitude: 39, longitude: -115.5, radius: 25, fillKey: 'gt50'},
 
-
{name: '<b>Disease:</b> Blastomycosis<br><b>Pathogen:</b><i> Blastomyces dermatitidis</i><br><b>Region:</b> Midwestern and Atlantic United States<br><b>Est. life-threatening infections per year</b>3: ~3,000', latitude: 37, longitude: -80, radius: 3, fillKey: 'gt51'},
 
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{name: '<b>Disease:</b> Paracoccidioidomycosis<br><b>Pathogen:</b><i> Paracoccidioides brasiliensis</i><br><b>Region:</b> Brazil<br><b>Est. life-threatening infections per year</b>: ~4,000', latitude: -15.7833, longitude: -47.8667, radius: 4, fillKey: 'gt50'},
 
 +
<h2>Enhancement of immune response in immunodeficient individuals</h2><br />
 +
<p>
 +
As for the stimulation of the immune system in case of individuals with immunodeficiencies, the use of adjuvants (immune response enhancers) to augment the response is one strategy. In addition to this, natural immuno-modulatory molecules called cytokines (such as Interleukin-1 and Interferon-gamma) to stimulate the appropriate branches of the immune system can be employed as well. </p>
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<h2>Homing the anti-fungal drug to the site of infection</h2><br />
 +
<p>Anti-mycotics have such as Amphotericin B are fluconazole have been used extensively to treat fungal infections. While they’ve been effective, they are more toxic to the human body than antibiotics that kill bacteria. This is due to the fact that bacteria are more dissimilar to humans than fungi are. As a result, it’s relatively simpler to find targets for antibiotics than anti-mycotics. Simply put, the more we humans have in common with a pathogen, the greater is the difficulty in coming up with a drug that harms only one (in other words, there is a need for selective toxicity).</p>
 +
<br />
 +
<p>Thus, yet another potential application of the novel peptides we developed is that they can act as “guides” to these molecules thereby reducing side-effects due to the drug in question.</p>
 +
<br />
 +
<hr>
 +
<h2>References</h2>
 +
<br /><br />
 +
<ul>
 +
<li>
 +
1. Raghavan M, Bjorkman P (1996). "Fc receptors and their interactions with immunoglobulins". Annu Rev Cell Dev Biol 12: 181–220.
 +
<br /><br /></li>
 +
<li>
 +
2. Swanson J, Hoppe A (2004). "The coordination of signaling during Fc receptor-mediated phagocytosis", J Leukoc Biol 76 (6): 1093–103. doi:10.1189/jlb.0804439
 +
<br /><br /></li>
 +
<li>
 +
3. Pan L, Pei P (2003). "Signaling transduction by IgG receptors". Chin Med J (Engl) 116 (4): 487–94.
 +
<br /><br /></li>
 +
<li>
 +
4.  Mueller-Loebnitz C, Ostermann H, Franzke A,Loeffler J, Uharek L, Topp M, and  Einsel H: Immunological Aspects of Candida and Aspergillus Systemic Fungal Infections: Interdisciplinary Perspectives on Infectious Diseases, Volume 2013 (2013), Article ID 102934
 +
<br /><br /></li>
 +
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<h2>Our project: paving the way for new diagnostic and therapeutic tools</h2>
 
-
    <p>
 
-
  Our aim is to develop a diagnostic technique capable of detecting the presence of fungal pathogens in  a sample collected from a patient. Briefly, our approach is as follows. Through a yeast two-hybrid assay we will select a set of peptides that show affinity towards surface proteins from different fungi (<i>Aspergillus nidulans</i>, <i>A. fumigatus</i>, <i>Candida albicans</i> and <i>C. glabrata</i>). After confirming the interaction between the surface proteins and a given peptide, we intend to attach a molecule to the peptide marker. In our project, this molecule will be a fluorescent protein, but in principle can also be an immune system activator which is then recognized by the immune cells or other chemical moiety that adds novel functionalities or increases the peptide stability. In comparison to antibodies or antibody fragments, peptides are small, easily synthesized, modified less expensively and show higher diffusion rates in tissues. We expect our method to be faster, more accurate and cheaper than other existing methods. Other laboratories may follow our approach to generate and refine their own peptides with specificity towards their proteins of interest.
 
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Latest revision as of 11:42, 2 October 2014

Project

14/15



Therapeutic Applications


Fungal Infections and the branches of the immune system that deal with them


The peptides we developed have significant applications from a clinical standpoint. It has been observed in that individuals suffering from deficiencies in antibody and complement mediated cytotoxicity are less vulnerable to fungal infections than the ones suffering from phagocytic defects. Moreover studies have shown that neutrophils are pivotal in fending off fungal infections. This is further supported by the fact that many cases of fungal infections were following a period of neutropenia (low neutrophil count in blood).


Two vital principles can be gathered from the aforementioned information:


  • - Phagocytes (especially neutrophils) play a very important role in the resolution (clearance) of the fungal infection.

  • - Antibodies and the complement system are not that effective against fungal pathogens due to the surface of these pathogens being unfriendly to binding.

    • As such, the modulation of these branches of the immune system should aid in the resolution of the disease. It's important to mention that since most patients suffering from invasive mycoses are immuno-compromised and that there are different types of immunodeficiencies. Depending upon which branch is dysfunctional, an appropriate strategy of immunomodulation can be adopted.


    Modifications to the peptide so that it can emulate an antibody's stimulatory function


    The novelty in our peptides is that it CAN bind to the fungal surface and it can be further modified using the Fc(constant) region of the IgG1 or IgG3 antibody subtype (IgG2a in mice). This region is important as it is recognized by the effector cells (neutrophils and macrophages) of the immune system and thereafter, leads to the death of the target cell. This way, not only can it bind to fungal pathogens but can also “draw attention” towards itself from the immune system. In addition to this, the constant region can also activate the compliment cascade via the "classical" pathway. Essentially, this set-up functions as a modified antibody with an added bonus of greater affinity.


    Enhancement of immune response in immunodeficient individuals


    As for the stimulation of the immune system in case of individuals with immunodeficiencies, the use of adjuvants (immune response enhancers) to augment the response is one strategy. In addition to this, natural immuno-modulatory molecules called cytokines (such as Interleukin-1 and Interferon-gamma) to stimulate the appropriate branches of the immune system can be employed as well.


    Homing the anti-fungal drug to the site of infection


    Anti-mycotics have such as Amphotericin B are fluconazole have been used extensively to treat fungal infections. While they’ve been effective, they are more toxic to the human body than antibiotics that kill bacteria. This is due to the fact that bacteria are more dissimilar to humans than fungi are. As a result, it’s relatively simpler to find targets for antibiotics than anti-mycotics. Simply put, the more we humans have in common with a pathogen, the greater is the difficulty in coming up with a drug that harms only one (in other words, there is a need for selective toxicity).


    Thus, yet another potential application of the novel peptides we developed is that they can act as “guides” to these molecules thereby reducing side-effects due to the drug in question.


    References



    • 1. Raghavan M, Bjorkman P (1996). "Fc receptors and their interactions with immunoglobulins". Annu Rev Cell Dev Biol 12: 181–220.

    • 2. Swanson J, Hoppe A (2004). "The coordination of signaling during Fc receptor-mediated phagocytosis", J Leukoc Biol 76 (6): 1093–103. doi:10.1189/jlb.0804439

    • 3. Pan L, Pei P (2003). "Signaling transduction by IgG receptors". Chin Med J (Engl) 116 (4): 487–94.

    • 4. Mueller-Loebnitz C, Ostermann H, Franzke A,Loeffler J, Uharek L, Topp M, and Einsel H: Immunological Aspects of Candida and Aspergillus Systemic Fungal Infections: Interdisciplinary Perspectives on Infectious Diseases, Volume 2013 (2013), Article ID 102934



      • 14/15

Retrieved from "http://2014.igem.org/Team:Goettingen/project_overview/therapeutics"