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 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 affects ONLY ONE (This is referred to as 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.

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Team:Goettingen/project overview/therapeutics

From 2014.igem.org

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