Mycosis is an infectious disease of humans and animals caused by a pathogenic fungus. In 2010, fungal infections were in fourth place among the most common skin diseases. Mycoses affect not only the skin, mucous membranes, nails, and hair. Fungal infections can also affect the lungs and other internal organs, and even the brain.
The frequency of fungal infections is currently increasing. There are several reasons for this:
- Development of broad-spectrum antibacterial agents for treatment and prevention. These tools allow the fungi to compete better and fill the gaps.
- Increased use of internal metal and plastic prostheses – a favorable environment for fungi.
- Increased use of invasive procedures and monitoring that open the way for fungal infestation.
- Increased use of parenteral nutrition (via a vein), which provides nutrients and fungi.
- More aggressive immunosuppression in various diseases, including autoimmune and rheumatological diseases.
- More intensive cancer chemotherapy keeps people with weakened immune systems alive.
- Increased use of internal organ transplants.
- AIDS.
- Increased drug addiction.
- Increased survival of preterm infants and low-birth-weight infants in intensive care units.
- Growing tourism to countries with hot climates, where there are rapid population growth and endemic mycoses.
The mortality rate from severe fungal infections affecting the body’s organs and systems is 85-90%. Often, mycoses’ treatment is ineffective since there are no specific signs and symptoms of fungal infections, diagnostic tests are not reliable enough, and antifungal drugs are weak or have an insufficiently broad spectrum of action. Therefore, new methods are needed to treat fungal diseases.
Interferon-gamma for immunotherapy of fungal diseases
To enhance the effectiveness of the treatment of fungal diseases, you can use methods that activate the body’s immune system. One of these methods is cytokine signaling proteins, which increase immune cells’ antifungal activity.
Scientists at Stanford University have demonstrated the antifungal effect of the cytokine interferon-gamma (IFN-γ):
- In vitro, IFN-γ activated tissue macrophages that destroyed fungal pathogens such as Blastomyces dermatitis, Paracoccidioides brasiliensis, and Candida albicans, as well as lung macrophages that engulfed Blastomyces, Paracoccidioides, and Histoplasma.
- IFN-γ administration in vivo activates ex vivo destruction of Blastomyces and Paracoccidioides by pulmonary macrophages.
- IFN-γ activates neutrophils in vitro, with increased respiratory burst and destruction of Blastomyces and ex vivo after systemic administration to destroy Blastomyces. Respiratory explosion – the rapid release of reactive oxygen species during the digestion of solid particles by phagocytes.
- IFN-γ is effective against intracellular and extracellular fungi, against dimorphic fungi of endemic mycoses, and opportunistic fungal microorganisms. It enhances the antifungal activity of mouse and human immune effector cells, monocyte-macrophage line cells, and neutrophils, both in vitro, ex vivo, and in vivo.
IFN-γ is a broad-spectrum antifungal agent. The antifungal activity of only some effector cells is weak, and the use of only some drugs only temporarily delays and stops fungi’ growth, which can continue after the drug is discontinued. The combination of an effector cell and an antifungal agent gives a synergistic effect. The cytokine enhances the antifungal activity of effector cells. Combining an effector cell, an antifungal agent, and a cytokine provides a powerful synergistic effect.
The researchers investigated the immune response to an experimental Blastomyces infection in vivo. The scientists observed a rapid IFN-γ reaction initially, but IgE antibodies and IL-4 interleukin production increased as it progressed. It corresponded to the transition from the Th1 T helper response to the Th2 response in advanced disease, since Th1 secrete IFN-γ, and Th2 secrete IL-4 and activate B-lymphocytes, which produce antibodies.
Studies of the effect of IFN-γ on fungal infections have shown:
- In the non-progressive paracoccidioidomycosis model, scientists observed a double production of IFN-γ and IL-4 by antigen-stimulated lymph node cells. In the chronic form of the disease, the introduction of IFN-γ with antifungal therapy produced a synergistic effect.
- IFN-γ is an integral part of the local immune response in the brain in experimental cryptococcosis. Cryptococcosis was more severe in mice with IFN-γ knockout or in mice receiving IFN-γ antibodies. Increased antifungal chemotherapy with IFN-γ improved survival in cryptococcosis. The researchers showed a moderate effect of IFN-γ alone on reducing infection and a 40-fold improvement in mice when treated with IFN-γ combined with amphotericin B compared to amphotericin B alone. It was found that only IFN-γ has a more substantial therapeutic effect on immunodeficient mice and, in combination with amphotericin B, can lead to a cure of the central nervous system.
- In a pilot placebo-controlled trial of IFN-γ as an adjunct therapy to conventional chemotherapy for cryptococcosis in HIV-positive people, faster sterilization of the cerebrospinal fluid decreased the antigen titer in the cerebrospinal fluid, and a decrease in the clinical manifestations of mycosis was observed.
- IFN-γ reduces the risk of systemic candidiasis.
Young animals and humans are more susceptible to invasive mycoses. It happens due to the reduced activity of neutrophils-they are worse at destroying pathogens of fungal infections and the fact that the spleen cells of young animals produce fewer IFN-γ in response to non-specific stimuli. The effectiveness of neutrophils can be restored in vitro to adult levels by using IFN-γ. The introduction of IFN-γ in vivo increases young mice’s survival rate to the levels of resistance observed in mature animals.
In addition to injecting IFN-γ, the researchers investigated the possibility of vector delivery of IFN to the central nervous system to fight fungal meningitis, such as cryptococcosis. This method allows you to overcome the blood-brain barrier. Vector-a safe genetically modified virus that is used to deliver the necessary proteins to the body. Once delivered to the central nervous system, the vector can lead to prolonged production of IFN-γ by the body’s cells. Scientists have demonstrated this with adenovirus with the mouse IFN-γ gene: a dose of the virus can produce > 30,000 pg/ml of IFN-γ in the cerebrospinal fluid even 5 days after administration.
Interferon gamma’s antifungal defense partner
The introduction of interleukin IL-12 is another method of immunotherapy for fungal infections. IL-12 turns the T helper response to the Th1 pathway, enhancing the Th1 cells ‘ production of IFN-γ. IL-12 increases the activity of NK cells, which destroy infected cells in the body.
Studies of the effect of IL-12 on fungal infections have shown:
- Administration of IL-12 in vivo can significantly increase resistance to experimental cryptococcosis and, when administered together with fluconazole, can substantially enhance the effect of fluconazole.
- Anti-IL-12 treatment in mice accelerates histoplasmosis mortality. IL-12 administered to immunodeficient or immunocompetent mice was effective and stimulated the production of IFN-γ.
- Anti-IL-12 exacerbates the disease in resistant mice infected with Coccidioides, and IL-12, administered to sensitive mice, increases resistance and stimulates the production of IFN-γ.
- IL-12 production is reduced in response to Blastomyces infection in a susceptible mouse line. The introduction of IL-12 can provide disease resistance. However, optimizing the IL-12 regimen is critical since excessively high doses lead to resistance but are not tolerated.
Interferon-gamma for the prevention of fungal infections
Prophylactic IFN-γ is a proven way to reduce infections in patients with congenital neutrophil deficiency. Neutrophils are cells of the immune system that absorb bacteria, fungi, and dead cells. Randomized trials have shown a reduction in the number of fatal Aspergillus infections in patients with neutrophil deficiency.
Possible mechanisms of the antifungal effect of cytokines
There are several explanations for the antifungal effect of cytokines:
- Synergistic interactions between effector cell products and antifungal agents. Cytokine signaling proteins regulate the production of effector cells.
- Antifungal therapy reduces the infectious load and stimulates NK cells, T-helper type 1, and T-killer cells. These cells destroy cancer and infected cells in the body.
- Antifungal drugs activate effector cells that receive a cytokine signal. It increases the respiratory explosion, and effector cells better absorb fungi.
- Antifungal agents increase the production of pro-inflammatory cytokines and suppress the production of anti-inflammatory cytokines.
- Synergistic interaction between chitinase-a mammalian gene product-and antifungal agents.
- Stimulation of effector cells by cytokines, which increases the uptake of antimicrobial drugs by cells.
- Antifungal agents stimulate the production of cytokines, which restore the body’s defenses.
- Increased susceptibility of fungi whose membranes are modified by antifungal agents to the oxidative products of effector cells.
These mechanisms can work together.
Conclusions
In vitro data show that some recombinant cytokines activate the body’s defense against mycosis. Animal studies have shown a protective and therapeutic effect of cytokines against fungal infections. These experimental data serve as the basis for clinical studies of recombinant cytokines in preventing and treating mycosis in patients. Clinical trials are needed to determine the role of IFN-γ and other cytokines in treating fungal infections.
