The Fungus Among Us: Why the Treatment of Fungal Infections Is So Problematic

When we think of microbes that can make us sick, it is usually bacteria that cross our minds first. We tend to forget about another major microbial type that can also cause severe diseases: the fungi. Yeasts and molds make up the majority of microscopic fungi and both types can cause various infections in humans, from mild skin rashes to deadly blood infections. These fungi have found several ways to cause us harm, such as using the body’s nutrients, escaping the surveillance of the immune system, or hijacking and destroying our cells. On cellular level, we have a lot in common with fungi. These common features between human cells and fungal cells makes the development of antibiotics and vaccines to treat fungal infections very difficult. In this article, we will describe some fungal infections and explain current options for their treatment.


Figure Figure
Images of fungi that infect humans. (a) Microscopic image of Cryptococcus neoformans stained with ink. (b) Seen through a scanning electron microscope, Candida albicans starts to form mycelium. (c) Rhizopus species growing on cooked beetroot. The fur-like substance is the mycelium and the tiny black dots on top contain the spores. (d) Aspergillus fumigatus, isolated from soil, as seen with the naked eye as it grows in the lab.

FUNGI AMONG US: FRIENDS AND FOES
In the tree of life, fungi are classified in their own kingdom. They are di erent from bacteria, plants, or animals. "Fungus" in Latin means mushroom. That is why we tend to think only about mushrooms as the fungi among us. However, the fungal kingdom is very diverse and there are thousands of fungi that we find only when we dive into the microbial world, where organisms are so tiny that they can only be seen under a microscope. The microscopic fungi come in many di erent shapes and forms ( Figure ), and can be found everywhere in nature, like in the soil or attached to living creatures. They play many important roles in our lives, such as decomposing organic matter in the compost pile or bringing nutrients to plants. For thousands of years, we have been using fungi to produce foods and beverages like bread, cheese, soy sauce, and beer. Fungi are also used to make the antibiotic penicillin, which kills bacteria, and to produce citric acid, which is what gives juices and sodas a sour note.
Some fungi even live in our bodies. Together with more than , other microbial species found in our guts and on our skin, fungi make up our microbiota. The microbiota is composed of millions of MICROBIOTA All the millions of harmless microorganisms that inhabit the human body. harmless microorganisms that inhabit the human body. Usually we live happily together. We can come into contact with other fungi from the environment by breathing them in, for example. But we almost never notice them, as the mucus that covers our airways usually clears them out. However, sometimes this is not the case: both types of fungi-the ones living in harmony inside us and the kinds in the environment-can cause infections.
Interestingly, only a few hundred fungal species of the almost million that inhabit the Earth can cause infections in humans [ ]. In contrast, about , species of fungi infect insects. Why is the number for humans so low? First, the relatively high and always stable body temperature of ∼ • C keeps them away. Most of the fungi favor much lower temperatures [ ]. Next, most fungi are successfully fought o by the human immune system, which does a very good job of eliminating fungi when they infect healthy people.
Fungi can cause a range of infections in humans, from unnoticeable to deadly. We barely notice the fungus that can cause dandru , for example. This condition is annoying and embarrassing, but rarely causes us harm. Other fungi can cause life-threatening infections that shut down the entire body. Typically, people with disturbed or defective immune systems, such as patients being treated for cancer, organ transplant recipients, or the elderly, su er the most. Such infections are very di cult to treat.

WHICH FUNGI ARE THE MOST DANGEROUS AND HOW DO THEY MAKE US SICK?
Cryptococcus Cryptococcus species, and particularly Cryptococcus neoformans, are like kryptonite for humans. Normally, this fungus lives on plants or in animals worldwide. Pigeons, for example, have a lot of Cryptococcus neoformans in their droppings, and although this does not bother them, it can bother us. The dust from pigeon droppings is spread in the air that we breathe. In healthy people, if Cryptococcus enters the lungs it is defeated by the immune system, but in people with immune defects it can survive, grow, and reach other parts of the body, such as the brain. If left untreated, it can cause death [ ].

Candida
Candida species, particularly one called Candida albicans, are the most common fungi that cause diseases in humans. Candida albicans is normally part of our microbiota, but can, if given the chance, turn against us. C. albicans can cause infections of the skin or the mouth and can even enter the bloodstream and cause a life-threatening blood infection called sepsis. Candida cells can transform from a SEPSIS The most severe form of an infection, which can lead to organ failure and often death. rounded shape into a long filament called a mycelium. The mycelium

Molds
Molds usually live in soil and on dead, decaying matter. They produce mycelium with thousands of tiny spores on top. These spores function SPORES Round-shaped reproduction units of a fungus, similar to seeds, which can grow into a mature mycelium.
as seeds as they can be used for reproduction or to withstand harsh conditions. The spores are easily spread by air and enter our lung when we breathe. As mentioned above, this is typically problematic only for people with weak immune systems.

HOW DO ANTIFUNGAL DRUGS FIGHT THE FUNGI?
On the cellular level, we have much in common with fungi. So, it is likely that a substance directed against fungi could also harm us. Therefore, it is quite di cult to design drugs that kill only the fungi. Any potential antifungal drugs have to pass toxicity tests on human cells and other rigorous tests to make sure they are safe for human use.
So far, only three fungus-specific vulnerable spots are targeted by drugs (Figure ). First is the cell membrane. The cell membrane of fungal cells has a certain type fat called ergosterol, which Another way to eradicate fungi is with a substance called flucytosine, which targets essential for fungal survival processes, such as production of DNA and building of proteins. But this medicine also leaks into human cells and has many severe side e ects. So, this drug is used mainly in combination with Amphotericin B and only for very serious cases.
The third drug target is the fungal cell wall. In contrast to human cells, fungal cells are surrounded by a thick wall made from a substance called chitin, as well as sugars and proteins. A class of drugs called CHITIN A sugar that is the major part of the fungal cell wall. Chitin also forms the exoskeleton of insects and other arthropods.
echinocandins interferes with the building of a sugar molecule called glucan, an essential brick of the cell wall. Echinocandins are very safe GLUCAN A complex sugar molecule that composes the fungal cell wall, a structural layer that surrounds the cell and provides support and protection.
for humans, but they work only when injected into the bloodstream, which is not very practical.
So, with only three types of drugs, each with some disadvantages, doctors are facing a problem choosing the most e ective and safe treatment for fungal infections. Therefore, there is an urgent need to find new targets and treatment strategies for these infections [ ].

CONCLUSION
Even though our body temperature and powerful immune system keep infections away, fungi can still cause us harm (Figure ). Patients with weak immune systems are particularly prone to invasive fungal infections. The number of patients at risk is continuously increasing. At the same time, treatment of these infections is complicated because of the limited number of drugs and the increase in drug-resistant fungal species. Doctors urgently need more safe and e ective medicines against fungal infections. Fungi are not only dangerous for humans: plants, insects, and cold-blooded animals like fish and amphibians get infected too. For example, the fungus Batrachochytrium dendrobatidis has already caused the extinction of over frog species worldwide [ ]. Therefore, researchers must keep working to find out more about how fungi cause infections and how to fight these potentially dangerous organisms.  . doi: . /frym. .

CONFLICT OF INTEREST:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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CHINMAYA, AGE:
My name is Chinmaya. I am in ninth grade. I love Mathematics. I am extremely interested in Science and Sanskrit language as well. I am a voracious reader. My hobbies are playing flute and writing poems.

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KATRIN HAUPT
Katrin holds a Ph.D. degree in Biology. She is a scientific coordinator at ZIK Septomics-a research institute of the Friedrich Schiller University in Jena, Germany. Her task is to support scientists in administrative matters of their research projects. She is fascinated by infection biology and the interaction between pathogens and kids.frontiersin.org November | Volume | Article | humans. In her spare time, she likes watching movies, riding her bike, and being outdoors in nature.

LYSETT WAGNER
Lysett is a microbiologist who loves fungi and likes to put things in the right order. That is why she classifies microorganisms in a scientific way. In addition, she is very curious about microbes that cause infections. Currently, she studies biofilms built by fungi and bacteria that can cause sepsis in patients. Even in her spare time, while cooking or gardening, she thinks a lot about microorganisms and how they are doing, for example the yeast in dough or the organisms growing on the roots of her pampered tomato plants.

ANTJE HÄDER
Antje is a Ph.D. student in the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute in Jena, Germany. She investigates how small di erences in the DNA sequences between individuals influence the immune response toward fungal and bacterial infections. The analysis of variability in human DNA is an interesting topic, because it helps scientists to understand why the susceptibility to certain diseases di ers between individuals.

SLAVENA VYLKOVA
Slavena is a leader of a young team of microbiologist at ZIK Septomics. She and her group study the interactions between infectious fungi and humans, with respect to factors that allow fungi to survive in the body and cause harm. Slavena's favorite subject at school was biology, an interest that turned into her hobby and career. She is an energetic and creative person who likes to "infect" young minds with her science enthusiasm. *slavena.vylkova@leibniz-hki.de