When most people think about infections, bacteria and viruses come to mind. But fungi are a major and growing global health challenge. Each year, fungal infections are responsible for over 1.5 million deaths worldwide. Despite this, they remain one of the most neglected areas of medicine and research.
Of the estimated 5 million fungal species on Earth, only a few hundred can infect humans. To do so, fungi must meet strict criteria: they must tolerate body temperature (around 37°C), penetrate tissue barriers, digest and absorb host tissues, and withstand or evade the immune system. This makes invasive fungal infections relatively rare in healthy individuals but devastatingly common in people with weakened immunity. (Check out this article!)
Pathogenic fungi can be divided into two groups based on their hosts’ health condition: primary and opportunistic pathogens. Primary pathogens have the ability to infect healthy individuals whereas opportunistic pathogens only target individuals with compromised immune systems. Both groups employ different strategies to fulfill the criteria needed to infect humans.
Primary pathogens evolved traits such as thermal dimorphism and immune evasion mechanisms that allow them to colonize and invade even intact immune systems. Thermal dimorphism refers to their ability to switch between two different forms depending on the temperature of the host. In a cool environment (colder than 25°C), they grow as molds, which form branching hyphae that can spread widely through soil or decaying organic matter. They also produce lightweight spores that can be easily dispersed and can survive dessication, UV light, and nutrient scarcity. These strategies serve to maximize their survival.
Once inhaled into a human host around 37 °C, the fungus shifts into yeast form. Yeast cells are small, round, and more compact, which makes them harder for immune cells to detect and easier to spread through tissues and the bloodstream. Unlike branching hyphae, yeast can survive and even replicate inside macrophages (white blood cells that kill foreign organisms). Their cell walls often change in this phase, masking immune-stimulating molecules like β-glucans, so they evade recognition.
Some species like Cryptococcus neoformans and Cryptococcus gattii use a powerful two-part defense strategy built on a capsule and melanin. The thick polysaccharide capsule is like a cloak; it prevents immune cells from engulfing the fungus and even dampening the host’s inflammatory signals. Melanin, meanwhile, protects the fungus from the toxic chemicals our immune system uses to kill invaders. Together, these adaptations let the fungus reach deep into the lungs and brain, and cause life-threatening meningitis.
Unlike primary pathogens, opportunistic fungi depend on defensive strategies. They don’t usually break through a strong immune system, but they exploit the weak spots. One key strategy they employ is biofilm formation, especially by Candida species. Biofilm formation is when fungi build a protective community on a surface. Instead of living as single, free-floating cells, they stick together and release a sticky matrix made of sugars, proteins, and DNA that acts like glue. This thick, sticky layer hinders the penetration of antifungal drugs. Inside the biofilm, fungi can communicate, share nutrients, and even swap resistance traits, which makes the whole community stronger than individual cells. (You can check out this article for an overview of all the various strategies that pathogenic fungi use)
Antifungal therapy:
One pressing problem associated with antifungal compounds is fungi’s adaptive nature. They can adjust their strategies to remain impervious to drugs. Overuse of antifungal agents in agriculture has fueled resistance, particularly in Aspergillus fumigatus. Meanwhile, Candida auris has emerged globally as a multidrug-resistant yeast. Climate change may also be expanding the range of fungi that can tolerate human body temperatures, escalating the global fungal infection problem to the next level.
Paradoxically, modern medicine itself has created new vulnerabilities. Advances like chemotherapy, organ transplantation, and immune-modulating drugs save lives, but they also suppress immune defenses and leave more patients susceptible to fungal infections.
Another challenge in antifungal therapy is that fungi are genetically closer to humans than bacteria are. This means developing drugs that kill fungi without collateral damage to human cells is really hard. The need to address this problem prompted a study focusing on one of the deadliest fungi: Cryptococcus neoformans. Scientists from Stowers Institute and University of Georgia have mapped over 1,400 genes essential to this fungus’s survival, including more than 300 that are completely unique to fungi and don’t exist in humans. Targeting these unique genes can overcome current challenges in antifungal therapy by enabling scientists to develop drugs with far fewer risks of harming human tissues. Even better, the team identified 30 genes shared across many dangerous fungi, meaning one treatment could fight multiple threats.
Fungal infections are frightening but new research offers hope that we might one day eliminate this threat for good!
fungitopia.org 