By Feng Lifi, Reporter of the China Science Daily; Su Fuyi, Intern
"Let me give you a Plan B, otherwise you won't be able to graduate!""I don't want a Plan B, I only want to do Plan A, even if it means delaying my graduation."Recalling the situation when they started researching fungal meningitis in 2016, Wang Linqi, a researcher at the Institute of Microbiology, Chinese Academy of Sciences (CAS), still vividly remembers the conversation she had with her student, Chen Lei.Because the research topic was difficult, Wang Linqi, as a supervisor, wanted to "think for the student" and suggested that Chen Lei pursue a simpler topic in order to graduate. However, adhering to the team's principle of "pursuing great failures rather than cheap successes," Chen Lei insisted on tackling the challenging problem. As a result, it took him an extra two years to obtain his PhD degree because of this research.Fortunately, after more than 7 years of perseverance, they finally saw the light at the end of the tunnel. They discovered the drug resistance mechanism of fungal meningitis and identified potential targeted treatment strategies. On January 16th, the research findings were published in "Nature Microbiology"."This research greatly advances the field. Based on these important findings, it will be possible to conduct translational and clinical research," said one of the reviewers of the journal.Diagram illustrating the "tug of war" between cryptococcal cells and fungal membranes during cryptococcal meningitis. Photo provided by the interviewee.Revealing the "Tug of War" in the Brain
Fungal meningitis is the most dangerous type of fungal infection, with a mortality rate of over 40%. As the leading pathogen of fungal meningitis, Cryptococcus neoformans not only infects immunocompromised patients but also easily infects the elderly and individuals with underlying diseases. It causes approximately 180,000 deaths worldwide each year.However, the means to combat this fungus are extremely limited, with only amphotericin B available as an antifungal drug. The infection mortality rate, clinical treatment failure rate, and recurrence rate are high.What exactly is the pathogenesis? Why is the recurrence rate so high?In 2016, Wang Linqi and her team attempted to answer this medical challenge. They systematically evaluated the effects of about 340 metabolites on the fungicidal efficacy of amphotericin B and unexpectedly discovered that glucose was a key influencing factor.The glucose concentration in the human brain is the highest among all organs, providing energy. The research team removed and re-introduced glucose into the cerebrospinal fluid, finding that glucose significantly induced Cryptococcus neoformans' tolerance to amphotericin B."The underlying mechanism is like a miniature 'tug of war'," explained Wang Linqi, the corresponding author of the paper, to the China Science Daily. "Amphotericin B primarily kills cells by binding to ergosterol in the fungal cell membrane, causing 'pores'. Glucose acts as the 'cheerleader.' When the external glucose concentration is high, it prompts the fungal transcription regulatory protein Mig1 to enter the cell nucleus, leading to the production of more inositol-phosphorylceramide (IPC) in the fungal cell membrane, which then competes with amphotericin B to 'tug of war' with ergosterol.""IPC has a higher affinity with ergosterol, exerting more force during the 'tug of war' and preventing effective binding between amphotericin B and ergosterol, thus rendering the fungal cell resistant to the drug," he said.Based on this, the research team has provided the first evidence of phenotypic drug resistance occurring in the host. Typically, drug resistance is caused by genetic mutations that make the pathogen resistant to medications. Phenotypic drug resistance, on the other hand, is not related to genetic mutations but is triggered by conditional or environmental changes. Over the past two decades, scientists have confirmed the existence of phenotypic drug resistance in fungi under in vitro conditions, but have not been able to find the key evidence of phenotypic drug resistance in vivo."Our research indicates that host factors can induce phenotypic drug resistance in vivo. Once drug treatment is stopped, the surviving fungal cells will further proliferate, leading to treatment failure and recurrence," said Chen Lei, the first author of the paper and a postdoctoral fellow at the Institute of Microbiology. He added that phenotypic drug resistance induced by host factors may be widespread in fungi, which will help inspire the scientific community to focus on this field and promote the development of drugs to combat phenotypic drug resistance in fungi.
Preventing Drug-Resistant Fungi from Making a Comeback
Due to its drug resistance, Cryptococcus neoformans is classified as one of the highest priority fungal pathogens on the World Health Organization's list. Discovering its pathogenesis is just the first step; if we want to reduce the drug tolerance of cryptococcal cells in the brain, we need to intervene in the "tug of war" within the brain.Wang Linqi and her team have targeted drugs that can inhibit IPC synthase, such as jingdansu compound A. This drug can work in conjunction with amphotericin B to limit IPC's competition for ergosterol, thus effectively eliminating the drug resistance of Cryptococcus neoformans in the brain.
