Kirsten Nielsen, PhD, discusses how her team’s research on Cryptococcus neoformans could lead to better understanding and treatment of cryptococcal meningitis.
Kirsten Nielsen, PhD
A study published in Nature Communications has revealed how genetic variations within Cryptococcus neoformans, the pathogen responsible for cryptococcal meningitis, impact patient outcomes. Using a mouse model, the researchers focused on the sequence type 93 (ST93) clade, which includes two subpopulations: ST93A and ST93B. The findings highlight how genetic differences between these subpopulations influence virulence and immune system interactions.
The study reveals that there is linkage disequilibrium (LD) among single nucleotide polymorphisms (SNPs) in both subpopulations, with ST93B exhibiting stronger LD compared to ST93A. LD, a measure of how genes are inherited together, suggests that while some SNPs linked to virulence are found in long-range LD, others evolve independently, providing insight into how these mutations contribute to the pathogen's evolution and ability to cause disease.
In addition to genetic analysis, the team employed contour-clamped gel electrophoresis and long-read sequencing to examine the karyotypes of both subpopulations. Their findings show that the LD observed was not due to chromosomal rearrangements, further validating the role of SNPs in virulence.
In an interview with Contagion, Kirsten Nielsen, PhD, professor of microbiology and immunology at Virginia Tech’s department of biomedical sciences and pathobiology, shared insights into the study and its implications. Nielsen and her team used a mouse model to investigate how genetic differences in Cryptococcus influence the severity of infection. Their research found that certain strains of Cryptococcus caused an overproduction of interferon gamma, a cytokine typically associated with beneficial immune responses. However, excessive production of interferon gamma worsened the disease outcome in the mouse model.
“Cryptococcus neoformans is a fungal pathogen that causes disease, primarily in immunocompromised individuals,” Nielsen explained. “Although we can also see disease in immunocompetent individuals, our study focused on how genetic differences—specifically gene alleles—of Cryptococcus can influence disease outcomes.”
The study built upon previous research using human clinical data, where variables such as patient genetics and disease severity made it difficult to draw definitive conclusions. By using a controlled mouse model, the researchers were able to pinpoint specific genes in the pathogen that influenced the immune response and disease progression.
Implications for Fungal Evolution and Treatment Strategies
The study has significant implications for understanding how Cryptococcus has evolved to infect different hosts, including humans. According to Nielsen, Cryptococcus is believed to have initially evolved to cause disease in single-celled organisms, using similar pathogenic mechanisms in humans. The study aims to differentiate between environmental strains of Cryptococcus that cause more lethal infections and those that do not lead to severe disease when infecting humans.
“We know that Cryptococcus is an organism that has evolved to cause disease,” Nielsen said. “We think it originally evolved to cause disease in single-celled organisms. However, it uses some of the same mechanisms in humans, though it’s primarily an environmental organism.”
The research also focuses on understanding the factors that differentiate strains of Cryptococcus acquired from the environment that cause more lethal disease and those that do not. "What we're trying to understand is how we can differentiate between strains that are acquired from the environment, which cause more lethal disease, and isolates that come from the environment but, when they infect humans, do not lead to significant disease,” Nielsen noted.
“We have treatments that can reduce the growth of Cryptococcus in the host, but these treatments are not fully effective,” she continued. “So, we're looking for ways to optimize the immune response, since the host immune system is generally very good at controlling Cryptococcus.”
Genetic differences within Cryptococcus neoformans’ ST93 clade influence the severity of infections and immune system responses.
The presence of linkage disequilibrium (LD) among SNPs reveals how certain mutations independently shape the pathogen’s evolution and virulence.
The findings open avenues for developing better diagnostic tools and personalized treatments based on the genetic profile of both the pathogen and the patient.
The ultimate goal is to improve the human immune response to Cryptococcus infections. By identifying which components of the immune system are critical for controlling infection, and understanding how the pathogen manipulates the host immune system, researchers hope to develop targeted therapies that can better address the specific genetic variations of both the pathogen and the patient.
Moving Toward Better Diagnostics and Treatment Plans
In addition to exploring immune responses, the study also opens the door for improved diagnostics and personalized treatment strategies. “We’re working on diagnostics that target some of the genes we’ve identified,” Nielsen explained. “The goal is to develop diagnostic tools that can differentiate between strains that might be very hard to treat in patients and those that would likely respond to standard treatments.”
She added, “and the hope is that by better understanding the biology of how these genetic differences change how Cryptococcus interacts with the host, we will be able to develop additional treatment strategies targeting some of these processes we’ve identified, which are driven by the underlying genetics.”
Nielsen's research highlights the critical role of genetic studies in improving patient outcomes for fungal infections, especially cryptococcal meningitis, a major health challenge for immunocompromised individuals. The study also finds that while SNPs in LD shape the genetic structure of the ST93 subpopulations, virulence-related SNPs are more likely to arise as independent mutations rather than being inherited with the pathogen’s phylogeny.
