Fungal infections—like ringworm, athlete's foot, or the infamous Candida infections—are frequently linked to exposure to the environment. Yet, a collection of uncommon, hereditary fungal diseases lurks in the shadows of these more common ailments. These are primarily brought on by genetic changes that weaken the immune system, rather than just being brought on by external fungal infections. Comprehending these illnesses is crucial for enhancing patient outcomes as well as expanding our general understanding of how the immune system works.
Fungal illnesses that are inherited occur when genetic flaws make it more difficult for the immune system to fight off fungus. Although fungal infections can strike anybody, those with genetic predispositions are far more likely to have them, and they frequently result in severe, uncommon, or repeated infections. Primary immunodeficiencies, a category of over 400 illnesses in which some immune system components are either lacking or malfunctioning as a result of genetic abnormalities, are the general term used to describe these conditions.
Because these illnesses are uncommon and frequently go undiagnosed, which increases morbidity and death significantly, they present unique challenges. These disorders have a hereditary foundation, which means that they can run in families and occasionally go undetected for many generations before showing symptoms.
Understanding how a healthy immune system normally reacts to fungal infections is essential to appreciating the impact of hereditary fungal illnesses. The immune system defends against infections in multiple ways: physical barriers such as skin and mucous membranes, as well as more complex reactions involving immune cells and proteins.
Immune cells like neutrophils and macrophages are among the first to respond to a fungal infection. These cells absorb the fungi and use a number of different processes, such as the generation of reactive oxygen species, to kill them. Furthermore, proteins such as cytokines aid in the synchronization of the immune response, guaranteeing that the appropriate cells are triggered at the appropriate moment.
However, when these procedures are interfered with by genetic changes, the immune system is unable to react appropriately, which permits the fungal infection to proliferate and perhaps spread throughout the body.
Chronic Granulomatous Disease is one of the most researched hereditary illnesses (CGD). This uncommon illness affects phagocytes, which are pathogen-eating cells. Reactive oxygen species, which are essential for eliminating some bacteria and fungi, are not produced by phagocytes in CGD due to a mutation in one of the genes that produces NADPH oxidase.
Because of this, people with CGD are more vulnerable to serious, recurring infections, especially those caused by Aspergillus species. Chronic granulomas, which are immune cell clusters that form in an attempt to limit the infection but can seriously damage surrounding tissue, especially in the lungs and gastrointestinal tract, are a possible result of these infections.
A genetic condition known as CARD9 (caspase recruitment-domain protein 9) deficiency makes it more difficult for the body to mount an effective defense against fungus-related diseases. In signaling pathways that notify the immune system of the presence of fungus, especially Candida species, the CARD9 protein is essential. Deep tissues such as the brain and bones can be impacted by invasive Candida infections, which are common in people with CARD9 deficiency. The management of these infections is significantly challenging because they are not only more severe but also frequently resistant to standard antifungal medications.
There is some recent research work on this genetic disease. Tokyo Medical and Dental University (TMDU) researchers have discovered a variant of the CARD9 gene, c.820dup, that is common in northern China, Korea, and Japan and is associated with severe fungal infections. People who are deficient in CARD9 are more susceptible to fungal infections because of its immune-system-regulating function. The team's work, which was published in the Journal of Clinical Immunology on May 17, 2024, involved genetic analyses performed on five CARD9-deficient patients, two of whom were found by DNA sequencing.
Upon discovering that all five patients have the c.820dup variation, the researchers postulated that the "founder effect" might be to blame. According to haplotype analysis, the c.820dup variant most likely descended from a common ancestor around 2,000–4,000 years ago. This dates the variant to the late Neolithic to Bronze Age, when migration was known to have occurred from northern China to Korea and Japan.
In this regard, the lead researcher quoted that
Modern Japanese and Koreans are believed to have a genetic background originating from northern China. During the late Neolithic to the Bronze Age, the migration of people from northern China to Korea and Japan spread rice and language. The origins of the variant identified in this study are consistent with this historical period.
Professor Hirokazu Kanegane MD, PhD (Immunology/ Hematology/ Oncology), Department of Child Health and Development, Tokyo Medical and Dental University Hospital, Japan
The defining feature of hyper-IgE syndrome, sometimes referred to as Job's syndrome, is abnormally elevated blood levels of immunoglobulin E (IgE). The STAT3 gene, which is essential for many immunological pathways, including those that protect the body from fungus, is mutated in this illness.
Staphylococcus aureus skin infections are common in patients with Job's syndrome, but they are also quite vulnerable to fungal infections, especially those that damage the skin and lungs. Because these infections are frequently chronic and resistant to conventional therapies, there can be serious consequences, including a decline in quality of life.
While MSMD primarily increases susceptibility to mycobacterial infections, it also makes individuals more prone to certain fungal infections, particularly those caused by Histoplasma, Coccidioides, and Candida. The underlying genetic mutations affect various components of the immune system, including cytokine signaling pathways, which are crucial for mounting an effective response to both mycobacteria and fungi.
These disorders are typically inherited in an X-linked or autosomal recessive fashion due to genetic alterations. A person must inherit two copies of the faulty gene—one from each parent—in order to have autosomal recessive diseases. Males are more likely to suffer from X-linked disorders, like some kinds of CGD, because they only have one X chromosome and can be caused by a single faulty gene.
Examples of Genes Involved
CYBB gene
Mutations in the CYBB gene impair the synthesis of an essential part of the NADPH oxidase enzyme complex, which results in X-linked CGD. This mutation makes it more difficult for phagocytes to create reactive oxygen species, which prevents them from eliminating some infections.
CARD9 gene
This gene's mutations result in a lack of the CARD9 protein, which is essential for immunological signaling pathways that recognize and react to fungal infections.
STAT3 gene
Mutations in this gene affect a variety of immunological pathways, especially those that are important for preventing bacterial and fungal infections because they affect the differentiation and functionality of immune cells like Th17 cells.
Although inherited fungal diseases are uncommon and their symptoms might overlap with those of more common infections, diagnosing them can be difficult. Patients may exhibit atypical pathogens that do not usually cause disease in healthy individuals, persistent inflammation, or repeated infections. In cases where there is a family history of comparable diseases or unexplained immunodeficiencies, a strong index of suspicion is necessary.
Diagnostic Tools
Genetic Testing: To pinpoint the precise mutation at play and provide a conclusive diagnosis, genetic testing is frequently necessary. To identify the precise genetic abnormality, targeted gene panels or whole exome sequencing might be employed.
Immunological Testing: Blood tests are able to evaluate the immune system's performance in terms of reactive oxygen species generation, cytokine reactions, and immunoglobulin levels.
Imaging and Fungal Cultures: Determining the precise fungal pathogen in question, frequently using imaging and fungal cultures, is essential for directing therapy.
The goals of treating hereditary fungal illnesses are to control current infections and stop them from happening again. Due to their chronic nature, many illnesses frequently necessitate therapy and lifelong attention.
To treat active infections, common antifungal drugs such amphotericin B, azoles, and echinocandins are frequently utilized. However, longer periods of treatment or greater doses may occasionally be required due to the severity and resistance of certain illnesses, which may raise the possibility of side effects.
Many patients get long-term prophylactic antifungal medication due to the significant risk of recurring infections. Although this strategy reduces the danger of infection, it also increases the possibility of antifungal resistance over time.
By substituting healthy immune cells for damaged ones, bone marrow transplantation may be able to treat certain patients, particularly those with severe forms of CGD or other immunodeficiencies. Using cytokines or immune-modulating medications as part of immunotherapy can also help strengthen the immune response.
By the correction of the underlying genetic flaw, gene therapy is an emerging medicine that shows promise in the treatment of inherited fungal illnesses. Although mainly at the experimental stage, promising results in circumstances such as CGD indicate that this method may eventually offer a permanent fix.
Supportive care is essential since these disorders are persistent. This entails routinely keeping an eye out for early indications of infection, providing nutritional support, and managing side effects, including granulomas or persistent inflammation.
The possibility for novel therapeutics grows along with our comprehension of the genetic underpinnings of fungal illnesses. The application of CRISPR-Cas9 and other gene-editing technologies to rectify genetic abnormalities at their origin is a subject of ongoing research. The potential for personalized medicine to improve efficacy and minimize negative effects by customizing therapies based on a patient's genetic profile is also promising. Additionally, researching these uncommon illnesses provides deeper understanding of the immune system. Researchers can create novel approaches to enhance immune responses in the general population by comprehending how particular genetic abnormalities increase susceptibility to infections. This understanding may pave the way for the development of new vaccines or immune-boosting treatments.
Fungal diseases that are inherited constitute a multifaceted and frequently overlooked field of medicine, wherein genetics and immunology deeply intertwine. Even though they are uncommon, these illnesses offer insightful perspectives on how the immune system works and emphasize how crucial genetic research is to the creation of efficient therapies. It is hoped that as genetic testing, medication, and research continue to progress, we will not only find new approaches to treat fungal infections more broadly but also improve the prognosis for those who suffer from these diseases.
This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits.
Yazdi M, Behnaminia N, Nafari A, Sepahvand A. Genetic susceptibility to fungal infections. Advanced Biomedical Research [Internet]. 2023 Nov 1;12. Available from: https://doi.org/10.4103/abr.abr_259_22
Du B, Shen N, Hu J, Tao Y, Mo X, Cao Q. Complete clinical remission of invasive Candida infection with CARD9 deficiency after G-CSF treatment. Comparative Immunology Microbiology and Infectious Diseases [Internet]. 2020 Jun 1;70:101417.
By Dr. Pallavi Saxena
