Introduction

Fungal infections can be commonly found on the skin and the scalp, but they can also be found in the mouth, urinary tract and, in severe cases, the brain or spinal cord (i.e. the central nervous system (CNS)).¹ CNS fungal infections are rare, but when they occur, they are difficult to diagnose and treat. They are more likely to appear in people who are immunocompromised (i.e. they have a weaker immune system).²

Many factors can cause people to be immunocompromised, such as medications, age, or even genetics. Genetic immunodeficiency, or primary immunodeficiency, refers to a group of disorders where the immune system is dysfunctional due to inherited genetic mutations/faults. One of these disorders, known as CARD9 deficiency, is particularly related to an increased susceptibility to fungal infections, including those in the CNS.³

To understand the role of CARD9 in antifungal immunity, the effects of CARD9 deficiency on the immune system and infection susceptibility, as well as the clinical, diagnostic, and therapeutic aspects, continue reading below.  

The role of CARD9 in antifungal immunity

There is a range of different proteins that are part of the immune system and play an important role in the system’s processes. The CARD9 protein (Caspase recruitment domain-containing protein 9), made from the CARD9 gene, is an adaptor protein that forms part of signalling complexes to help with the recognition of pathogens like viruses, bacteria, and fungi, in addition to activating immune cells to fight against them. CARD9 is particularly important in innate antifungal immunity, which is the rapid response and first line of defence for fighting fungal infections. Proteins on the surface of white blood cells, for example, neutrophils and macrophages, recognise the foreign fungal pathogens and use CARD9 adaptor proteins to activate their function of attack and defend against fungal invasion.⁴ 

CARD9 deficiency and CNS fungal infections

CARD9 deficiency is an autosomal recessive disorder where there are mutations in the CARD9 gene, resulting in either the absence of the protein or abnormal protein production.³ Since it is a recessive disorder, the individual would have to have inherited two mutated genes, one from each parent, to be affected by this. Inheriting just one mutated gene would not present symptoms of CARD9 deficiency. CARD9 deficiency mainly presents with an increased susceptibility to fungal infections, especially those that affect the central nervous system (CNS) (i.e. the brain and the spinal cord).^3,5 Recently, the number of cases of fungal infections that have been linked with an underlying CARD9 deficiency has been increasing.⁶

Pathogenesis of CNS fungal infections in CARD9 deficiency

With the deficiency of adaptor protein CARD9, the result is an impaired immune system, leading to an ineffective immune response against pathogens such as fungi. CARD9 deficiency is likely to have a more severe effect on immune system dysfunction due to the shared importance and use of this adaptor protein by other proteins.⁴  Without an immune response, your body won’t be able to control the rate at which fungi grow, proliferate, and disseminate, causing severe damage. Without CARD9, there are many factors that will be affected, such as reduced recognition of fungal pathogens, reduced cytokine production, and consequent reduced white blood cell recruitment, leading to potentially persistent infections of the CNS. Studies have shown that CARD deficiency specifically affects the CNS rather than affecting fungal control in other peripheral areas.^4,5 

Clinical spectrum of CNS fungal infections in CARD9 deficiency

The term “fungi” usually refers to two main types - yeasts and moulds (i.e. dermatophytes and “black mould”). Many fungal pathogens take advantage of the effects of CARD9 deficiency, including yeast pathogens such as various Candida species, including Candida albicans, that lead to various forms of candidiasis affecting the skin, bones, and CNS. 

The most common forms known are chronic mucocutaneous candidiasis (CMC) and systemic/invasive candidiasis. CMC mainly affects the skin and the tissues around it, whereas systemic candidiasis is associated with the bloodstream and the CNS. This can be life-threatening as it leads to the conditions of meningitis (infection and/or inflammation of the membranes surrounding the brain), meningoencephalitis (infection and/or inflammation of the membrane and the brain tissue itself) and sepsis. Cerebral abscesses may also be present, adding harmful pressure on the brain. Various moulds, such as Exophiala dermatitidis and various Aspergillus species, can also be the cause of these infections.⁵ 

Considering infections mainly occur in the CNS, many symptoms will be related to the brain and spinal cord. The symptoms include a fever, nausea, persistent headaches or back pain, a stiff neck, seizures, neurological effects such as hearing and vision problems, numbness and paralysis if the spinal cord is infected, and a different mental state.⁷ 

Diagnostic considerations

Your doctor/medical professional will make a judgment based on clinical suspicion of fungal infections that are either atypical or recurring. Infections are sometimes the only way to know if there is an underlying genetic disorder. Genetic testing will be the main diagnostic method for confirming any abnormal genetic mutations within the CARD9 gene.⁵ 

Diagnostic imaging and tests are also used to detect CARD9 deficiency-related CNS infections. People who have CARD9 deficiency with fungal infections in the brain or spine may undergo imaging such as an MRI or CT scan to locate the sites of abnormalities, e.g. abscesses.² A biopsy may help to confirm if it is caused by an infection or if it is a mass related to cancer. 

Molecular testing, such as PCR or next-gen sequencing, can help determine the specific pathogen. In your spinal cord, there is a fluid called cerebrospinal fluid (CSF), and this can be extracted and tested to show irregular protein or glucose levels due to potential infections. The CSF sample can be cultured within a lab to show the presence of fungi and narrow down the cause.⁷ As in most cases, early detection is essential and important to quickly determine specifics and provide targeted therapy for a better prognosis and outcome.

Therapeutic approaches

Antifungal therapy will be required to treat the complex fungal infections. Diagnostic tests would allow medical professionals to make judgments regarding the treatment, from how long the therapy should last to which antifungal agents should be used to ensure that they will be effective and penetrate the CNS. Examples of antifungal agents include liposomal amphotericin B, voriconazole, and flucytosine.⁵  

Regarding the reduced immune response effect of CARD9 deficiency, immunomodulatory therapy helps to stimulate and increase the immune response is used alongside antifungal therapy. For example, granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as Sargramostim or Leukine, can be used to stimulate your body to produce more white blood cells to help fight the infection.⁸ In severe cases, haematopoietic stem cell transplantation (HSCT), or most known as bone marrow transplantation, can be done to restore a functional immune response.

Symptom-specific treatments, such as draining abscesses, may also be used to help manage pain and provide relief. Supportive care from medical professionals for both the person experiencing this condition and their family/friends will be important to enhance their quality of life. Regular check-ups and follow-ups will be required and essential to minimise any effects of the condition. 

Summary

CARD9 is a valuable protein that is part of the processes that help immune cells recognise pathogens such as fungi and stimulate the immune cells to fight against the pathogens. CARD9 deficiency is a genetic immunodeficiency disorder that affects this valuable protein and allows the body to be more susceptible to infections, especially fungal infections of the skin, bone, and CNS. Without CARD9, the immune system cannot carry out its function as well as it should, and some fungal pathogens take advantage of this.

Central nervous system fungal infections, involving those of the brain and spinal cord, can be caused by different types of fungi, including yeasts such as Candida species, and moulds such as Aspergillus species and the typical “black mould”. If the infections are systemic and affect the CNS, the symptoms will affect the whole body or specifically the brain and spinal cord. Fever, nausea, and sepsis are common systemic symptoms. Specific symptoms such as back pain and numbness can be present in spinal cord infections, with headaches, meningitis, and possible neurological hearing or vision problems being present as symptoms of brain infections.

CNS fungal infections are difficult to diagnose due to the presence of nonspecific symptoms and limited tools for diagnosis. Fungal infections are difficult to treat overall since fungal cells are very similar to our cells, and therefore, medications may impact both the fungal cells and our own cells. There is a limited range of antifungal agents available, and so further research is needed to expand this range for different fungal infections. However, advances in genetics and immunology have allowed for some useful methods of diagnosis and treatments/therapies to be used. Further research into CARD9 deficiency and associated fungal infections will be needed to provide early diagnosis and early treatment to help improve prognosis and outcomes.