Caspase recruitment domain-containing protein 9, known as CARD9, is a protein. It plays a role in the immune system, the body’s defense mechanism. CARD9 is present in many cell types, especially immune cells like macrophages and dendritic cells, and also in tissues such as the spleen, lung, heart, and brain.
CARD9’s Role in Our Defenses
CARD9 functions as an adaptor protein, meaning it helps connect different parts of signaling pathways within immune cells. It operates downstream of pattern recognition receptors (PRRs), which are like sensors on immune cells that detect specific components of pathogens, such as fungi, bacteria, and viruses. When these PRRs recognize a threat, CARD9 helps transmit the signal further into the cell, initiating a cascade of immune responses.
A primary function of CARD9 involves its role in the innate immune system’s response to fungi. Specifically, C-type lectin receptors (CLRs) like Dectin-1, Dectin-2, and Mincle recognize fungal components and then utilize a signaling pathway involving spleen tyrosine kinase (Syk) and CARD9. Once activated, CARD9 forms a complex with other proteins, BCL10 and MALT1, to activate important cellular pathways such as NF-κB and MAPK. These activations lead to the production of signaling molecules like cytokines and chemokines, which are small proteins that coordinate immune cell activities.
CARD9 helps orchestrate the production of a wide array of these immune signaling molecules, including innate chemokines like CXCL1 and CXCL2, and cytokines such as TNF-α, IL-1β, and IL-6. It also influences adaptive cytokines like IL-17 and IL-22, which are involved in more specific, long-lasting immune responses. These molecules are responsible for recruiting immune cells, such as neutrophils, to the site of infection and promoting inflammation, which is a necessary process to contain and clear pathogens. For instance, in fungal infections of the central nervous system, CARD9 promotes the recruitment of neutrophils, which are infection-fighting white blood cells, to the affected areas.
Health Conditions Linked to CARD9
When CARD9 does not function properly, often due to genetic mutations, it can lead to various health problems, particularly those involving increased susceptibility to infections. CARD9 deficiency is a rare primary immunodeficiency disorder inherited in an autosomal recessive manner, meaning an individual must inherit two copies of a mutated CARD9 gene to develop the condition. This deficiency significantly compromises the body’s ability to mount an effective immune response, especially against fungal pathogens.
Individuals with CARD9 deficiency frequently experience recurrent and persistent fungal infections. One common manifestation is chronic mucocutaneous candidiasis (CMC), characterized by yeast infections of the skin, nails, and mucous membranes. These infections typically begin in early childhood and can be caused by various Candida species, such as Candida albicans, Candida parapsilosis, and Candida tropicalis. In some cases, CARD9 deficiency can lead to more severe, invasive fungal infections, known as systemic candidiasis, where the fungus spreads to the bloodstream and internal organs like the brain, kidneys, liver, or spleen. Infections with dermatophytes, which cause conditions like ringworm, and certain black molds (phaeohyphomycetes) are also common in these patients.
Beyond fungal infections, CARD9 dysfunction has also been linked to inflammatory disorders like inflammatory bowel disease (IBD). IBD involves a dysregulated immune response to the gut microbiota, leading to chronic inflammation in the intestines. While some CARD9 genetic variations may increase the risk of IBD by promoting inflammation, other variants have been found to have a protective effect. For example, a protective CARD9 variant, called CARD9Δ11, is unable to activate the inflammation-promoting NF-κB pathway because it cannot bind with another protein called TRIM62.
Unlocking New Treatments Through CARD9 Understanding
Understanding CARD9’s role in immune signaling has opened avenues for new therapeutic strategies. Research is exploring how to modulate CARD9 pathways to treat diseases associated with its dysfunction. For instance, small-molecule compounds are being investigated that can interfere with CARD9’s normal function, particularly its ability to promote inflammation.
One promising approach involves developing small-molecule inhibitors that directly bind to CARD9, preventing its interaction with other proteins like TRIM62. This mimics the protective effect seen in individuals with certain CARD9 gene variants associated with a reduced risk of inflammatory bowel disease. Such targeted therapies could offer a more precise way to control inflammatory responses in conditions like IBD, potentially reducing broad side effects often associated with conventional immune-modulating drugs. Additionally, for patients with CARD9 deficiency, insights into CARD9’s role in immune cell recruitment and cytokine production could lead to improved antifungal therapies and strategies to bolster their immune responses.