Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

CARD9 Deficiency

  • Christina Gavino
  • Marija Landekic
  • Donald C. VinhEmail author
Living reference work entry

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DOI: https://doi.org/10.1007/978-1-4614-9209-2_59-2

Introduction

Despite an estimated 1.5 million species of fungi, ubiquitous in distribution resulting in constant exposure, few cause human disease. Those that do reflect a defect of immunity, either inherent or acquired. Although the taxonomy of fungi and the field of medical mycology are relatively young compared to other fields of microbiology, historical reports of fungi causing nail, hair, and superficial skin infections, as well as invasive disease, can be traced back to the mid-nineteenth century, prior to the advent of advanced therapeutics accounting for modern-day iatrogenic mycoses. Further, rather than causing true epidemics like bacteria and parasites, fungi were recognized to typically cause “sporadic” disease, that is, affecting select individuals, families, or races. The study of primary immunodeficiencies (PID) has led to the identification of critical genes that account, at least in part, for this inherent basis for susceptibility.

Spontaneously occurring fungal disease is increasingly recognized as a manifestation of an underlying primary immunodeficiency (PID); further, distinct PIDs are associated with a characteristic spectrum of fungal pathogens (Vinh 2011). Fungal disease has long been categorized as being either primarily superficial (i.e., involving mucosal and/or cutaneous membranes) or invasive. Chronic mucocutaneous candidiasis (CMC) is a superficial, recurrent/recalcitrant infection due to Candida sp. (discussed in greater detail in chapter 9). Invasive fungal diseases (IFDs) associated with PID have previously been defined within the context of susceptibility to a broader range of microbial pathogens. For example, chronic granulomatous disease (CGD), which results from defects in the phagocyte NADPH oxidase complex, is associated with increased susceptibility not only to select bacteria but also to Aspergillus spp. and other hyaline filamentous fungi (Cohen et al. 1981; Winkelstein et al. 2000; Segal et al. 1998; Roilides et al. 1999; Jabado et al. 1998). Likewise, Mendelian susceptibility to mycobacterial disease (MSMD), due to defects in the interleukin (IL)-12/−23/Interferon-γ axis, predisposes not only to infections with mycobacteria and Salmonella sp. (Bustamante et al. 2014), but also to thermally dimorphic endemic mycoses (e.g., Coccidiodes sp.; Paracoccidioides; Histoplasma sp.) (Vinh et al. 2009, 2011; Sampaio et al. 2013; Moraes-Vasconcelos et al. 2005; Zerbe and Holland 2005). In contrast to these, deficiency of caspase recruitment domain-containing protein 9 (CARD9) is a recently described PID with a susceptibility that, for now, seems distinctly restricted to fungi.

Clinical Features

The central feature of CARD9 deficiency is increased susceptibility to the following fungi: Candida; dermatophytes; and pheohyphomycetes. Interestingly, these fungi share the common features of being pleomorphic with the natural capacity for indolent hyphal invasion into cutaneous or subcutaneous layers to produce chronic infection.

Candida

The genus Candida is characterized by yeast-like cells that reproduce by budding. Depending on the species, pseudohyphae and true hyphae may develop in vivo, under growth conditions routinely employed in the medical mycology diagnostic laboratory and/or under specialized conditions used in research. CARD9 deficiency is associated with two forms of candidiasis: CMC and invasive candidiasis (IC).

In the seminal discovery that recessive mutations in CARD9 cause susceptibility to candidiasis (candidiasis familial 2, CANDF2; OMIM# 212050), four members from a single Iranian pedigree with intermittent episodes of mucocutaneous candidiasis only (oral, vaginal, and/or angular cheilitis) were found to be homozygous for a nonsense mutation (Glocker et al. 2009). Since then, a total of 38 patients with CARD9 deficiency have been reported; of these, CMC occurred in 15 (39.5%) (Lanternier et al. 2015a). Thus, it appears that a loss of CARD9 function predisposes to CMC, but apparently with variable penetrance and/or severity.

In contrast to its original association with CMC, a distinctive phenotype of CARD9 deficiency that has emerged is IC. In the original Iranian pedigree, it should be noted that three family members had previously died with anecdotal evidence of candidal infection of the central nervous system (Glocker et al. 2009): Patient 2B1 died of “candida meningitis” at the age of 19 years; Patient 5G1 died of a brain tumor with skull destruction at age 15 years; Patient 5G2 developed headache and diplopia and was suspected of having a brain tumor, but in fact, was found to have “candida meningoencephalitis” and died at age 15 years. None of these individuals had reported histopathologic or microbiologic data to corroborate the clinical diagnosis of invasive fungal disease. Understandably, none could be genetically sequenced to confirm CARD9 deficiency, although it may be reasonable to presume they were. These three cases, while incomplete, nonetheless provided an important signal that the salient phenotype of CARD9 deficiency actually extended beyond superficial candidiasis, to cause invasive disease.

Of the invasive forms of candidiasis associated with CARD9 deficiency, the most striking and consistent manifestation is that of involvement of the central nervous system (CNS), either brain parenchyma, meninges, and/or eye, in the absence of trauma (including iatrogenic bases, such as catheters, shunts, and surgeries), chemotherapeutic immunosuppression, or underlying systemic disease, which we have termed “spontaneous central nervous system candidiasis” (sCNSc) (Gavino et al. 2014). Table 1 summarizes the current published reports of sCNSc in which recessive mutations in CARD9 have been identified or presumed by pedigree analysis. Based on available microbiologic data, the primary pathogen was Candida albicans (12 of 18; 67%). In one case, the phylogenetically related C. dubliniensis was isolated (Drewniak et al. 2013). Another patient had a history of sCNSc with Candida sp. (no species provided), including relapse with sino-orbital invasion (again without speciation), but subsequently developed colitis with isolation of C. glabrata from colonic biopsy (Lanternier et al. 2015a); thus, it is unclear if the sCNSc was caused by the same species or not. Altogether, C. albicans appears to be the primary cause of sCNSc due to CARD9 deficiency. Intriguingly, despite CARD9 deficiency being an inborn error of innate immunity, and despite epidemiologic surveillance data demonstrating that humans are typically colonized with C. albicans very early in life (e.g., ~50% before 1 year of age) (Marks et al. 1975), the age of onset that sCNSc clinically manifested was in young adulthood (mean: 21.8; median 21.5). From the reported symptomatic cases, there appears to be a female preponderance (M:F = 5:11). The presenting symptoms have been variable and related to the CNS location involved. Cerebrospinal fluid (CSF) analysis has revealed the following pattern: a mononuclear cell predominance (i.e., lymphocytes and/or mononuclear cells), with a distinct relative eosinophilic pleocytosis in multiple cases; absence of neutrophilic pleocytosis in most cases; increased protein concentration; and hypoglycorrhachia. On CNS imaging, best characterized by magnetic resonance imaging (Bertin et al. 2000), the appearance of brain abscesses has been variable, ranging from a solitary mass, to cystic lesions, to multiple nodules; in some of the cases, these have been radiologically misinterpreted as brain malignancies, but from which histopathology revealed inflammatory mass lesions with no malignancy, identified fungal elements, and complemented by microbiologic isolation of the yeast. The masses have been contrast-enhancing and surrounded by edema, often with mass effect, hence explaining the presentation. There has been no singular CNS zone consistently affected. When the meninges are involved, MRI has revealed leptomeningeal enhancement.
Table 1

CARD9 deficiency and sCNSc

Reference

Age of clinical disease onset/gender

Bi-allelic mutationsa

Salient fungal disease

Features of CNS disease

Other clinical features

Outcome

Glocker et al. (2009)

18 years old/F (Iranian)

Presumed (by genetic sequencing of other family members): c.883C>T (p.Q295X)

Presumed candida meningitis

Clinical: seizures, loss of consciousness, complicated by hydrocephalus

Intermittent thrush (since early childhood)

Deceased

CSF: NR

Imaging: NR

13 years old/F (Iranian)

Presumed (by genetic sequencing of other family members): c.883C>T (p.Q295X)

Presumed candida brain abscess

Clinical: unilateral paresthesis

Ventricular septal defect (infancy); geographic tongue (presumed chronic candidiasis)

Deceased (from a brain tumor with severe skull destruction) at age 15

CSF: NR

Imaging: NR

15 years old/F (Iranian)

Presumed (by genetic sequencing of other family members): c.883C>T (p.Q295X)

Presumed candida meningo-encephalitis

Clinical: severe headache, fever, diplopia, suspected to be brain tumor

Recurrent thrush (since early childhood)

Deceased 6 months later

CSF: NR

Imaging: NR

Drewniak et al. (2013)

7 years old/F (Asian)

c.214G>A (p.G72S); c.1118G>C (p.R373P)

Recurrent C. dubliniensis meningo-encephalitis

Clinical: fevers, headaches, behavioral changes, seizures

NR

Discontinuation of antifungals associated with clinical relapse

CSF: eosinophilic pleocytosis; increased protein; decreased glucose

Imaging: infarction of left striatum; meningeal enhancement; mild ventricular dilatation

Gavino et al. (2014)

30 years old/M (French-Canadian)

c.439T>C (p.Y91H)

Recurrent C. albicans meningitis and brain abscess

Clinical: recurrent seizures; headaches; confusion/dis-orientation

Occasional dermatophytosis

Discontinuation of antifungals associated with clinical relapse

CSF: mononuclear pleocytosis (with 11% eosinophils); increased protein; decreased glucose

Alive, on antifungal and GM-CSF therapy

Imaging: left parieto-occipital mass

Lanternier et al. (2015a)

39 years old/F (P1; Turkish)

c.208C>T (p.R70W)

C. albicans meningitis and brain abscess

Clinical: fever, headache, vomiting; altered mental state; right arm paresis; facial palsy

Recurrent vulvo-vaginal candidiasis (since age 36)

Induction combination antifungal therapy. Required cerebral shunt. Alive on maintenance mono-therapy

CSF: lymphocytic pleocytosis (with 16%) eosinophils); increased protein; decreased glucose

Imaging: frontal lesion with mass effect and contrast enhancement; ventricular dilation

7 years old/F (P2; Turkish)

c.208C>T (p.R70W)

Recurrent C. albicans meningitis and brain abscess

Clinical: fever for weeks, headache, vomiting

Thrush

Relapse on antifungal therapy. Alive after re-induction (for 5 months) followed by maintenance with mono-therapy

Onycho-mycosis (both since age 5)

CSF: pleocytosis (20% eosinophils)

Imaging: several enhancing lesions, including brain medulla

17 years old/M (P3; Iranian)

c.104G>A (p.R35Q)

Recurrent C. albicans brain abscess

Clinical: left hemiplegia (17 years old) due to brain abscess (confirmed Candida sp. from surgical biopsy). Fever and right ptosis (20 years old)

Bloody diarrhea and anemia (22 years old); found to have linear ulcers and polyps in colon, from which biopsy showed invasive C. glabrata

Surgical resection. Alive, on maintenance antifungal therapy

CSF: NR

Imaging:

for the episode at 20 years old, found to have soft tissue opacities and calcifications in the sphenoids, ethmoids, and left maxillary and frontal sinsues, with 2 regions of bone erosion in the median wall of the right orbit adjacent to the right orbital apex

37 years old/F (P4; Moroccan)

c.865C>T (p.Q289*)

C.albicans brain abscess

Clinical: severe headache, vomiting, right hemiparesis

Recurrent thrush (since age 34)

Induction combination antifungal therapy (liposomal amphotericin B and 5-fluorocytosine) for 15 days, followed by fluconazole treatment. Alive

CSF: NR

Imaging: 30 × 40 mm left tempero-parietal lesion; several contrast-enhancing peripheral nodules; peri-lesional edema with mass effect

Gavino et al. (2016)

38 M (P2)

c.439T>C (p.Y91H)

C. albicans brain abscess

Clinical: headaches worsening over several weeks, dysphasia, left-sided weakness. Progressing to left hemiparesis and decreasing level of consciousness over next 2 months

Onycho-mycosis

Relapse on antifungal therapy. Alive on antifungal and GM-CSF therapy

CSF: NR

Imaging: multiple intracranial cystic masses (thought to be glioblastoma multiforme)

French-Canadian

 

39 F (P3)

c.439T>C (p.Y91H)

C. albicans endophthalmitis; brain abscess; vertebral osteomyelitis

Clinical: painless loss of vision in left eye (endophthalmitis)

Bipolar disorder (since adolescence; no imaging). Intermittent episodes of tinea versicolor (no cultures)

Alive on maintenance mono-therapy, no relapse

French-Canadian

CSF: NR

Imaging: right parieto-temporal lesions with mass effet. Numerous, non-enhancing lesions in the basal ganglia bilaterally

Found to have L4-L5 vertebral osteomyelitis (no culture; resolved with antifungal therapy)

 

39 F (P4; twin of P3)

c.439T>C (p.Y91H)

Asymptomatic

Clinical: intermittent episodes of migraines

Intermittent episodes of tinea versicolor and oral white plaques, presumed thrush (no cultures)

On fluconazole mono-therapy

CSF: declined

Imaging: numerous, nonenhancing lesions in the basal ganglia bilaterally; wedge-shaped encephalomalacia in left cerebral hemisphere

Herbst et al. (2015)

4 years old/F (Turkish)

c.883C>T (p.Q295X)

Recurrent C. albicans meningitis

Clinical: fever for 2 days, headache, fatigue (preceding 6 months of fever)

Recurrent thrush (since age 1.5)

Difficulty to sterilize CSF, with relapse, requiring prolonged induction combination therapy, prior to maintenance with fluconazole. Alive

CSF: granulocytic pleocytosis; increased protein; decreased glucose

Imaging: MRI revealed no inflammatory process

Celmeli et al. (2016)

25 years old/M (Turkish)

c.883C>T (p.Q295X)

C. albicans meningo-encephalitis

Clinical: headache, vomiting

Recurrent mild CMC and tinea versicolor (since age 3)

Failed induction mono-therapy with fluconazole. Required induction combination therapy. Eventually, transitioned to maintenance mono-therapy with voriconazole. After 4 months, clinical relapse, requiring combination induction therapy and G-CSF

CSF: lymphocytic pleocytosis; increased protein; decreased glucose

Imaging: NR

25 years old/M (Turkish; twin of proband)

c.883C>T (p.Q295X)

Asymptomatic

Clinical: none

Episode of meningitis at age 8 (no etiology provided)

Alive

CSF: NR

Imaging: NR

Episodes of tinea versicolor and tinea corporis

Drummond et al. (2015)

9 years old/F (El Salvadorian)

c.170G>A (p.R57H)

C. albicans meningitis and brain abscess; vertebral osteomyelitis

Clinical: fever, neck and back pain, headache, vomting (age 9; 15 months after completing fluconazole mono-therapy for osteomyelitis)

Recurrent oral thrush (since birth)

Alive at age 11

At age 8: fever, headache, vomiting, back pain; found to have T12-L1 vertebral osteomyelitis with diskitis and paraspinal abscess. Resolved with 6 months of fluconazole mono-therapy

CSF: lymphocytic pleocytosis (with 22% eosinophils); increased protein; decreased glucose

Imaging: cervical spine osteomyelitis, lepto-meningeal enhancement, syrinx, obstructive hydrocephalus, brain abscesses

Jones et al. (2016)

25 years old/F

c.1138G>C (p.A38P); c.951G>A (p.R317R)

C. albicans endophthalmitis; vertebral osteomyelitis

Clinical: R eye redness and blurred vision (panuveitis with focal inflammatory mass at the right macula). Worsening over months

Two years and 9 months after endophthalmitis, developed left him osteomyelitis, osteonecrosis, septic arthritis with C.albicans, requiring total hip replacement

Multiple surgeries, but loss of vision in right eye

CSF: NR

Imaging: NR

Alves de Medeiros et al. (2016)

5 years old/M (VII:3, Turkish)

Presumed (by genetic sequencing of other family members): c.208C>T (p.R70W)

C.albicans brain abscess

Clinical: right hemiparalysis

CMC (since age 5); chronic onychomycosis; hypoparathyroidism

Induction combination antifungal therapy, but difficult to sterilize CSF; eventual good recovery

CSF: pleocytosis (59% polymorphonuclear; 41% mononuclear); decreased glucose

Imaging: hypodense zone in left hemisphere; internal carotid artery aneurysm with infarctio

aHomozygous cases are indicated by the sole mutation identified. Compound heterozygous cases are indicated with both mutations identified

Interestingly, there have been two key reports in which there has been a set of twins bearing genetically identical CARD9 alleles to the proband, but who were asymptomatic clinically (Gavino et al. 2016; Celmeli et al. 2016). In one, no further investigations were reported (Celmeli et al. 2016). In the other, brain MRI revealed multiple, nonenhancing hypodense lesions in the basal ganglia (similar to her affected sister, who also had active, enhancing lesions), as well as wedge-shape cerebellar encephalomalacia, suggesting a previous embolic infarction or a healed focal infection (Gavino et al. 2016). This “unaffected” twin had suffered only from intermittent episodes of headaches that were diagnosed as migraines, as well as intermittent episodes of nonrecalcitrant dermatophytosis. Because she was relatively well, she refused further investigations (e.g., lumbar puncture; brain biopsy). Whether the “unaffected” twin in the other report similarly would have abnormalities in imaging or CSF analysis would be informative. Nonetheless, these “twin studies” with genetically identical CARD9 mutant alleles, and presumably with a relatively similar fungal exposure history (at least in early childhood), demonstrate that sCNSc from CARD9 deficiency is a phenotype of variable penetrance and/or variable expressivity.

Despite being a fungal disease of the brain, sCNSc due to CARD9 deficiency appears to frequently have a subacute course, that is, symptoms can develop and worsen over weeks-to-months (or even years), prior to the precipitous presentation. However, this should not be misinterpreted as being a benign disease. In the original report of CARD9 deficiency, the three family members with presumed sCNSc died (Glocker et al. 2009). Likewise, reports of sCNSc in French-Canadians (but without genetic confirmation of bi-allelic mutations in CARD9) also confirm a high mortality rate in the absence of antifungal therapy (Morris et al. 1945; Belisle et al. 1968; Black 1970; Germain et al. 1994). Surgery may be required therapeutically; it has at least provided the means to make the diagnosis of fungal infection accurately. The sCNSc is marked by difficulty to sterilize the CSF during induction antifungal therapy, often requiring combination of agents for prolonged periods of time. Relapses appear typical and can occur during appropriate suppressive (maintenance) antifungal therapy. In two reports (Gavino et al. 2014, 2016), symptomatic relapses were accompanied by isolation of C. albicans that remained susceptible in vitro to antifungal agents, including the ones used during maintenance therapy. Based on an in vitro cellular phenotype of impaired granulocyte-monocyte colony stimulating factor (GM-CSF) response to fungal agonists, these two patients were treated with maintenance antifungal therapy along with adjunctive, recombinant human GM-CSF (Gavino et al. 2014, 2016). This combination resulted in sterilization of CSF, normalization of CSF parameters, and radiologic amelioration. In one of the patients, cessation of GM-CSF was followed soon after by a clinical relapse with re-worsening of CSF parameters, all of which resolved with reinitiation of GM-CSF. The temporal relation of GM-CSF to symptoms in this single case, along with the in vitro data of a defective C. albicans-specific GM-CSF response, buttresses a cause-and-beneficial effect of adjunctive GM-CSF therapy. No further relapse occurred in the subsequent 3 years for either patient while on adjunct GM-CSF. Subsequently, G-CSF has also been used, along with three antifungal agents (fluconazole, amphotericin B, and the non-CNS penetrating caspofungin), during the re-induction treatment for a sCNSc relapse, which led to improvement and the eventual cessation of G-CSF after 2 months (Celmeli et al. 2016). Most other patients with sCNSc due to CARD9 deficiency have not needed adjunctive colony-stimulating factor therapy and survived with aggressive antifungal therapy, apparently with no significant sequela, although the accurate evolution of many cases were censored at the time of publication. While hematopoietic stem cell transplant has been considered as potentially curative for CARD9 deficiency (Drewniak et al. 2013), no report demonstrating the efficacy or safety of this approach is available.

Dermatophytes

Dermatophytes are a group of hyalohyphomycetous fungi that typically cause superficial diseases on humans and other mammals. By classical morphologic criteria in diagnostic mycology laboratories, the dermatophytes are composed of three genera: Trichophyton, Microsporum, and Epidermophyton. Superficial dermatophytosis (also called “tinea” or “ringworm”) can be associated with irritative symptoms, as well as cosmetic consequences, but are not generally life-threatening.

In distinction to superficial disease, deep dermatophytosis (DD) is a rarer presentation that may be severe and even life-threatening. DD is characterized by extensive – and often destructive – dermal and subcutaneous tissue invasion, often with dissemination to lymph nodes and, occasionally, to the CNS. Cases of DD have been historically traced back to at least the 1950s, with in-depth contemporaneous characterization suggesting an autosomal recessive transmission. However, the basis for this host susceptibility to DD had remained elusive until a collaborative effort between the Casanova and Grimbacher research groups discovered that DD was due to CARD9 deficiency, in at least a subset of affected individuals (Lanternier et al. 2013). Table 2 summarizes the current published reports of DD in which recessive mutations in CARD9 have been identified or presumed by pedigree analysis. Based on available microbiologic data, the primary pathogens causing DD associated with CARD9 deficiency are Trichophyton violaceum and T. rubrum, which are common anthrophilic dermatophytes. However, it should be noted that this conclusion is based primarily on patients from North Africa, where T. violaceum also happens to be the dermatophytic species most frequently isolated from patients (Lanternier et al. 2013). Whether the same or distinct Trichophyton species (or other dermatophytes) cause DD in CARD9 deficient patients from other parts of the world is unknown. Interestingly, T. violaceum and T. rubrum are closely related and may constitute a single clade (Graser et al. 2008); whether this translates into shared antigens relevant for CARD9-dependent host defenses remains to be addressed. Thus, it is currently unclear if the loss of CARD9 permits a species/clade-specific or genus-specific dermatophytic susceptibility.
Table 2

CARD9 deficiency and DD

Reference

Age of clinical disease onset/gender

Bi-allelic mutationsa

Sentinel fungal disease (fungal etiology if reported)

Features of deep dermatophytosis (fungal etiology if reported)

Other clinical features

Outcome

Lanternier et al. (2013)

6 years old/M (A-II-1; Algerian)

c.865C>T (p.Q289X)

Tinea corporis; tinea capitis; onychomycosis with pachyonychia

Lymphadenopathy in left axilla; also, submaxillary and mesenteric lymphadenopathy (at age 52)

Non-insulin-dependent diabetes mellitus (at age 50)

Treated with itraconazole. Alive

2 year old/M (cousin of A-II-1; Algerian)

Presumed (by genetic sequencing of other family members): c.865C>T (p.Q289X)

Onychomycosis; recurrent tinea capitis; tinea corporis; lymphadenopathy

Erythrodermic cutaneous nodules and ulcers, alopecia, onychodystrophy, with iliac, inguinal, axillary, and cervical fistulizing lymphadenopathy (at age 25) with T. violaceum. Subsequently developed 3 cerebral abscesses (no biopsy/microbiology)

Oral thrush (at age 9)

Deceased (at age 29)

9 years old/F (B-II-6; Algerian)

c.865C>T (p.Q289X)

Recurrent tinea capitis; extensive tinea corporis

General skin thickening, lichenification, squamous areas, pruritus, multiple erythematous nodules, palmo-plantar keratotic lesions, severe nail involvement with onychogryphosis and scaly scalp. Also developed multiple lymphadenopathies with fistula formation, worsening between the ages of 12 and 17 years. (T. rubrum)

Insulin-dependent diabetes mellitus (at age 35)

Griseofulvin treatment (at age 17), with clear improvement, but relapse when treatment stopped. Disease controlled with itraconazole. Alive

8 years old/M (C-II-1; Algerian)

c.865C>T (p.Q289X)

Recurrent tinea capitis and tinea corporis. Extensive foot and hand onychomycosis and glabrous skin lesion with lichenification. (T. violaceum)

Extensive foot and hand onychomycosis and glabrous skin lesion with lichenification. (T. violaceum)

Recurrent oral candidiasis

Griseofulvin treatment (at age 17), with some improvement, but relapses occurred when treatment stopped. Alive, treated with griseofulvin

 

8 years old/M (C-II-5; brother of C-II-1; Algerian)

Presumed (by genetic sequencing of other family members): c.865C>T (p.Q289X)

Extensive tinea capitis and onychomycosis

Extensive keratotic and ichthyotic lesions, disseminated papules, nodules, alopecia, pachyonychia, and onycholysis; subcutaneous abscesses; peripheral lymphadenopathy that fistulized (T. violaceum)

Recurrent thrush with C. albicans

Griseofulvin (at age 15), which led to improvement initially. Deceased (at age 34); no postmortem data available

8 years old/F (C-II-11; sister of C-II-1 and C-II-5; Algerian)

c.865C>T (p.Q289X)

Chronic onychomycosis of all nails (T. violaceum)

NR

None

Treated with griseofulvin

19 years old/M (D-II-6; Algerian)

c.865C>T (p.Q289X)

 

Ulcerative and nodular lesions of the left thigh and scalp (at age 19). Recurrent tinea capitis, onychomycosis of the hands and feet, cervical lymphadenopathy (at age 39)

 

Treatment with griseofulvin and fluconazole led to temporary improvement; relapse when the antifungal drugs were stopped. Alive, maintained with griseofulvin and fluconazole

21 years old/M (D-II-7; brother of D-II-6; Algerian)

c.865C>T (p.Q289X)

 

Extensive ulcerating skin lesions on the face, scalp, and perineum. Also, extensive tinea versicolor, oncyhomycosis, and inguinal lymph node involvement

 

Treated initially with griseofulvin, then fluconazole, with improvement. Cutaneous expansion and tissue extension when antifungal therapy stopped, leading to a stenotic anus that required surgery

N/A/M (D-II-4; brother of D-II-7 and D-II-7; Algerian)

Presumed (by genetic sequencing of other family members): c.865C>T (p.Q289X)

   

Deceased from pseudotumoral and ulcerating lesions on face (at age 28)

 

NA/M (E-II-7; Algerian)

c.865C>T (p.Q289X)

Recurrent tinea in childhood

Erythematosquamous warty lesions with onychomycosis and giant palmo-plantar horns, with onychogryphosis (at age 27; T. violaceum)

 

Improved on griseofulvin, but relapse. Deceased (at age 39)

NA/F (E-II-10; sister of D-II-7; Algerian)

c.865C>T (p.Q289X)

Chronic onychomycosis since childhood

  

Alive

NA/M (F-II-6; Moroccan)

c.301C>T (p.R101C)

Recurrent thrush and tinea during childhood

Squamous hyperkeratosic skin lesions on left foot (at age 16). Worsening to vegetative and ulcerating lesions extending to feet, calves, and the left thigh (at age 35), with left inguinal lymphadenopathy, squamous pigmented lesions of the groin, left foot onychomycosis, and radiographic osteolysis of left toes. (T. rubrum)

 

Initial improvement with antifungals, but then relapse (despite multiple antifungals), requiring amputation of left foot. Alive, but disease relapsed despite voriconazole

NA/F (F-II-3; sister of F-II-6; Moroccan)

c.301C>T (p.R101C)

Recurrent severe tinea since childhood. Hand and foot onychomycosis as adult

  

Alive

12 years old/M (G-III-1; Tunisian)

c.865C>T (p.Q289X)

Tinea corporis (at age 12)

Extension of skin lesions (at age 16), with nodules and onychomycosis of all nails (T. rubrum)

 

Fluconazole treatment stabilized lesions, without regression. Alive

5 years old/F (G-III-4; sister of G-III-1; Tunisian)

c.865C>T (p.Q289X)

Tinea capitis (at age 5); tinea corporis and onychomycosis (at age 8). (T. violaceum and T. rubrum)

Fistulized skin nodules and axillary lymphadenopathy (at age 12)

 

Stabilization of skin lesions with griseofulvin, ketoconazole, and fluconazole. Alive

 

6 years old/M (G-II-6; Tunisian)

c.865C>T (p.Q289X)

Tinea capitis (at age 6), followed by tinea corporis and onychomycosis of all nails

  

Deceased bed-ridden (at age 91)

6 years old/M (H-II-1; Tunisian)

 

Severe tinea capitis (at age 6)

Extensive tinea corporis and numerous skin nodules, onychomycosis affecting all nails and inguinal, cervical, and axillary lymphadenopathy (at age 40). (T. rubrum and T. violaceum)

 

Initially required treatment with griseofulvin, fluconazole, terbinafine, and itraconazole. Alive, lesions stable on voriconazole

Grumach et al. (2015)

3 years old/M; (Italian)

c.302G>T (p.R101L)

Thrush and tinea of the mandibular area, with alopecia (at age 3)

Delineated, scaly, pruritic skin lesions on the face (at age 11). Progressed to ulcerative paiful lesions in the lips and spread to the mandibular area. Progressing to affect his back and shoulders, with alopecia and onychodystrophy. (T. mentagrophytes)

 

Mild improvement initially with multiple antifungal drugs, with progression during or after antifungal treatment completed. Alive, on posaconazole

Jachiet et al. (2015)

13 years old/M; (Egyptian)

c.865C>T (p.Q289X)

Erythematous lesions on his hands and lower limbs

Coalescent, annular, squamous, erythematous, and pigmented plaques scattered on his abdomen, back, gluteal region, and lower limbs. Onychomycosis. (T. rubrum)

 

Mild improvement initially with multiple antifungal drugs, with progression during or after antifungal treatment completed. Alive, on posaconazole

Alves de Medeiros et al. (2016)

8 years old/M (VI:5; Turkish)

c.208C>T (p.R70W)

Tinea capitis, tinea corporis, oral candidiasis, and onychomycosis (at age 8) (T. violaceum, T. verrucosum, T. rubrum, and Malassezia furfur)

Tumoral skin lesion (at age 41), failing antifungal therapy and requiring resection. Axillary lymphadenopathy (at age 45)

 

Treatment of lymphadenopathy with antifungals. Alive, with regression of lesions on posaconazole

aHomozygous cases are indicated by the sole mutation identified. Compound heterozygous cases are indicated with both mutations identified

In affected individuals, the age of onset of dermatophytosis has generally been in childhood, manifesting as superficial disease (tinea) affecting various sites of the body. However, the dermatophytosis progresses indolently to become destructive, with visible nodular/tumoral and/or ulcerative lesions in adulthood. Dissemination to regional lymph nodes, manifesting as lymphadenopathy, is common. Interestingly, multiple noncontiguous lymph node clusters may be affected in the same individual, implying a significant degree of dissemination, although it is not clear if this derives from a single port of entry or multiple ones from the vast surface area of the skin barrier. Less commonly, bone may be involved. It is particularly intriguing that one presumed case of DD due to CARD9 deficiency developed CNS involvement probably with a dermatophyte (Lanternier et al. 2013): That a loss of CARD9 function could permit a mold, which typically resides at the cutaneous interface, to invade to the brain, may reflect a common immuno-pathophysiologic mechanism with sCNSc. Further cases with definitive phenotype, microbiology, and genotype will be profoundly informative.

As with sCNSc, the DD associated with CARD9 deficiency is difficult to treat. Induction therapy, to bring cure, appears to be infrequently successful. In some cases, there is initial improvement or stabilization of lesions; however, relapse seems to be the typical natural history of the disease once antifungal therapy is stopped. In more recent cases, maintenance therapy with the extended-spectrum azole, posaconazole, seems to be adequate. Impaired GM-CSF response of PBMC to fungal stimulation has been recently demonstrated in one patient with DD due to CARD9 deficiency (Alves de Medeiros et al. 2016), reiterating the finding observed in sCNSc due to CARD9 deficiency and suggesting that adjunctive cytokine therapy for DD may be an option in recalcitrant cases.

Pheohyphomyces

The pheohyphomyces, or dematiaceous fungi, are a heterogeneous group of molds with septated hyphae that are darkly pigmented due to the presence of melanin in their cell wall. These molds cause three distinct human diseases: chromoblastomycosis, eumycotic mycetoma, and phaeohyphomycosis.

The first indication that CARD9 played a central role in human susceptibility to phaeohyphomycosis was when bi-allelic mutations in the gene were identified in four patients with disfiguring subcutaneous disease due to Phialophora verrucosa (Wang et al. 2014; Table 3). In one of the patients, disease seemed to extend contiguously to the eye, resulting in blindness, suggesting a role for protection against deeper tissue invasion (Wang et al. 2014). Subsequently, CARD9 deficiency was identified in two patients with systemic phaeohyphomycosis due to Exophiala sp. (Lanternier et al. 2015b): One patient had chronically progressive invasive disease due to E. dermatitidis, involving the liver and, interestingly, the CNS; the other patient had musculo-skeletal, periorbital, lung, and lymph node disease due to E. spinifera. It is intriguing to note that historical reports of E. (Wangiella) dermatitidis long recognized its ability to cause fatal infections of the central nervous system in otherwise healthy subjects (Sudhadham et al. 2008). While the sporadic, neurotropic pathophysiology of E. dermatitidis is not well characterized, it is equally intriguing to note that human intestinal colonization with this mold is well documented (Sudhadham et al. 2011). These features are shared with Candida sp., which can distinctly cause sCNSc in the presence of deficient CARD9 function, raising speculation of a potentially common pathophysiologic process of dissemination. Lastly, CARD9 deficiency has been reported in a patient with subcutaneous phaeohyphomycosis due to Corynespora cassiicola, a mold pathogen of grasses, cucumber, rubber tree, soybean, tomato, cacao, and other fruit and ornamental plants (Yan et al. 2016). Although this fungal etiology seems bizarre, it should be noted that C. cassiicola has been previously reported – albeit rarely – as a human pathogen (Mahgoub 1969; Yamada et al. 2013; Huang et al. 2010; Lv et al. 2011); it would be informative to evaluate CARD9 in these other cases. While the number of phaeohyphomycotic cases associated with CARD9 deficiency are less numerous than sCNSc or DD, perhaps preventing a more-robust prototypical profile of associated disease, the aggregate of reports suggest that mutations in CARD9 should be assessed in patients presenting with subcutaneous or invasive phaeohyphomycosis.
Table 3

CARD9 deficiency and pheohyphomycosis (dematiaceous fungal disease)

Reference

Age of clinical disease onset/gender

Bi-allelic mutationsa

Sentinel fungal disease (fungal etiology if reported)

Other clinical features

Outcome

Wang et al. (2014)

13 years old/M (Chinese)

c.191-192insTGCT; c.472C>T (p.L64fsX59; p.Q158X)

Progressive dark red plaques and nodules on cheeks and ears bilaterally (Phialophora verrucosa)

NR

Induction combination antifungal therapy had limited effect. Lesions progressed with subcutaneous dissemination. Alive

6 years old/M (Chinese)

c.819-820insG (p.D274fsX60)

Progressive enlargement of red plaques on right cheek (Phialophora verrucosa)

NR

Induction therapy was followed by 2 years of maintenance therapy, but recurrence with cessation of antifungal drug. Alive

20 years old/F (Chinese)

c.819-820insG (p.D274fsX60)

Slowly enlarging plaque and nodule on right cheek (Phialophora verrucosa)

NR

Surgical excision of the nodule, with antifungal therapy. Alive, on antifungal maintenance

48 years old/M (Chinese)

c.819-820insG (p.D274fsX60)

Severe biolet place on face and scalp, which involved eye to cause blindness (Phialophora verrucosa)

NR

Oral itraconazole combined with terbinafine for half a year. The lesions improved slightly without satisfactory response

Lanternier et al. (2015b)

5 years old/F (Angolan)

c.52C>T (uniparental disomy) (p.R18W)

Granulomatous cholestatic hepatitis (E. dermatitidis). Multiple cerebral abscesses on brain imaging, without neurological symptoms (presumably same E. dermatitidis)

None

Initial episode treated with biliary tract irrigation with AmB, L-AmB iv, and oral voriconazole for 3 months, followed by voriconazole monotherapy maintenance, with clinical and radiologic resolution of liver lesions and majority of brain lesions. Relapse on voriconazole therapy (25 months after 1st episode) with E. dermatitidis pachymeningitis requiring induction combination antifungal therapy

18 years old/F (Iranian)

c.GAG967-969del (p.E323del)

Multiple small nodules in wrists bilaterally and in the right periorbital region with submental lymphadenopathy (at age 18). Lesion on the right forearm (at age 19). Subsequently found to have: abnormal bone scan with increased activity at multiple sites consistent with osteomyelitis; submandibular lymphadenopathy; lesions on the dorsum of right foot and side of neck

None

Failure of disease control with antifungal monotherapy. After 5 years of combination antifungal therapy, she developed multiple small nodules in right periorbital region and wrists and left lung mass (E. spinifera)

Yan et al. (2016)

35 years old/F (Chinese)

c.191–192InsTGCT

Extensive, destructive, dark red facial plaques with purulent foul-smelling discharge, and with postauricular lymphadenopathy (Corynespora cassiicola)

None

Induction therapy with AmB led to only slight improvement. Patient left the hospital for financial reasons

aHomozygous cases are indicated by the sole mutation identified. Compound heterozygous cases are indicated with both mutations identified

Singular Fungal Susceptibility

CARD9 deficiency has been consistently and independently shown to be associated with increased susceptibility to at least four fungal genera: Candida sp.; Trichophyton sp.; Phialophora verrucosa; and Exophiala sp. It may also account for sporadic susceptibility to unusual fungi (see Corynespora cassiicola above). It has recently been implicated in spontaneous extrapulmonary aspergillosis (Rieber et al. 2016); however, the identification of another subject who also had extrapulmonary aspergillosis, but who was only heterozygous for a germline CARD9 mutation and who expressed both mutant and wild-type CARD9 alleles (D. Vinh, unpublished data), suggests that additional definitive cases are required to firmly determine if CARD9 deficiency predisposes to invasive aspergillosis. Despite these nascent understandings of the natural history of CARD9 deficiency, it appears that these patients are not at increased risk for severe viral, bacterial or parasitic infections. Furthermore, it is intriguing that the reported CARD9 deficient patients have each displayed invasive disease with only a single fungus. The mechanistic basis for this singular fungal susceptibility remains unclear.

Genetic, Molecular, and Pathophysiologic Studies

CARD9 is located on chromosome 9 and encodes a protein of 536 amino acids. Like other CARD proteins, CARD9 has an N-terminal CARD domain that mediates binding to other CARD-domain containing molecules such as the protein B-cell lymphoma 10 (BCL10), and a C-terminal coiled-coil domain enabling protein oligomerization (Fig. 1) (Ruland 2008; Hara and Saito 2009; Roth and Ruland 2013). CARD9 is expressed primarily in myeloid cells ; consequently, CARD9 signaling is dispensable in lymphocytes but not in myeloid cells (Hara and Saito 2009; Roth and Ruland 2013).
Fig. 1

CARD9 protein schema with identified mutations to date. Coding exons are numbered with Roman numerals. The regions corresponding to the CARD domain and the coiled coil domain are indicated. Mutations indicated correspond to those identified in patients with CARD9 deficiency and invasive candidiasis/spontaneous central nervous system candidiasis [Black], deep dermatophytosis (blue), or phaehyphomycosis (orange)

Bi-allelic mutations in CARD9 are required for invasive fungal disease. Several mutations in CARD9 have been identified; they range from null alleles (i.e., loss of expression: L64 fs*59 (Wang et al. 2014), Q158X (Wang et al. 2014), D274fs*60 (Wang et al. 2014), Q289X (Lanternier et al. 2013), Q295X (Glocker et al. 2009), E323del (Lanternier et al. 2015b)) to missense mutations with detectable protein but loss of function (i.e., R57H (Drummond et al. 2015), R70W (Lanternier et al. 2015a, b), G72S (Drewniak et al. 2013), Y91H (Gavino et al. 2014, 2016), R101C (Lanternier et al. 2013), R373P (Drewniak et al. 2013; Fig. 1)). The mutations cluster in the two functional domains of CARD9 (Fig. 1). Although CARD9 deficiency confers singular fungal susceptibility (see above), there appears to be no genotype-phenotype correlation for this phenomenon, as the exact same mutation can predispose to sCNSc in some individuals and to DD in others (e.g., R70W; Q289X; Fig. 1). In addition to mutations in coding regions, allelic imbalance resulting from nonexonic variants has been reported (Gavino et al. 2016): In a French-Canadian cohort with sCNSc, genomic DNA sequencing revealed the c.439T>C (p.Y91H) mutation in heterozygosity. However, further analysis revealed that only the p.Y91H mutant allele was expressed at the mRNA (cDNA) level. This mono-allelic expression was abnormal, as SNP analysis in unaffected family members and numerous healthy controls confirm that CARD9 is normally bi-allelically expressed. Although a private nucleotide variant in the putative promoter region upstream of CARD9 was identified in patients and those unaffected family members with allelic imbalance (but associated with wild-type allele), reporter assay studies did not demonstrate that this variant affected transcription. Thus, the basis for the allelic imbalance in these cases remains unresolved. In a distinct patient who was not French-Canadian and who had DD, the c.439T>C (p.Y91H) was found, along with an intronic mutation (c.1435+18G>A; NM_052813) that created a novel splice acceptor site and abolished expression of the corresponding allele, again resulting in mono-allelic expression of the p.Y91H variant (D. Vinh, manuscript in preparation). These cases illustrate the diversity of mutations that affect CARD9 and emphasize the need to comprehensively evaluate both genomic DNA and mRNA (cDNA) sequences, to ensure the detection of nonexonic variants affecting allelic expression.

The identification of humans with CARD9 deficiency provides profound insight into its immunobiology. In its seminal discovery in experimental systems, CARD9 was identified as a cytosolic adaptor molecule that signals downstream of the C-type lectin pattern recognition receptor, Dectin-1, in myeloid cells but was redundant for lymphocyte signaling (Bertin et al. 2000; Gross et al. 2006; LeibundGut-Landmann et al. 2007; Hara et al. 2007). In mice, the CARD9-null state was associated with increased death following challenge with C. albicans. Dissection of the cellular signaling pathway demonstrated that the recognition of β-glucan by Dectin-1 activates spleen tyrosine kinase (SYK), which triggers the assembly of CARD9 with B-cell lymphoma/leukemia 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) to activate nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), c-Jun N-terminal kinase (JNK), and p38 to stimulate production of chemokines/cytokines (e.g., tumor necrosis factor, TNF; interleukin(IL)-6; IL-23; IL-2) and antigen presentation (Gross et al. 2006; LeibundGut-Landmann et al. 2007); of note, Dectin-1-dependent SYK activation of phagocytosis was found to be CARD9-independent. The Dectin-1-based activation of the CARD9 signaling pathway resulted in the effective generation of a CD4+ IL-17-producing effector T cell response (Th17). Collectively, these pioneering works demonstrated that the CARD9/BCL10/MALT1 cascade was key for mammalian antifungal innate immunity.

Shortly thereafter, the discovery of CARD9 deficiency in an Iranian pedigree with familial candidiasis was reported. Glocker et al. demonstrated that the CARD9-null patients (Q295X) had significantly reduced Th17 cells ex vivo and the mutant allele failed to trigger Dectin-1-based activation of TNF production, confirming that the phenomena identified in the above fundamental work was seen in humans (Glocker et al. 2009).

CARD9/BCL10/MALT1 signaling pathway is fundamental to human host defense to invasive fungal disease, then the corollary is that loss of either BCL10 or MALT1 should phenocopy CARD9 deficiency. Herein lies the elegance – and the necessity – to study human immunodeficiencies. Pedigrees with deficiency of BCL10 or MALT1 have been subsequently identified and invasive fungal disease was notably absent (Jabara et al. 2013; Punwani et al. 2015; Torres et al. 2014). To this end, Jia et al. subsequently defined a distinct signaling axis, whereby fungal stimulation results in CARD9 interaction with Ras Protein Specific Guanine Nucleotide Releasing Factor 1 (RASGRF1) to recruit V-Ha-Ras Harvey Rat Sarcoma Viral Oncogene Homolog (H-RAS) for downstream Extracellular Signal-regulated Kinase (ERK) (Gazendam et al. 2014) activation, and that loss of this ERK activation increased the death of C. albicans-infected mice (Jia et al. 2014). As ERK plays an important role in macrophage responses (Iles and Forman 2002; Richardson et al. 2015; Valledor et al. 2000), including regulating GM-CSF responses (de Groot et al. 1998), this pathway was interrogated in the French-Canadian CARD9 deficient cohort (Gavino et al. 2016). Although the p.Y91H mutation had no demonstrable effect on CARD9’s interaction with BCL10 or MALT1, it was found to decrease the ability of CARD9 to complex with RASGRF1, relative to wild-type CARD9 protein, thus reducing downstream ERK activation. While this may suggest that the CARD9/RASGRF1/ERK signalosome is important for human antifungal (at least, anti-candidal) immunity, demonstration of a similar effect due to other known CARD9 mutations would be informative. Similarly, human diseases with loss-of-function of RASGRF1, H-RAS, or ERK, either at germline level or in acquired or iatrogenic state, have not yet been reported, but their phenotype may provide significant advances in understanding the antifungal relevance of the CARD9/RASGRF1/ERK hub. Thus, the molecular pathway(s) by which CARD9 confers susceptibility to invasive fungal disease remains to be deciphered. Further, whether the singular fungal susceptibility seen clinically reflects divergence of CARD9-dependent pathways remains to be answered.

While the molecular pathways implicating CARD9 are beginning to be deciphered, our understanding on the pathophysiology of invasive fungal disease lags behind. The typical site of human colonization with C. albicans is the gastrointestinal tract or skin, whereas for dermatophytes like Trichosporon, it is, by definition, at the skin, and for phaehyphomycetes, it is either the respiratory tract or the gastrointestinal tract. What has remained enigmatic to date is understanding not only how loss-of-function in CARD9 permits a fungus to transition from commensal to invasive pathogen at the portal of entry, but what accounts for the unusual predilection to involve the CNS? What is the process by which these fungi are able to disseminate with minimal systemic symptoms, in a clearly nonfatal process, prior to seeding distant organs, including the CNS? The demonstration of impaired neutrophilic response to C. albicans, both in capacity to migrate toward foci of fungal infection (Drummond et al. 2015) as well as in fungal handling (Drewniak et al. 2013; Gazendam et al. 2014; Liang et al. 2015), may contribute to invasion and/or dissemination. Likewise, the impaired proinflammatory response of peripheral blood mononuclear cells (Glocker et al. 2009; Lanternier et al. 2015a, b; Gavino et al. 2014, 2016; Drewniak et al. 2013) may contribute to this impaired neutrophilic response, as well as impaired handling of fungi, perhaps permitting the establishment of an intracellular latent reservoir that can escape immune recognition while serving as a nidus for subsequent reactivation, in a manner similar to that for M. tuberculosis and select other fungi (e.g., Histoplasma; Cryptococcus) (Woods 2016; Alanio et al. 2015). These processes are, however, speculative. Nonetheless, CARD9 deficiency uniquely provides a natural human model to study the pathogenesis of invasion and dissemination with respect to its spectrum of fungi.

Concluding Remarks and Future Challenges

Bi-allelic mutations in CARD9 predispose to invasive candidiasis, including sCNSc, DD, and subcutaneous/invasive phaehyphomycosis. It may also be associated with susceptibility to Aspergillus sp. or unusual molds. Onset of disease is variable, and select pedigrees suggest some variability in either penetrance, expressivity, or both. Natural history of disease is one of recalcitrance, with either suboptimal response to appropriate antifungal agents (as deemed by in vitro antifungal susceptibility testing) and/or relapse. Anecdotal evidence suggests potential benefit with adjunctive cytokine therapy for these cases. The investigation of more patients is clearly required to understand the clinical diseases associated with CARD9 deficiency, to dissect the mechanistic basis for unusually severe and distinctive manifestations of the various mycoses, and to explore genotype-phenotype correlations, including the enigmatic singular fungal susceptibility phenotype.

Are There Other Genes Associated with Increased Susceptibility to Fungal Diseases?

CARD9 can be added to a growing list of genes that, when lesioned, predispose to invasive fungal diseases. In distinction to other genes, mutations in CARD9 appear to predispose only to fungal diseases. There remain patients with spontaneous, invasive fungal diseases who do not have mutations in CARD9. Relevant genes upstream and downstream of CARD9, as well as pathways unrelated to CARD9, are expected to broaden our understanding of those nonredundant processes that mediate human susceptibility to fungal infections.

Is There a Role for These Genes in Iatrogenic Fungal Diseases?

Invasive fungal diseases are typically not spontaneous, but rather, develop as a complication or during treatment of various underlying disorders. Whether or not CARD9, or related pathway proteins, influences susceptibility in these conditions has not been adequately explored. A single study, assessing the impact of a singular SNP in CARD9, found no association with the risk of candidemia in critically ill patients (Rosentul et al. 2011); however, given that the development of candida bloodstream infection in this group of patients is typically from central venous catheters or from intestinal transection (Bow et al. 2010), it would not be expected to find an effect of a gene SNP on disease biology in these conditions. Other polymorphisms, particularly those that are functional (i.e., modify the expression of a normal protein, or result in normal expression of a slightly modified protein), may ultimately impact on the development of specific syndromes. For example, the development of chronic disseminated (“hepato-splenic”) candidiasis in select patients recovering from intensive cytoreductive therapy for acute myeloid leukemia remains unexplained but may be influenced by CARD9 variants. Additionally, understanding the cellular mechanistic basis by which CARD9 mediates antifungal host resistance will likely identify nonredundant processes that may be therapeutically actionable.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Christina Gavino
    • 1
  • Marija Landekic
    • 1
  • Donald C. Vinh
    • 2
    • 3
    • 4
    Email author
  1. 1.Research Institute-MUHC (RI-MUHC)MontréalCanada
  2. 2.Infectious Disease Susceptibility ProgramMcGill University Health Centre (MUHC) and Research Institute-MUHC (RI-MUHC)MontréalCanada
  3. 3.Department of Medicine, Division of Infectious Diseases & Medical MicrobiologyMcGill University Health CentreMontréalCanada
  4. 4.Department of Human GeneticsMcGill UniversityMontréalCanada

Section editors and affiliations

  • Stuart Turvey
    • 1
  1. 1.Child & Family Research InstituteVancouverCanada