Pulmonary cryptococcosis in a patient with Crohn's disease treated with prednisone, azathioprine and adalimumab: Exposure to chicken manure as a source of contamination

Fraison, J.B.; Guilpain, Philippe; Schiffmann, A.; Veyrac, M.; Moing, Vincent Le; Rispail, P.; Quellec, A. Le

doi:10.1016/j.crohns.2012.04.016

Cited by 32 publications

(11 citation statements)

References 15 publications

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“…136 Immunocompetent people with cryptococcal infection are mostly asymptomatic or present with a solitary lung nodule, whereas the immunosuppressed population may present with disseminated cryptococcosis involving the lungs, skin, and central nervous system. Clinical disease due to Cryptococcus is mainly seen in the immunocompromised population.…”

Section: Cryptococcosismentioning

confidence: 99%

“…Mortality rates are variable depending on the site of involvement (49% with CNS infections compared with 2.8% with isolated lung infections). 136 Treatment consists of induction with amphotericin B (or preferably using its lipid formulation) and flucytosine for at least 2 weeks, and this is followed by consolidation therapy with oral fluconazole for 6 to 12 months.…”

Section: Cryptococcosismentioning

confidence: 99%

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Opportunistic Infections Due to Inflammatory Bowel Disease Therapy

Dave

Purohit

Razonable

et al. 2014

Inflammatory Bowel Diseases

116

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The use of biological agents and immunomodulators for inflammatory bowel disease (IBD) has remarkably improved disease management in the current era but at the same time has increased the risk of infectious complications. Patients with IBD on corticosteroids, immunomodulators, and biological agents are considered immunocompromised and are at risk for opportunistic infections. These are infections caused by organisms that take advantage of a weakened immune system, and cause disease, when they ordinarily would cause mild illness or no disease in an immunocompetent host. Risk factors for opportunistic infections include malnutrition, older age, congenital immunodeficiency, HIV infection, chronic diseases, and use of corticosteroids, immunomodulators, and anti-tumor necrosis factor alpha therapy. Apart from immunosuppressive medications and older age, there is only indirect evidence for above risk factors contributing directly to opportunistic infection risk in patients with IBD. Opportunistic infections in patients with IBD include viral infections (herpes viruses, human papillomavirus, influenza virus, and JC virus), bacterial infections (tuberculosis, nocardiosis, Clostridium difficile infection, pneumococcal infection, legionellosis, and listeriosis), fungal infections (histoplasmosis, cryptococcosis, Pneumocystis jirovecii infection, aspergillosis, and candidiasis), and parasite infections (Strongyloides stercoralis). Although these infections lead to high morbidity and mortality, only a minority of patients with IBD develop opportunistic infections. Currently, we lack a test to accurately predict patients at risk of opportunistic infection, and future research needs to focus on biomarkers or predictive models for risk stratification. Until such a test is developed, we need to screen, prevent, diagnose, and treat opportunistic infections in all patients with IBD in a timely manner.

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Section: Cryptococcosismentioning

confidence: 99%

Section: Cryptococcosismentioning

confidence: 99%

Opportunistic Infections Due to Inflammatory Bowel Disease Therapy

Dave

Purohit

Razonable

et al. 2014

Inflammatory Bowel Diseases

116

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“…In addition to being a purine analogue, azathioprine functions by blocking GTP binding to Rac and prevents Rac activation (65,66). Patients treated with azathioprine have been reported to develop both pulmonary cryptococcosis and cryptococcal meningitis (63,64). Our data suggest that the increased susceptibility to Cryptococcus could be caused in part by defective NK cell function, because of azathioprine-induced blockage of the Rac 3 PI3K 3 Erk cytotoxicity pathway.…”

Section: Discussionmentioning

confidence: 72%

“…The involvement of Rac in NK cell-mediated cryptococcal killing may provide clinical insights into the susceptibility to cryptococcosis in patients taking azathioprine (63,64). In addition to being a purine analogue, azathioprine functions by blocking GTP binding to Rac and prevents Rac activation (65,66).…”

Section: Discussionmentioning

confidence: 99%

Ras-related C3 Botulinum Toxin Substrate (Rac) and Src Family Kinases (SFK) Are Proximal and Essential for Phosphatidylinositol 3-Kinase (PI3K) Activation in Natural Killer (NK) Cell-mediated Direct Cytotoxicity against Cryptococcus neoformans

Xiang

Stack

Huston

et al. 2016

Journal of Biological Chemistry

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The activity of Rac in leukocytes is essential for immunity. However, its role in NK cell-mediated anti-microbial signaling remains unclear. In this study, we investigated the role of Rac in NK cell mediated anti-cryptococcal killing. We found that Cryptococcus neoformans independently activates both Rac and SFK pathways in NK cells, and unlike in tumor killing, Cryptococcus initiated a novel Rac 3 PI3K 3 Erk cytotoxicity cascade. Remarkably, Rac was not required for conjugate formation, despite its essential role in NK cytotoxicity against C. neoformans. Taken together, our data show that, unlike observations with tumor cells, NK cells use a novel Rac cytotoxicity pathway in conjunction with SFK, to kill C. neoformans. NK3 cells are a subset of lymphocytes that have well characterized anti-tumor and anti-viral activity. However, it is now apparent that NK cells also have the capacity to kill microbial targets, which contribute to host defense, and differ in important ways from tumor killing (1). Receptor-mediated NK antitumor signaling depends on sequential activation of PI3K 3 Rac 3 Erk (2); however, because the receptors required for cryptococcal killing differ from those required for tumor killing (3), we predicted that anti-microbial signaling would also differ. Our previous studies have shown that a PI3K 3 Erk signaling pathway was essential for cryptococcal killing (4). Because other laboratories showed that PI3K can activate Erk via either Rac or phospholipase C␥ (PLC␥), we sought to examine the pathway used in NK cell-mediated cryptococcal killing by investigating both PI3K 3 Rac 3 Erk and PI3K 3 PLC␥ 3 Erk pathways (5-9).Rac is a subfamily of Ras homology (Rho) GTPases consisting of Rac1, Rac2, Rac3, and RhoG. They are activated by guanine nucleotide exchange factors by exchanging GDP for GTP (reviewed in Ref. 10). Activation of Rac in NK cells is crucial for conjugate formation between NK and tumor targets (11,12). During tumor killing, Rac-GTP regulates actin remodeling by activating downstream effectors such as WAVE (WASP family verprolin-homologous protein), SRA1 (specifically RAC1-associated protein 1), and p21-activated kinases (PAKs) (13-16). In addition to its important role in cytoskeletal modulation, Rac plays a role in the activation of Erk and NK cell-mediated tumor cytotoxicity (9). Against Raji tumor targets, the human NK cell line, NK92 and primary NK cells required Rac to initiate a PAK1 3 Mek1/2 3 Erk1/2 signaling cascade that allows for cytotoxic granule mobilization and release (2). Rac activation was found to be dependent on PI3K, because NK92 cells transfected with a constitutively active Rac were able to continue killing tumor targets in the presence of PI3K inhibitors, whereas control cells were not (2).In addition to Rac, PLC␥ can also become activated by PI3K and lead to Erk activation. PLC␥ is best known for the production of diacyl glycerol and inositol 3-phosphate, which activates downstream kinases and regulates intracellular calcium (reviewed in Ref. 17). In certain cells,...

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“…Since a percentage of HIV-infected patients are subclinically infected with C. neoformans (56), treatment with IL-12, or similar agent, could reduce or eliminate this complication. Another example is the development of pulmonary cryptococcosis and cryptococcal meningitis in patients with Crohn’s disease or autoimmune hepatitis that were treated with the purine analog, azathioprine (57, 58). Azathioprine prevented Rac1 activation by blocking GTP binding to Rac1 (59, 60), and Rac1 activation in NK cells is required for NK cell cytotoxicity of tumors (32) and Cryptococcus (15).…”

Section: Implication For Therapeutic Approachesmentioning

confidence: 99%

Granule-Dependent Natural Killer Cell Cytotoxicity to Fungal Pathogens

Ogbomo

Mody

2017

Front. Immunol.

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Natural killer (NK) cells kill or inhibit the growth of a number of fungi including Cryptococcus, Candida, Aspergillus, Rhizopus, and Paracoccidioides. Although many fungi are not dangerous, invasive fungal pathogens, such as Cryptococcus neoformans, cause life-threatening disease in individuals with impaired cell-mediated immunity. While there are similarities to cell-mediated killing of tumor cells, there are also important differences. Similar to tumor killing, NK cells directly kill fungi in a receptor-mediated and cytotoxic granule-dependent manner. Unlike tumor cell killing where multiple NK cell-activating receptors cooperate and signal events that mediate cytotoxicity, only the NKp30 receptor has been described to mediate signaling events that trigger the NK cell to mobilize its cytolytic payload to the site of interaction with C. neoformans and Candida albicans, subsequently leading to granule exocytosis and fungal killing. More recently, the NKp46 receptor was reported to bind Candida glabrata adhesins Epa1, 6, and 7 and directly mediate fungal clearance. A number of unanswered questions remain. For example, is only one NK cell-activating receptor sufficient for signaling leading to fungal killing? Are the signaling pathways activated by fungi similar to those activated by tumor cells during NK cell killing? How do the cytolytic granules traffic to the site of interaction with fungi, and how does this process compare with tumor killing? Recent insights into receptor use, intracellular signaling and cytolytic granule trafficking during NK cell-mediated fungal killing will be compared to tumor killing, and the implications for therapeutic approaches will be discussed.

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Pulmonary cryptococcosis in a patient with Crohn's disease treated with prednisone, azathioprine and adalimumab: Exposure to chicken manure as a source of contamination

Cited by 32 publications

References 15 publications

Opportunistic Infections Due to Inflammatory Bowel Disease Therapy

Opportunistic Infections Due to Inflammatory Bowel Disease Therapy

Ras-related C3 Botulinum Toxin Substrate (Rac) and Src Family Kinases (SFK) Are Proximal and Essential for Phosphatidylinositol 3-Kinase (PI3K) Activation in Natural Killer (NK) Cell-mediated Direct Cytotoxicity against Cryptococcus neoformans

Granule-Dependent Natural Killer Cell Cytotoxicity to Fungal Pathogens

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