General practice activity in Australia 2012-13

Patients with chronic granulomatous disease (CGD) have a mutated NADPH complex resulting in defective production of reactive oxygen species; these patients can develop severe colitis and are highly susceptible to invasive fungal infection. In NADPH oxidase-deficient mice, autophagy is defective but inflammasome activation is present despite lack of reactive oxygen species production. However, whether these processes are mutually regulated in CGD and whether defective autophagy is clinically relevant in patients with CGD is unknown. Here, we demonstrate that macrophages from CGD mice and blood monocytes from CGD patients display minimal recruitment of microtubule-associated protein 1 light chain 3 (LC3) to phagosomes. This defect in autophagy results in increased IL-1β release. Blocking IL-1 with the receptor antagonist (anakinra) decreases neutrophil recruitment and T helper 17 responses and protects CGD mice from colitis and also from invasive aspergillosis. In addition to decreased inflammasome activation, anakinra restored autophagy in CGD mice in vivo, with increased Aspergillus-induced LC3 recruitment and increased expression of autophagy genes. Anakinra also increased Aspergillus-induced LC3 recruitment from 23\% to 51\% (P < 0.01) in vitro in monocytes from CGD patients. The clinical relevance of these findings was assessed by treating CGD patients who had severe colitis with IL-1 receptor blockade using anakinra. Anakinra treatment resulted in a rapid and sustained improvement in colitis. Thus, inflammation in CGD is due to IL-1-dependent mechanisms, such as decreased autophagy and increased inflammasome activation, which are linked pathological conditions in CGD that can be restored by IL-1 receptor blockade

Recognition and cytokine signalling pathways in host defence against Aspergillus fumigatus

Contains fulltext : 140191.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 29 mei 2015Promotores : Netea, M.G., Joosten, L.A.B. Co-promotor : Veerdonk, F.L. van d

The Role of Interleukin-1 Family Members in the Host Defence Against Aspergillus fumigatus

Contains fulltext : 138722.pdf (publisher's version ) (Closed access)The interleukin (IL)-1 family consists of 11 members, which all play significant roles in regulating inflammatory responses in the host. IL-1alpha and IL-1beta exert potent pro-inflammatory effects and are key players in the recruitment of neutrophils to the site of inflammation. Protective anti-Aspergillus host responses during the early stages of invasive aspergillosis are critically dependent on neutrophil recruitment, and several lines of evidence support that there is an important role for IL-1 in this process. However, IL-1-mediated inflammation needs to be tightly regulated, since uncontrolled inflammation can result in inflammatory pathology and thereby be detrimental for the host. Aspergillus-induced IL-1-mediated inflammation could therefore be amendable for IL-1 blockade under specific circumstances. This review describes the current understanding of the role of IL-1 family members in the host response against Aspergillus fumigatus and highlights the importance of balanced IL-1 responses in aspergillosis

Biology of IL-36 cytokines and their role in disease.

Item does not contain fulltextIL-36alpha, IL-36beta, IL-36gamma, and IL-36Ra, collectively called IL-36 cytokines, are part of the IL-1 family. IL-36alpha, IL-36beta, and IL-36gamma are IL-36 receptor (IL-36R) agonists, while IL-36Ra is a receptor antagonist that blocks the activation of IL-36R signaling. IL-36 cytokines require processing in order to become fully active, however the protease(s) responsible for this are currently not known. The IL-36 receptor pathway activates dendritic cells and plays a role in polarizing T-helper responses. The skin is the predominant site where IL-36 cytokines are expressed and several reports have established that they play a significant role in the pathogenesis of skin diseases. In this review the discovery and biological function of the cytokines IL-36alpha, IL-36beta, IL-36gamma and IL-36Ra will be discussed, and their role in the pathogenesis of a wide variety of diseases

LC3-associated phagocytosis: a crucial mechanism for antifungal host defence against Aspergillus fumigatus

LC3-associated phagocytosis (LAP) is a non-canonical autophagy pathway involved in the maturation of single-membrane phagosomes and subsequent killing of ingested pathogens by phagocytes. This pathway is initiated following recognition of pathogens by pattern recognition receptors and leads to the recruitment of LC3 into the phagosomal membrane. This form of phagocytosis is utilized for the antifungal host defence and is required for an efficient fungal killing. Here, we provide an overview of the LAP pathway and review the role of LAP in anti-Aspergillus host defence, as well as mechanisms induced by Aspergillus that modulate LAP to promote its survival in the host

Pattern recognition receptors and their role in invasive aspergillosis

Item does not contain fulltextPattern recognition receptors (PRRs) are germline receptors that recognize conserved structures on microorganisms. Several PRRs have been identified in the recent years that are involved in the immune response against Aspergillus fumigatus. The role of PRRs in invasive pulmonary aspergillosis becomes especially apparent in the setting of an immunocompromised status of the host because of the redundancy of many PRRs in the host defense against A. fumigatus. Studies that investigated the PRRs and their effector pathways in invasive aspergillosis have led to a better understanding of the pathogenesis of invasive aspergillosis in immunocompromised patients. This knowledge may pave the way for novel diagnostic and immunomodulatory treatment strategies that are needed to overcome the high mortality associated with invasive A. fumigatus infection in immunocompromised patients

Adjuvant interferon-gamma immunotherapy in a patient with progressive cerebral Nocardia abscesses

Contains fulltext : 174790.pdf (publisher's version ) (Open Access)Despite advances in medical care, mortality due to cerebral Nocardia abscesses remains unacceptably high. The case of a typical immunocompromised patient, who deteriorated clinically despite optimal antimicrobial treatment, is reported here. Adjuvant immunotherapy with interferon-gamma resulted in partial restoration of the immune response and a corresponding clinical and radiographic recovery

Toll-like receptor 2 induced cytotoxic T-lymphocyte-associated protein 4 regulates Aspergillus-induced regulatory T-cells with pro-inflammatory characteristics

Contains fulltext : 177488.pdf (publisher's version ) (Open Access)Patients with cystic fibrosis, chronic obstructive pulmonary disease, severe asthma, pre-existing pulmonary lesions, and severely immunocompromised patients are susceptible to develop infections with the opportunistic pathogenic fungus Aspergillus fumigatus, called aspergillosis. Infections in these patients are associated with persistent pro-inflammatory T-helper (TH)2 and TH17 responses. Regulatory T-cells, natural suppressor cells of the immune system, control pro-inflammatory T-cell responses, but can also contribute to disease by shifting to a pro-inflammatory TH17-like phenotype. Such a shift could play an important role in the detrimental immunopathology that is seen in aspergillosis. Our study demonstrates that Aspergillus fumigatus induces regulatory T-cells with a TH17-like phenotype. We also demonstrate that these regulatory T-cells with a pro-inflammatory TH17-like phenotype can be reprogrammed to their "classical" anti-inflammatory phenotype by activating Toll-like receptor 2 (TLR2), which regulates the induction of cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Similarly, soluble CTLA4 could reverse the pro-inflammatory phenotype of Aspergillus-induced regulatory T-cells. In conclusion, our results suggest a role for regulatory T-cells with a pro-inflammatory TH17-like phenotype in Aspergillus-associated immunopathology, and identifies key players, i.e. TLR2 and CTLA4, involved in this mechanism

Protective host defense against disseminated candidiasis is impaired in mice expressing human interleukin-37

Contains fulltext : 153756.pdf (publisher's version ) (Open Access)The effect of the anti-inflammatory cytokine interleukin-37 (IL-37) on host defense against Candida infections remains unknown. We assessed the role of IL-37 in a murine model of disseminated candidiasis using mice transgenic for human IL-37 (hIL-37Tg). Upon exposure to Candida albicans pseudohyphae, macrophages from hIL-37Tg mice release 39% less TNFalpha compared to cells from wild-type (WT) mice (p = 0.01). In vivo, hIL-37Tg mice displayed a decreased capacity to recruit neutrophils to the site of infection. These defects were associated with increased mortality and organ fungal growth in hIL-37Tg compared to WT mice. We conclude that IL-37 interferes with the innate protective anti-Candida host response by reducing the production of proinflammatory cytokines and suppressing neutrophil recruitment in response to Candida, resulting in an increased susceptibility to disseminated candidiasis

Aspergillus fumigatus morphology and dynamic host interactions

Item does not contain fulltextAspergillus fumigatus is an environmental filamentous fungus that can cause life-threatening disease in immunocompromised individuals. The interactions between A. fumigatus and the host environment are dynamic and complex. The host immune system needs to recognize the distinct morphological forms of A. fumigatus to control fungal growth and prevent tissue invasion, whereas the fungus requires nutrients and needs to adapt to the hostile environment by escaping immune recognition and counteracting host responses. Understanding these highly dynamic interactions is necessary to fully understand the pathogenesis of aspergillosis and to facilitate the design of new therapeutics to overcome the morbidity and mortality caused by A. fumigatus. In this Review, we describe how A. fumigatus adapts to environmental change, the mechanisms of host defence, and our current knowledge of the interplay between the host immune response and the fungus