No metagenomic evidence of tumorigenic viruses in cancers from a selected cohort of immunosuppressed subjects.

The possible existence of yet undiscovered human tumorigenic viruses is still under scrutiny. The development of large-scale sequencing technologies, coupled with bioinformatics techniques for the characterization of metagenomic sequences, have provided an invaluable tool for the detection of unknown, infectious, tumorigenic agents, as demonstrated by several recent studies. However, discoveries of novel viruses possibly associated with tumorigenesis are scarce at best.

IL-37 inhibits inflammasome activation and disease severity in murine aspergillosis.

Since IL-37 transgenic mice possesses broad anti-inflammatory properties, we assessed whether recombinant IL-37 affects inflammation in a murine model of invasive pulmonary aspergillosis. Recombinant human IL-37 was injected intraperitoneally into mice prior to infection and the effects on lung inflammation and inflammasome activation were evaluated. IL-37 markedly reduced NLRP3-dependent neutrophil recruitment and steady state mRNA levels of IL-1β production and mitigated lung inflammation and damage in a relevant clinical model, namely aspergillosis in mice with cystic fibrosis.

IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans.

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.

Hypoxia promotes danger-mediated inflammation via receptor for advanced glycation end products in cystic fibrosis.

Rationale: Hypoxia regulates the inflammatory-antiinflammatory balance by the receptor for advanced glycation end products (RAGE), a versatile sensor of damage-associated molecular patterns. The multiligand nature of RAGE places this receptor in the midst of chronic inflammatory diseases.

Objectives: To characterize the impact of the hypoxia-RAGE pathway on pathogenic airway inflammation preventing effective pathogen clearance in cystic fibrosis (CF) and elucidate the potential role of this danger signal in pathogenesis and therapy of lung inflammation.

Th17/Treg imbalance in murine cystic fibrosis is linked to indoleamine 2,3-dioxygenase deficiency but corrected by kynurenines.

Rationale: Mutations in the cystic fibrosis (CF) transmembrane conductance regulator affect the innate epithelial immune function of the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pathogenic fungi. The appreciation of whether such fungi are primarily responsible for or a consequence of ineffective airway inflammation is important for future therapeutics development.

Objectives: To characterize the impact of the tryptophan/kynurenine pathway on pathogenic airway inflammation preventing effective fungal clearance in CF.

Jack of all trades: thymosin α1 and its pleiotropy.

Thymosin α1 (Tα1), a thymosin-related 28-mer synthetic amino-terminal acetylated peptide, has gained increasing interest in recent years, due to its pleiotropy. The peptide has been used worldwide as an adjuvant or immunotherapeutic agent to treat disparate human diseases, including viral infections, immunodeficiencies, and malignancies. The peptide can enhance T cell, dendritic cell (DC), and antibody responses, modulate cytokine and chemokine production, and block steroid-induced apoptosis of thymocytes.

Role of innate immune receptors in paradoxical caspofungin activity in vivo in preclinical aspergillosis.

This study investigated the possible mechanisms underlying the paradoxical caspofungin activity in vivo in preclinical aspergillosis. We evaluated the activity of escalating doses of caspofungin in vivo in different preclinical models of invasive aspergillosis, including mice deficient for selected innate immune receptors. The therapeutic efficacy of caspofungin in experimental invasive aspergillosis was strictly dose dependent, being observed at doses of 0.

Host defense pathways against fungi: the basis for vaccines and immunotherapy.

Fungal vaccines have long been a goal in the fields of immunology and microbiology to counter the high mortality and morbidity rates owing to fungal diseases, particularly in immunocompromised patients. However, the design of effective vaccination formulations for durable protection to the different fungi has lagged behind due to the important differences among fungi and their biology and our limited understanding of the complex host-pathogen interactions and immune responses. Overcoming these challenges is expected to contribute to improved vaccination strategies aimed at personalized efficacy across distinct target patient populations.

Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis.

The recognition of β-glucans by dectin-1 has been shown to mediate cell activation, cytokine production and a variety of antifungal responses. Here, we report that the functional activity of dectin-1 in mucosal immunity to Candida albicans is influenced by the genetic background of the host. Dectin-1 was required for the proper control of gastrointestinal and vaginal candidiasis in C57BL/6, but not BALB/c mice; in fact, the latter showed increased resistance in the absence of dectin-1.

CD4(+) T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease.

Aspergillus fumigatus is a model fungal pathogen and a common cause of infection in individuals with the primary immunodeficiency chronic granulomatous disease (CGD). Although primarily considered a deficiency of innate immunity, CGD is also linked to dysfunctional T cell reactivity. Both CD4(+) and CD8(+) T cells mediate vaccine-induced protection from experimental aspergillosis, but the molecular mechanisms leading to the generation of protective immunity and whether these mechanisms are dysregulated in individuals with CGD have not been determined.

Immunogenetic profiling to predict risk of invasive fungal diseases: where are we now?

Invasive fungal diseases remain nowadays life-threatening conditions affecting multiple clinical settings. The onset of these diseases is dependent on numerous factors, of which the "immunocompromised" phenotype of the patients is the more often acknowledged. However, and despite comparable immune dysfunction, not all patients are ultimately susceptible to disease, suggesting that additional risk factors, likely of genetic nature, may also be important.

Pyrimethamine induces apoptosis of melanoma cells via a caspase and cathepsin double-edged mechanism.

The unresponsiveness of metastatic melanoma to conventional chemotherapeutic and biological agents is largely due to the development of resistance to apoptosis. Pyrimethamine belongs to the group of antifolate drugs, and in addition to antiprotozoan effects, it exerts a strong proapoptotic activity, which we recently characterized in human T lymphocytes. However, no data regarding pyrimethamine anticancer activity are available thus far.