Pulmonary histoplasmosis: A case report

Histoplasmosis is a systemic fungal infection caused by dimorphic fungus Histoplasma capsulatum. It is widely distributed throughout the world. In present study, the case of a 50-year-old male patient diagnosed as pulmonary histoplasmosis. Initially, the patient was suspected as a case of alcoholic hepatitis but subsequently the diagnosis of pulmonary histoplasmosis was confirmed by lung biopsy. The symptoms were dissuaded following amphotericin B and itraconazole treatment.

Disseminated coccidioidomycosis in a patient who is immunocompromised in the setting of immune reconstitution inflammatory syndrome

Coccidioidomycosis is a systemic fungal infection first described in 1892. More than 95% of annual cases occur in Arizona and California. It is an opportunistic infection (OI) transmitted via inhalation of airborne spores (arthroconidia) and rarely via percutaneous inoculation into a tissue or solid organ transplantation in patients who are immunocompromised and with HIV. With the advent of antiretroviral therapy (ART), the incidence of OIs has markedly reduced; however, OIs continue to occur, particularly in patients who present late for medical care or delay ART initiation. In rare cases, immunodeficient individuals may experience a paradoxical worsening or unmasking of OI symptoms, known as the immune reconstitution inflammatory syndrome (IRIS). We present a case of a 31-year-old man with disseminated coccidioidomycosis affecting the spleen, lymph nodes, lungs, bone marrow, and adrenals who developed IRIS after the initiation of ART.

Interaction between Phagocytic Cells with Antiphagocytic Properties of Cryptococcus neoformans: When Love and Hate Collide

Global systemic fungal infection, including meningeal cryptococcosis caused by the encapsulated yeast Cryptococcus spp, continue to rise in number, especially among HIV infected individuals. Infection occur through inhalation of spore which is abundant in the environment. Initially this fungus stay in the lungs for a certain time without causing any symptoms and when the host’s cellular immune status is depleted, it can uses monocyte as a vehicle to take them to the brain, using a mechanism called Trojan Horse mechanism. Normal alveolar macrophage as the first line of innate immune system in the lungs are supposed to phagocytose, internalized and then destroy it inside an organelle named phagolysosome. But Cryptococcus spp seemed to have a built in antiphagocytic mechanism to avoid destruction and even can multiply therein. The interaction between this clever yeast and the host’s phagocytic cells determine the course of the disease.

Aberrant type 1 immunity drives susceptibility to mucosal fungal infections

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)– and signal transducer and activator of transcription 1 (STAT1)–dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)–STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell–dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.

Amphotericin B, the Wonder of Today’s Pharmacology Science: Persisting Usage for More Than Seven Decades

Background: Despite several available topical and systemic antifungal drugs for the treatment of fungal infections, Amphotericin B (AmB) is still one of the most common first-line choices in treating systemic fungal infection for more than seven decades after its discovery. Objectives: Amphotericin B which belongs to the polyene group has a wide spectrum of in vitro and in vivo antifungal activity. Its mechanism of antifungal action is characterized by creating a pore in the fungal plasma membrane leading to cell death. Methods: In addition to the old formula of deoxycholate-Amphotericin B (D-AmB), three lipid formulas have been developed to reduce the adverse effects of conventional AmB (D-AmB) in the human body and increase its therapeutic efficacy. All of the known available formulas of AmB are administrated via intravenous injection to treat severe systemic fungal infections, while the development of the topical formula of AmB is still under preliminary research. Numerous pharmaceutical formulas of systemic and topical applications with clinical uses of AmB in just humans, not in vitro or animals model, against various fungal infections are discussed in this review. Topical AmB formulas are a promising way to develop effective management and to reduce the adverse effects of intravenous formulas of AmB without laboratory monitoring. Results: The wonderful pharmacological properties of AmB with its prolonged use for about seven decades may help researchers to apply its unique features on other various antimicrobial agents by more understanding about the AmB mechanisms of actions. Conclusion: Amphotericin B is widely used intravenously for the treatment of systemic fungal infection, while the topical formula of AmB is still under experimental study.

Molecular mechanisms of LC3-associated phagocytosis in the macrophage response to Paracoccidioides spp

Paracoccidiomycosis is a systemic fungal infection that is endemic in Latin America. The etiologic agents are thermodimorphic fungi from the Paracoccidiodes genus, which are facultative intracellular parasites of macrophages. LC3-associated phagocytosis (LAP), a noncanonical form of autophagy, is important in the immune response to similar pathogens, so we sought to determine the role LAP plays in the macrophage response to Paracoccidioides spp. By immunofluorescence, we found that LC3 was recruited to phagosomes containing Paracoccidioides spp. in both RAW264.7 and J774.16 cell lines and in bone marrow-derived macrophages. Interference with autophagy using RNAi against ATG5 reduced the antifungal activity of J774.16 cells, showing that LC3 recrutiment is important for proper control of the fungus by macrophages. Finally, we used pharmacological Syk kinase and NAPH oxidase inhibitors, which inhibit signalling pathways necessary for macrophage LAP against Aspergillus fumigatus and Candida albicans, to dissect part of the signaling pathways that trigger LAP agains Paracoccidioides spp. Interestingly, these inhibitors did not decrease LAP against P. brasiliensis, possibly due to differences in the fungal cell surface compositions. These observations suggest a potential role for autophagy as target for host-directed paracoccidioidomycosis therapies.

Candidalysin: From Mechanism of Action to Biomarker Development and Therapeutic Response

ABSTRACT The incidence of systemic fungal infection is increasing, and millions of people around the world suffer from fungal infections. Candida albicans is one of the most frequently isolated fungal pathogens in clinical settings. As a polymorphic organism, the transition between yeast and hyphae is critical for C. albicans virulence and pathogenesis. However, the mechanism of hyphae-associated virulence remains unclear. Candidalysin is the first human fungal cytolytic peptide toxin originating from the hyphae-specific gene, ECE1. This review will summarize the most recent progress underlying candidalysin-mediated epithelial damage and host defense pathways, which might shed new light on the development of a novel antifungal strategy and early diagnostic biomarker.

Disseminated histoplasmosis and tuberculosis: dual infection in a non-endemic region

Histoplasmosis is a systemic fungal infection caused by Histoplasma capsulatum, a dimorphic fungus that spreads commonly by contamination of soil with bird and bat droppings. The infection remains latent in most patients until manifested by reduced immune status, for example, HIV/AIDS, corticosteroid/immunosuppressive therapy or in solid organ transplant recipients. Tuberculosis and histoplasmosis may cooccur rarely in HIV and the clinical resemblance of both diseases may hinder identification of patients’ harbouring dual infection, especially in regions non-endemic for histoplasmosis. We report a case of disseminated histoplasmosis with disseminated tuberculosis in an incidentally detected patient with HIV-positive who presented with reports of fever and skin rash for 10 days. The Mantoux positivity and CT of chest and abdomen revealing multiple necrotic lymph nodes coupled with bone marrow and skin biopsy divulging histoplasmosis and tuberculosis helped us clinch the concurrent infection.

Restoring glucose uptake rescues neutrophil dysfunction and protects against systemic fungal infection in mouse models of kidney disease

Disseminated candidiasis caused by the fungus Candida albicans is a major clinical problem in individuals with kidney disease and accompanying uremia; disseminated candidiasis fatality is twice as common in patients with uremia as those with normal kidney function. Many antifungal drugs are nephrotoxic, making treatment of these patients particularly challenging. The underlying basis for this impaired capacity to control infections in uremic individuals is poorly understood. Here, we show in multiple models that uremic mice exhibit an increased susceptibility to systemic fungal infection. Uremia inhibits Glut1-mediated uptake of glucose in neutrophils by causing aberrant activation of GSK3β, resulting in reduced ROS generation and hence impaired killing of C. albicans in mice. Consequently, pharmacological inhibition of GSK3β restored glucose uptake and rescued ROS production and candidacidal function of neutrophils in uremic mice. Similarly, neutrophils isolated from patients with kidney disease and undergoing hemodialysis showed similar defect in the fungal killing activity, a phenotype rescued in the presence of a GSK3β inhibitor. These findings reveal a mechanism of neutrophil dysfunction during uremia and suggest a potentially translatable therapeutic avenue for treatment of disseminated candidiasis.