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Animal models are frequently used as surrogates to understand human disease. In the fungal pathogen Cryptococcus species complex, several variations of a mouse model of disease were developed that recapitulate different aspects of human disease. These mouse models have been implemented using various inbred and outbred mouse backgrounds, many of which have genetic differences that can influence host response and disease outcome. In this review, we will discuss the most commonly used inbred mouse backgrounds in C. neoformans infection models. [ABSTRACT FROM AUTHOR]

ABSTRACT AFP is an antimicrobial peptide (AMP) produced by the filamentous fungus Aspergillus giganteus and is a very potent inhibitor of fungal growth that does not affect the viability of bacteria, plant, or mammalian cells. It targets chitin synthesis and causes plasma membrane permeabilization in many human- and plant-pathogenic fungi, but its exact mode of action is not known. After adoption of the “damage-response framework of microbial pathogenesis” regarding the analysis of interactions between AMPs and microorganisms, we have recently proposed that the cytotoxic capacity of a given AMP depends not only on the presence/absence of its target(s) in the host and the AMP concentration applied but also on other variables, such as microbial survival strategies. We show here using the examples of three filamentous fungi (Aspergillus niger, Aspergillus fumigatus, and Fusarium graminearum) and two yeasts (Saccharomyces cerevisiae and Pichia pastoris) that the important parameters defining the AFP susceptibilities of these fungi are (i) the presence/absence of glycosylceramides, (ii) the presence/absence of Δ3(E) desaturation of the fatty acid chain therein, and (iii) the (dis)ability of these fungi to respond to AFP inhibitory effects with the fortification of their cell walls via increased chitin and β-(1,3)-glucan synthesis. These observations support the idea of the adoption of the damage-response framework to holistically understand the outcome of AFP inhibitory effects. IMPORTANCE Our data suggest a fundamental role of glycosylceramides in the susceptibility of fungi to AFP. We discovered that only a minor structural difference in these molecules—namely, the saturation level of their fatty acid chain, controlled by a 2-hydroxy fatty N-acyl-Δ3(E)-desaturase—represents a key to understanding the inhibitory activity of AFP. As glycosylceramides are important components of fungal plasma membranes, we propose a model which links AFP-mediated inhibition of chitin synthesis in fungi with its potential to disturb plasma membrane integrity.

The virulence factor concept has been a powerful engine in driving research and the intellectual flow in the fields of microbial pathogenesis and infectious diseases. This review analyzes virulence factors from the viewpoint of the damage--response framework of microbial pathogenesis, which defines virulence factor as microbial components that can damage a susceptible host. At a practical level, the finding that effective immune responses often target virulence factors provides a roadmap for future vaccine design. However, there are significant limitations to this concept, which are rooted in the inability to define virulence and virulence factors in the absence of host factors and the host response. In fact, this concept appears to work best for certain types of bacterial pathogens, being less well suited for viruses and commensal organisms with pathogenic potential. [ABSTRACT FROM AUTHOR]

AFP is an antimicrobial peptide (AMP) produced by the filamentous fungus Aspergillus giganteus and is a very potent inhibitor of fungal growth that does not affect the viability of bacteria, plant, or mammalian cells. It targets chitin synthesis and causes plasma membrane permeabilization in many human- and plant-pathogenic fungi, but its exact mode of action is not known. After adoption of the "damage-response framework of microbial pathogenesis" regarding the analysis of interactions between AMPs and microorganisms, we have recently proposed that the cytotoxic capacity of a given AMP depends not only on the presence/absence of its target(s) in the host and the AMP concentration applied but also on other variables, such as microbial survival strategies. We show here using the examples of three filamentous fungi ( Aspergillus niger , Aspergillus fumigatus , and Fusarium graminearum ) and two yeasts ( Saccharomyces cerevisiae and Pichia pastoris ) that the important parameters defining the AFP susceptibilities of these fungi are (i) the presence/absence of glycosylceramides, (ii) the presence/absence of Δ3( E ) desaturation of the fatty acid chain therein, and (iii) the (dis)ability of these fungi to respond to AFP inhibitory effects with the fortification of their cell walls via increased chitin and β-(1,3)-glucan synthesis. These observations support the idea of the adoption of the damage-response framework to holistically understand the outcome of AFP inhibitory effects. IMPORTANCE Our data suggest a fundamental role of glycosylceramides in the susceptibility of fungi to AFP. We discovered that only a minor structural difference in these molecules-namely, the saturation level of their fatty acid chain, controlled by a 2-hydroxy fatty N-acyl-Δ3( E )-desaturase-represents a key to understanding the inhibitory activity of AFP. As glycosylceramides are important components of fungal plasma membranes, we propose a model which links AFP-mediated inhibition of chitin synthesis in fungi with its potential to disturb plasma membrane integrity., (Copyright © 2019 Paege et al.)

The Damage-Response Framework (DRF) is a powerful tool to inform research in infectious diseases. It can integrate clinical observation with microbiology and immunology to incorporate the role of the host response into the outcome of microbial pathogenesis. Although the role that microbial factors may play in the pathogenesis of infectious diseases is well recognized, the DRF brings the indispensable role of the host response to the fore. For example, inflammation may induce microbial control, but it can also produce host damage. On the other hand, insufficient inflammation may fail to induce sufficient microbial control. Each scenario may lead to the diagnosis of an infectious disease. Given the central role that the host response plays in the pathogenesis of infectious diseases, new strategies for treatment need to consider the nature of the host response as well as microbial factors. [ABSTRACT FROM AUTHOR]

Abstract: Outcomes of fungal infections in immunocompromised individuals depend on a complex interplay between host and pathogen factors, as well as treatment modalities. Problems occur when host responses to an infection are either too weak to effectively help eradicate the pathogen, or when they become too strong and are associated with host damage rather than protection. Immune reconstitution syndrome (IRS) can be generally defined as a restoration of host immunity in a previously immunosuppressed patient that becomes dysregulated and overly robust, resulting in host damage and sometimes death. IRS associated with opportunistic mycoses presents as new or worsening clinical symptoms or radiographic signs consistent with an inflammatory process that occur during receipt of an appropriate antifungal, and that cannot be explained by a newly acquired infection. Because there are currently no established tests or biomarkers for IRS, it can be difficult to distinguish from progression of the original infection, although culture and biomarkers for the fungal pathogen or infection are typically negative during diagnostic workup. IRS was originally characterized in human immunodeficiency virus-infected patients receiving antiretroviral therapy, but has subsequently been described in solid-organ transplant recipients, neutropenic patients, women in the postpartum period, and recipients of tumor necrosis factor–α inhibitor therapy. In each of these cases, recovery of the host''s immunity during treatment of an initial infection results in a powerful proinflammatory environment that overshoots and leads to host damage. Optimal management of IRS has not been established at present, but often involves treatment with a corticosteroid or other anti-inflammatory compounds. This article uses a number of patient cases to explore the intricacies of diagnosing and managing a patient with IRS, as well as the other extreme, namely patients who are so immunocompromised without immune recovery that they essentially become breeding grounds for a wide range of opportunistic pathogens, often simultaneously. [Copyright &y& Elsevier]