Fungal pathogenesis: Past,present and future

Over the last 20 years a record number of fungal and fungal-like diseases have jeopardized wild species the world over, causing several of the most severe population declines and extinctions ever witnessed (Fisher et al. 2012). Such events include the devastating impact of Batrachochytrium dendrobatidis on amphibian populations and the extinction of bat populations as a result of Geomyces destructans infection. This commentary focusses on two human-infecting fungal pathogens causing much scientific interest, that is, Cryptococcus gattii and Trichophyton rubrum. It summarises recent research findings into their pathogenic evolution and adaptive strategies and highlights key gaps in our knowledge. Finally, the prose attempts to fuse such data with the work of Casadevall, exploiting his theories to predict the future of fungal pathogenesis, that is, where pathogenesis refers to the mechanism that results in disease (Casadevall 2012).     

Fungal entomopathogens: new insights on their ecology

An important mechanism for insect pest control should be the use of fungal entomopathogens. Even though these organisms have been studied for more than 100 y, their effective use in the field remains elusive. Recently, however, it has been discovered that many of these entomopathogenic fungi play additional roles in nature. They are endophytes, antagonists of plant pathogens, associates with the rhizosphere, and possibly even plant growth promoting agents. These findings indicate that the ecological role of these fungi in the environment is not fully understood and limits our ability to employ them successfully for pest management. In this paper, we review the recently discovered roles played by many entomopathogenic fungi and propose new research strategies focused on alternate uses for these fungi. It seems likely that these agents can be used in multiple roles in protecting plants from pests and diseases and at the same time promoting plant growth.     

Snake venom proteins in hemostasis: new results

Biological features of venomous snakes as well as biochemical properties and actions of their venoms which serve for prey acquisition, indicate the vertebrates' haemostasis system as a vulnerable target for snake venom actions. Components exerting a specific, either stimulating or inactivating effect on basal membrane or endothelial cells of the vascular wall, on platelets, on almost every step of plasma coagulation or fibrinolysis respectively, have been isolated and purified from snake venoms. Snake venom proteins acting with a defined specificity on cellular or plasmatic components of the human haemostatic system are being used in coagulation and aggregation tests, in photometric assays in conjunction with chromogenic substrates as well as in immunological systems as biochemical tools for research and diagnostic purposes.     

Fungal pathogenesis: gene clusters unveiled as secrets within the Ustilago maydis code

The genome sequence of a second plant pathogenic fungus is now available, revealing unique gene clusters encoding secretory proteins that are induced during infection and regulate pathogenesis. Gene clusters play important roles in pathogenic fungi, yet their evolution and maintenance remain a mystery.     

Snake venom metalloproteinases: their role in the pathogenesis of local tissue damage

The biochemical characteristics of hemorrhagic metalloproteinases isolated from snake venoms are reviewed, together with their role in the pathogenesis of the local tissue damage characteristic of crotaline and viperine snake envenomations. Venom metalloproteinases differ in their domain structure. Some enzymes comprise only the metalloproteinase domain, others have disintegrin-like and high cysteine domains and others present, besides these domains, an additional lectin-like subunit. All of them are zinc-dependent enzymes with highly similar zinc binding environments. Some metalloproteinases induce hemorrhage by directly affecting mostly capillary blood vessels. It is suggested that hemorrhagic enzymes cleave, in a highly selective fashion, key peptide bonds of basement membrane components, thereby affecting the interaction between basement membrane and endothelial cells. As a consequence, these cells undergo a series of morphological and functional alterations in vivo, probably associated with biophysical hemodynamic factors such as tangential fluid shear stress. Eventually, gaps are formed in endothelial cells through which extravasation occurs. In addition to hemorrhage, venom metalloproteinases induce skeletal muscle damage, myonecrosis, which seems to be secondary to the ischemia that ensues in muscle tissue as a consequence of bleeding and reduced perfusion. Microvessel disruption by metalloproteinases also impairs skeletal muscle regeneration, being therefore responsible of fibrosis and permanent tissue loss after snakebites. Moreover, venom metalloproteinases participate in the degradation of extracellular matrix components and play a relevant role in the prominent local inflammatory response that characterizes snakebite envenomations, since they induce edema, activate endogenous matrix metalloproteinases (MMPs) and are capable of releasing TNF-alpha from its membrane-bound precursor. Owing to their protagonic role in the pathogenesis of local tissue damage, snake venom metalloproteinases constitute relevant targets for natural and synthetic inhibitors which may complement antivenoms in the neutralization of these effects.     

Fungal epoxide hydrolases: new landmarks in sequence-activity space

Epoxide hydrolases are useful catalysts for the hydrolytic kinetic resolution of epoxides, which are sought after intermediates for the synthesis of enantiopure fine chemicals. The epoxide hydrolases from Aspergillus niger and from the basidiomycetous yeasts Rhodotorula glutinis and Rhodosporidium toruloides have demonstrated potential as versatile, user friendly biocatalysts for organic synthesis. A recombinant A. niger epoxide hydrolase, produced by an overproducing A. niger strain, is already commercially available and recombinant yeast epoxide hydrolases expressed in Escherichia coli have shown excellent results. Within the vast body of activity information on the one hand and gene sequence information on the other hand, the epoxide hydrolases from the Rhodotorula spp. and A. niger stand out because we have sequence information as well as activity information for both the wild-type and recombinant forms of these enzymes.     

Fungal resistance to plant antibiotics as a mechanism of pathogenesis.

Many plants produce low-molecular-weight compounds which inhibit the growth of phytopathogenic fungi in vitro. These compounds may be preformed inhibitors that are present constitutively in healthy plants (also known as phytoanticipins), or they may be synthesized in response to pathogen attack (phytoalexins). Successful pathogens must be able to circumvent or overcome these antifungal defenses, and this review focuses on the significance of fungal resistance to plant antibiotics as a mechanism of pathogenesis. There is increasing evidence that resistance of fungal pathogens to plant antibiotics can be important for pathogenicity, at least for some fungus-plant interactions. This evidence has emerged largely from studies of fungal degradative enzymes and also from experiments in which plants with altered levels of antifungal secondary metabolites were generated. Whereas the emphasis to date has been on degradative mechanisms of resistance of phytopathogenic fungi to antifungal secondary metabolites, in the future we are likely to see a rapid expansion in our knowledge of alternative mechanisms of resistance. These may include membrane efflux systems of the kind associated with multidrug resistance and innate resistance due to insensitivity of the target site. The manipulation of plant biosynthetic pathways to give altered antibiotic profiles will also be valuable in telling us more about the significance of antifungal secondary metabolites for plant defense and clearly has great potential for enhancing disease resistance for commercial purposes.     

A new insight into the pathogenesis of filarial disease

Filariasis is a major public health problem throughout many regions of the tropics. The disease is caused by several species of filarial nematode including Wuchereria bancrofti and Brugia malayi, the agents of lymphatic filariasis, and Onchocerca volvulus, the cause of 'riverblindness'. Disease caused by these worms varies depending on the tissue location of the parasite, and is associated with episodes of acute and chronic inflammation. These pathologies, including elephantiasis and blindness, rank among the most disabling in the world. Studies aimed at characterizing the molecular nature of the inflammatory stimuli derived from filarial nematodes uncovered a long forgotten secret, their symbiont Wolbachia. LPS-like molecules from these intracellular bacteria are responsible for potent inflammatory responses from macrophages and in animal models of filarial disease. Wolbachia has also been associated with severe inflammatory reactions to filarial chemotherapy, being released into the blood following the death of the parasite. Recent studies in animal models even implicate Wolbachia in the onset of lymphodema and blindness. Taken together these studies suggest a major role for Wolbachia in the pathogenesis of filarial disease. It may be possible, through the use of antibiotic therapy, to clear worms of their bacteria, in the hope that this will prevent the onset and development of filarial pathology.     

Autoimmune heart failure: new understandings of pathogenesis

Besides genetic susceptibility and infections with cardiotropic viruses, autoimmune responses against heart tissue play a major role in the pathogenesis of dilated cardiomyopathy, the most common cause of heart failure in young patients. Recent findings suggest that the combination of tissue damage resulting in release of self-antigens, together with non-specific activation of the innate immune system triggers various responses that are crucial for the development of heart-specific autoimmunity. Understanding these mechanisms is critical for the design and development of novel treatment strategies against devastating heart diseases in the future.     

Microbial pathogenesis: new niches for salmonella.

Salmonella occupies a vacuolar compartment inside cells of its host. Recent studies have shown that the fate of this vacuole is different in various cell types, and that the outcome of colonization is determined by both the infecting bacterium and defense mechanisms of the host cell.     

Snake venom phosphodiesterase: A zinc metalloenzyme

Snake venom phosphodiesterase fromCrotalus adamanteus can be purified by blue sepharose chromatography followed by gel exclusion chromatography on Sephadex G-100. The enzyme is judged to be homogeneous by SDS gel electrophoresis. Atomic absorption spectrometry indicates a stoichiometry of 1.07 g-atom of zinc per mole of purified enzyme. The enzyme is inhibited by a wide variety of structurally different metal binding agents, e.g., 1,10-phenanthroline, thioglycolic acid,l-cysteine, 8-hydroxy-5-quinoline sulfonic acid, EDTA, and dipicolinic acid. The results of both the chelator inhibition and the atomic absorption analysis indicate that snake venom phosphodiesterase is a zinc metalloenzyme. Snake venom phosphodiesterase shares a number of mechanistic features in common with the nucleotidyl transferases. All of these enzymes contain zinc, are activated by magnesium, and catalyze α-β phosphoryl bond cleavage. Mechanistic studies of phosphodiesterase may therefore be helpful in understanding the mechanism of the hydrolytic step catalyzed by all of these enzymes.