Virulence Genes In A Street Smart Mold Biology Essay

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David Askew's paper describes the importance of genes in Aspergillus fumigatus for virulence. Disruption in function can hinder or help virulence. Askew discusses the different gene products and how they affect virulence if knocked out. He also addresses which gene products have redundancy in the genome. Knowing this information is important for better understanding all virulence factors and potential targets for treatment.

The species A. fumigatus usually lives in compost with a diverse environment of predators, competition, and temperature variation (Askew, 1). When the species' spores are inhaled by a host, conida enter the lungs (Askew, 1). Here, conida are usually terminated by host immune response (Askew, 1). However, in the immunocompromised, A. fumigatus starts germination and hyphae develop (Askew, 1). Hyphae can travel to distal sites if enough damage is done to the epithelial layer of the lung (Askew, 1).

The first contribution to A. fumigatus virulence is its thermotolerance (Askew, 2). There are three known genes for thermotolerance in this species: "the ribosome biogenesis protein CgrA , the O-mannosyltransferase Pmt1 and a protein of unknown function, thtA" (Askew, 2). CgrA impairs thermotolerance at 37゚C (Askew, 2). This makes CgrA an optional target for medicine because it would hinder A. fumigatus growth in the host environment (Askew, 2).

The cell wall is dire to the integrity of the organism. A. fumigatus has redundancy in its genome for many of its cell wall components as insurance to its livelihood (Askew, 2). One is α-(1,3) glucan. There are three known genes associated with α-(1,3) glucan: ags1, ags2, and ags3 (Askew, 2). However, only deletion of ags1 causes a reduction in cell wall α-(1,3) glucan (Askew, 2). Deletion of ags3 increased virulence of the fungi (Askew, 2). Chitin, another important part of A. fumigatus' cell wall, is connected with seven genes (Askew, 2). This high number of genes infers redundancy. Another, glycophophatidyl-inositol (GPI)-linked proteins, is disrupted best by a "catalytic subunit of an enzyme involved in GPI anchor biosynthesis" named Afpig-a (Askew, 3). Disruption of the Afpig-a gene hinders cell wall integrity and virulence (Askew, 3). The pigment melanin is also a part of A. fumigatus' cell wall. Melanin mutants showed less virulence and higher susceptibility to phagocytosis (Askew, 3). Cell wall components have gene redundancy but would still likely be a good target for medicine because most of these components are unique to fungi. They are not present in eukaryotic cell wall structure. However, "overlapping pathways" can deter cell wall components as a medicine target because the cwll has back up and therefore can still thrive (Askew, 3).

A. fumigatus expels many different secondary metabolites into its environment (Askew, 3). Gliotoxin is one of them but has not been shown to effect virulence (Askew, 3). It is likely that neutrophils are the target of gliotoxin (Askew, 3). Also, A. fumigatus has defenses against damage by oxidation (Askew, 3). Anti-oxidant features of A. fumigatus include catalases, PKA subunit PkaR, MAPK pathway, and transcription factors yap1 and skn7 (Askew, 3). Disruption in most of these features did not weaken virulence (Askew, 3). Therefore, anti-oxidant responses of A. fumigatus are not dire to its pathogenesis (Askew, 3).

Signal transduction pathways are essential to the response to changes in the environment. For A. fumigatus, imbalance in this system is harmful to its virulence (Askew, 3). This is probably because it diminishes the efficiency of sensing and responding (Askew, 3). Another important part of signaling is Calcineurin, which is "a Ca2+-calmodulin-activated protein phosphatase" (Askew, 3). Calcineurin helps with calcium signaling of A. fumigatus (Askew, 3). Deletion of cnaA calcineurin subunit made A. fumigatus avirulent (Askew, 3). This is because the mutant hindered hyphae growth, an important feature of fungus pathogenesis (Askew, 4).

Acquiring nutrition in different, changing environments makes it important for storage of compounds that are not consistently available. Iron is obtained and stored by siderophores in A. fumigatus (Askew, 4). Disruption in siderophore function severely effects viability of A. fumigatus, highlighting their importance (Askew, 4). Nutritional acquisition is done by secreting more than 99 proteases by A. fumigatus (Askew, 4). These secreted proteases destruct the host tissue and allow the fungus to consume amino acids (Askew, 4). Amino acid consumption is analogous with toxic propionyl-CoA (Askew, 4). Accumulation of propionyl-CoA is controlled by methylcitrate synthase (Askew, 5). Disruption in the function of methylcitrate synthase hampers virulence (Askew, 5).

Askew did well in outlining the different gene products that affected virulence. I liked how he also contributed gene products that have been thought to contribute to virulence, but in experiments do not show any association to pathogenecity. However, it was controversial that he second-guessed his experiment technique of measuring virulence by growth rate in vitro (Askew, 4). Also, using knock out genes to study what the gene product is has drawbacks. With this method, it is unclear whether more than one gene was changed to develop a phenotype, and therefore results can be misleading (Latge, 320).

Humans inhale a couple hundred conida from the species A. fumigatus per day and this opportunistic pathogen is now the most common "airborne fungal infection" with high mortality rates in the immunocompromised (Latge, 311). Latge suggests A. fumigatus is the primary fungal pathogen "because it resists host defenses and survives in vivo longer than other airborne saprophytes" (Latge, 326). Therefore, it would be important to do further research on why this species can last longer and defend itself. Understanding these features is necessary to understanding A. fumigatus' increased pathogenecity in comparison to other airborne saprophytes.

In conclusion, there are several different gene products that directly and indirectly affect the virulence of A. fumigatus (Askew, 5). Some gene products that affect virulence have redundancy in the genome and therefore would not be the best candidate for medicine targets, such as cell wall genes (Askew, 2). Other characteristics directly affect pathogenesis and are unique to the fungal family (Askew, 3). One example is the CgrA gene (Askew, 3). The fungal gene products outlined in Askew's article contribute to A. fumigatus' adaptability to different environments and virulence within the changing host environment.

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