Aspergillus fumigatus are a growing medical problem primarily because they contribute to the death of immunocompromised human patients (Slonczewski 259) . Among the features which help promotes its pathogenicity are small spore size, thermotolerance and an innate resistance to various killing mechanism of the host, accomplished by both its surface composition and secreted molecules. Once in the host, it eventually becomes systemic and will have to adapt to the hosts environment in order to survive. What makes these infections difficult to treat ,unlike bacterial infections is in part because like the pathogen, the host is eukaryotic. Several gene products secreted by A. fumigatus enables it to survive and cause harm to host. As such, by regulating or disrupting gene expression on the organism
In order to cause a systemic infection, entry into the host must first be accomplished. This is done through the respiratory route. A. fumigatus forms a microscopic asexual fruiting structure for airborne spore dispersal that once inhaled and aided by its saprophytic mode of nutrition, can reside, germinate into hyphae and cause infections in the lungs of immunocompromised persons.
Once in the host, it eventually becomes systemic and will have to adapt to the hosts environment in order to survive. The ability to grow at body is aided by the fact that in nature, the conidia are prevalent in environments(compost). This may have allowed A. fumigatus to evolve mechanisms to deal with and adapt to such pressures in order to thrive and thus contribute one way or the other to its virulence(Askew p.331). This unique ability can be exploited to treat infections caused by A. fumigatus by targeting and disrupting the genes responsible for its ability to grow at 37oC. Experiments undertaken have shown the genes CgrA,O-mannosyltransferase Pmt1 are necessary for A. fumigatus tolerance for changing temperature and that only CgrA when mutated was virulence and slowed growth at normal body temperature(Askew p.331).
In all of these processes of survival in the host, the cell wall is of prime importance. The fungal cell wall performs many functions, giving cell its shape, serving a protective role and regulating flow of molecules including digestive enzymes. As such, understanding of the mechanism in which it is built by using mutant strain can be exploited for antifungal agents. Its cell wall includes chitin(an acetylated amino-polysaccharide of immense tensile strength),chitosan,galactomannan,α-(1,3) glucan and branched and linear β-(1,3) and β-(1,4) glucan (Askew 332). Experiments undertaken involving several mutated genes responsible for synthesis of components of the cell wall produced conflicting observation. For instance, mutating ags1 and ags 3 gene of α-(1,3) glucan (a component of the cell wall)synthase resulted in a decrease in the cell wall with no effect on the virulence on the former and a rather increase in virulence and melanin in the latter (Askew 332).
Chitin, has several synthase genes in the organism. Of the three examined in the experiment, only one when mutated showed a decrease in virulence indicating that somehow an alternate pathway of cell wall generation occur.
β-1,3 glycan is another component of the cell wall of A.fumigatus synthesis of this sugar is believe to occur when GPI proteins binds the enzyme β-1,3-glucaosyltransferase resulting in the lengthening of the chain in the wall of A.fumigatus. Deletion of GPI linked protein resulted in increased virulence as the mutant was able to grow at a faster rate, however blocking of the enzyme responsible for the synthesis of the GPI linked protein produced a decrease in the cell wall and virulence(Askew 332) . A. fumigatus also produce Gliootoxins,a secondary metabolite as a defense mechanism that produces long term health effects. Studies undertaken have shown that these mycotoxins are secreted as a defense mechanism against neutrophilic attack by host defense mechanism. A strain of A. fumigatus lacking gliotoxin was found to be less virulent (Askew 332).
Sensing changes in the environment is essential to the survival of A. fumigatus in the host. This is accomplished by the organisms' ability to undertake sense and convert mechanical and chemical stimuli in the environment and elicit a specific cellular response. Central to this pathway is cAMP produced using AMP and the enzyme adenylate cyclase . cAMP activates PKA which in turn activate target cell downstream eliciting a proper response. Thus ,blocking or causing over-expressing of the pathways will lead to the pathogen inability to respond to these chemical signals(stress). For instance, studies on a mutant A. fumigatus lacking the catalytic A subunit of calcineurin(a calcium signaling and stress protein) showed a decrease in virulence . Other experiment involving disrupting a different kinase (MAP) and a protein regulator of high osmolarity glycerol in the A. fumigatus genome showed increase virulence in the former and no effect on the latter despite evidence of cell wall stress (Askew 333).
As an absorptive heterotroph, A. fumigatus absorb nutrients for growth as well as undertake metabolic functions by secreting proteases in the tissues of the host. Disrupting its ability to acquire key nutrients such as nitrogen,zinc,iron, p-aminobenzoic acid, and lysine are another way to destroy the pathogen. Experiments conducted in mice lacking the transcription factors that respond to nitrogen in the environment showed a decrease in the virulence of the pathogen. However, mutant strains lacking the genes necessary for protease release was inconclusive as to its effects on virulence(Askew 333).
Amino acids released from tissues as a result of the proteases actions is an important nutrient for growth in a fungi. Amino acids metabolism in the fungi results in the accumulation of propionyl-CoA. This by product is cleared in by the fungi using the enzyme methyl citrate sysnthase. mutant strains of the fungi lacking enzyme was observed less virulent in vivo indicating the pathogens dependant on protein degradation. It turns out that the mechanism of dealing with propionyl-CoA in the cells of fungi and humans is different thus presenting an opportunity to design antifungal agents to target this pathway the body without harming hosts cells( Askew 333).
While many similarities with respect to A. fumigatus virulence are not unique to this species, its ability to survive, usually at the expense of the host is one that requires further studying. Among the features that help promote its pathogenicity are a collection of genes on its genome that produces the small spore size, the composition of the cell walls, signaling transduction pathways, and the nutritional pathways.
The above finding using mutant strains provides valuable knowledge into the functions of the genes and the biochemical pathways/strategies used by A. fumigatus to infects the host tissues. It presents other avenues of study with regards how to treat infection besides targeting the cell wall. For instance, the fungi mechanism for dealing with propionyl-coA accumulation presents an opportunity to structure antifungal agents to deal with infection with harming host cells.
Askew S, David. Aspergillus fumigatus: Virulence genes in a street-smart mold . Current Opinion in Microbiology 2008,11:331-337.
Slonczewski, Joan L., and John W. Foster. Microbiology An Evolving Science. New York: W. W Norton, 2008. Print.