Responsabilidades Elaboración Gerente General.

1.8.1. Mechanisms o f resistance against host defences bv

Aspergillus

Autopsy studies have shown that A, fum igatus spores are present and viable in human lungs more frequently than would be expected on the basis o f their prevalence among fungal spores in the air (Mullins and Seaton 1978). This suggests ih a i A. fum igatus has properties that protect it from normal lung defences.

Factors that enhance the pathogenicity o f Aspergilli include their ability to withstand a broad range o f temperatures, and their small, aerodynamic size that allows them to penetrate easily into the alveolar spaces (Elstead 1991). The conidial diameter itself also may be a factor influencing the risk o f disease. For example, conidia o f A. fum igatus measure 2 to 3pm across, a size ideal for inhalation and

deposition in the distal respiratory tract. By contrast, conidia o f the relatively less common pathogens A.niger and A. flavus are 4 to 5 p m in diameter, a size more likely to be associated with proximal

airway deposition, and, possibly, more rapid mucociliary clearance. This, however, cannot be the sole explanation for variation in species pathogenicity, as some species that are rare causes of human disease have a conidial diameter similar to that o f A. fumigatus (Fraser

1993).

Proteolytic destruction o f lung tissue by enzymes such as elastase play a role in the pathogenesis o f IP A, as demonstrated by the fact that elastase production by A. fumigatus correlates with its ability to cause lung disease and death in mice (Kothary et al 1984). A. fum igatus also produces a substance that interferes with the

alternative complement pathway and decreases the binding o f C3b (an opsonin) to the fungal surface. Furthermore, conidia do not cause the generation o f the chemoattractant C3a unless they have germinated. Thus both the opsonic and the chemoattractant functions o f complement are inefficient in response to A. fumigatus conidia (Washburn et al 1986). In addition, gliotoxin, a metabolite o f A. fum igatus, inhibits the phagocytic function o f macrophages, and also

inhibits the induction o f alloreactive cytotoxic T cells in vitro (Mullbacher et al 1984).

Reactive oxygen species are important mediators o f Aspergillus

killing by phagocytes (Washburn et al 1987) but there is evidence that Aspergillus conidia are relatively resistant to cell free killing by oxidants (Levitz and Diamond 1985). They are also inhibitory to oxygen radical production in neutrophils exposed to phorbol myristate acetate, and relatively poor stimulants o f superoxide anion and hydrogen peroxide production by mouse peritoneal exudate cells (Robertson et al 1987). The significance o f these potential

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pathogenic mechanisms to pulmonary disease in humans is poorly understood.

1.8.2. Host defence against conidia

In mice, conidia have been shown to be phagocytosed by alveolar macrophages within 15 minutes o f exposure to aerosolised A. flavus

and such phagocytosis prevented subsequent germination and invasion o f lung tissue, even in neutropenic or athymic mice (Merkow et al 1971, Schaffner et al 1982). The binding of A. fum igatus conidia to murine macrophages in vitro is not enhanced by

opsonisation (Kurup 1984), but is inhibited by soluble polysaccharides that block the mannose receptor on the surface of macrophages, suggesting that attachment is mediated by the interaction o f a carbohydrate component on the fungal wall with specific receptors on the macrophage (Kan and Bennett 1988).

Following phagocytosis, macrophages kill microorganisms largely by oxidative killing. The addition o f catalase (which degrades hydrogen peroxide) has been shown to reduce fungal killing by nonnal macrophages in vitro (Washburn et al 1987).

In summary, alveolar macrophages and are the first line o f defence against Aspergillus. Failure o f macrophages to phagocytose or destroy inhaled spores results in germination and extracellular growth o f hyphae.

1.8.3. Host defence against hyphae

Clinical observation demonstrates that neutropenia is a major risk factor for the development o f aspergillosis, and it appears that the neutrophil is involved in defence against Aspergillus hyphae. Diamond et al, using both light and electron microscopy (Diamond

et al 1978) demonstrated that neutrophils attached to and spread over the surfaces o f hyphae in vitro, and that shortly thereafter, morphological changes in the fungus suggested severe damage and death. Metabolic inhibitor studies suggested that oxidative mechanisms were responsible for neutrophil mediated killing o f the extracellular hyphae. Monocytes may also be involved in killing

Aspergillus hyphae (Diamond et al 1983). The importance of oxidative killing by phagocytes in the defence against Aspergillus is evidenced further by the susceptibility o f clironic granulomatous disease patients (who fail to produce reactive oxygen species in response to phagocytosis) to Aspergillus infections (Johnson and Baehner 1971, Cohen et al 1981, Ezekowitz et al 1988).

1.8.4. Other host defence mechanisms including humoral

Aspergillus pneumonia is not common in patients with the acquired immunodeficiency syndrome (Broaddus et al 1985, Rankin and Daniele 1988, Murray and Mills 1990), implying that lymphocyte directed cell mediated immunity is unlikely to be o f major importance in defence against Aspergillus. Similarly, immunosupressed patients with invasive aspergillosis tend not to have a detectable antibody response (Young and Bennett 1971, see

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also section 1.10.9.1.), although there does not appear to be a high rate o f Aspergillus infection in patients with hypogammaglobulinaemia.

The major defence mechanisms o f the central airways include mucociliary clearance, cough, bronchoconstriction, and local secretion o f inflammatory mediators by airway cells such as mast cells, eosinophils, neutrophils, lymphocytes and intraluminal macrophages.

Diseases that are primary disorders o f the conducting airways (namely asthma and cystic fibrosis) predispose to allergic bronchopulmonary aspergillosis, the development of which requires colonisation by Aspergillus. It is frequently stated that such colonisation is promoted in airway disorders by alteration in mucociliary clearance and/ or characteristics o f the mucus. A hyperactive immune response is likely to be involved in the subsequent reaction to Aspergillus colonisation that results in allergic bronchopulmonary aspergillosis (see section 1.9.3.4).

Excessive immunity also results in Aspergillus induced asthma and hypersensitivity pneumonitis (see sections 1.9.3.1 and 1.9.3.4).