Aspergillus fumigatus biology and pathology

The molds such as Aspergillus fumigatus are filamentous fungi. They are especially prevalent growing on the nonliving organic materials in the soil. They disperse their non-sexual spores called conidia in the air. Most Aspergilli are harmless to humans and A. fumigatus in particular is harmless to humans whose immune system has not been compromised by disease, drug therapy or genetic conditions. Exposure to A. fumigatus can cause an allergic response in sensitive individuals. More importantly, A. fumigatus is an opportunistic pathogen of bone marrow transplant patients, AIDS patients, and other immune compromised individuals.

Aspergillus fumigatus - Is the most common mold causing infection worldwide. (Image Courtesy of Aspergillus Web Site, University of Manchester)

Aspergillus fumigatus is the most common mold causing infection worldwide. The first infection described in man, an aspergilloma, was reported in Edinburgh in 1842 (Bennett, 1842) and many cases of invasive disease in non-immunocompromised patients were reported from the UK between 1890 (Wheaton, 1890) and 1947 (Cawley, 1947). These cases and more recent epidemiological data emphasize that A. fumigatus is a primary, albeit rare, pathogen of man. Allergic disease due to Aspergillus was first described in London in 1952 (Hinson et al., 1952) and the first invasive (and fatal) infection in an immunocompromised patient was described in 1953 in the British Medical Journal in a patient from Gloucester (Rankin, 1953).

The frequency of invasive disease has risen approximately 14-fold over the 12 years to 1992, as judged after death in unselected autopsies. Invasive aspergillosis has overtaken candidiasis as the most frequent fungal pathogen detected post mortem in tertiary care hospitals in Europe. Thus 4% of all patients dying had invasive aspergillosis, compared with about 2% with invasive candidiasis (Groll et al., 1996; Vogeser et al., 1999). Patients at risk based on the disease frequency include those with chronic granulomatous disease (25-40%), lung transplant recipients (17-26%), allogeneic bone marrow transplant patients (4-30%), neutropenic patients with leukemia (5-25%), heart transplant recipients (2-13%), pancreas transplant recipients (1-4%), renal transplant patients in Europe and the USA (~1%) and in India (~10%), and patients with AIDS, multiple myeloma and severe combined immunodeficiency (~4%) (Denning, 1998). Over 500,000 transplants are performed annually in the world. Acute leukemia affects about 3/100,000 of the population and on average each patient receives 3 cycles of chemotherapy, with each cycle defining a major risk period. Similar incidence is observed for high grade lymphoma patients who are also at high risk of invasive aspergillosis. In the industrialised nations alone these treatment protocols generate about 250,000 periods of major risk per year. AIDS cases are predicted to exceed 40 million by the end of the year 2000 which would result in about 1.4 million cases of invasive aspergillosis, although in developing countries most patients will not live long enough to get this disease.

The crude mortality from invasive aspergillosis is around 85% and falls to around 50% if treated (Denning, 1996). The new drugs in trial (voriconazole, etc.) may reduce the mortality slightly (~10%) (Denning et al., 1997a), but patients in trials tend to do better than those treated in clinical practice.

In addition to invasive disease, Aspergillus causes a number of other diseases in man. These include aspergilloma ("colonisation" of existing pulmonary cavities), sinusitis in normal people, allergic bronchopulmonary and sinus infections, keratitis (which usually leads to blindness in that eye and is common in the developing world) and postoperative infections in immunocompetent patients. Aspergilloma numbers are set to rise dramatically due to the increasing incidence of tuberculosis and such aspergilloma cases are notoriously difficult to treat. Cavities of 2 cm or larger after tuberculosis subsequently develop aspergillomas in 15-20% of patients (in the UK). The 5 year survival of patients with aspergillomas is about 40%. Allergic bronchopulmonary aspergillosis occurs in patients with cystic fibrosis and asthmatics (an increasing number) causing pulmonary fibrosis and death usually within 10 years of diagnosis.

Aspergillus fumigatus genome sequencing project

Dr. David Denning at the University of Manchester has coordinated the development of an international group of scientists to participate in the sequencing of A. fumigatus. The group has selected a clinical isolate, Af293 as the strain to be sequenced. Three BAC libraries have been constructed and BAC end sequencing and restriction enzyme fingerprinting are in progress at the Sanger Center and the Institut Pastuer. The National Institute of Allergy and Infectious Disease has provided funding to The Institute for Genomic Research (TIGR) through Dr. Denning (U01 AI 48830) to sequence and close half of the A. fumigatus genome. Dr. William Nierman is directing the sequencing effort at TIGR. Shotgun sequencing was initiated early in April, 2001 and the project has progressed quickly to greater than 2X sequence coverage.

Literature Cited