More about the workshop (HKUPRC, Hong Kong)

Functional genomics analyze the functions of proteins encoded by the genes (in particular genes of unknown function) discovered in all genome sequencing programmes. Fundamental results obtained using comparative genomics of various yeasts has permitted Prof Dujon (Head of the Molecular Biology of Yeast Unit, IP, France) to propose new tools for studying pathogenic fungi present in Hong Kong.

Aspergillus fumigatus, a common saprophyte of the environment, infects patients with pre-existing lung diseases, as well as cancer patients receiving chemotherapy or undergoing bone-marrow transplantation. Under such circumstances the disease is often fatal. The Aspergillus Unit at the IP in Paris (Headed by JP Latgé) is involved in the study of various aspects of the biology of A. fumigatus. This thermophilic filamentous fungus sporulates abundantly in nature. Severe pulmonary diseases as a result of inhalation of airborne conidia of A. fumigatus are often fatal among immunosuppressed patients. Indeed, A. fumigatus today has become the most important fungal aerial pathogen in developed countries. JP Latgé presented his first medical research theme, focused on the study of invasive aspergillosis (diagnosis, epidemiology and pathophysiology). A second research area developed is more fundamental and concerns the study of the fungal cell wall biosynthesis, which is a key event in the fungal life.

Scientists from the HKU Department of Microbiology presented important data on A. fumigatus and P. marneffei. Dr Woo presented the discovery of a novel gene of A. fumigatus encoding a particularly antigenic cell wall protein. This permitted investigation aiming at creating a new rapid diagnostic test and could permit one to understand the cell wall construction and its role in pathogenesis. Dr Wong, presented results on studies on the biochemical properties of P. marneffei and a concentration-dependent growth inhibition of P. marneffei by galactose. The significance of this finding is unknown at present but functional genomics study may shed light on this new finding.

Penicillium marneffei, a very pathogenic fungus, was first isolated in 1956 from the viscera of a bamboo rat (Rhizomys sinensis) in the highlands of central Vietnam, at the Pasteur Institute in Dalat, Vietnam. The isolates were sent to Paris for further study. A second isolate of the fungus was identified by G. Ségrétain and named Penicillium marneffei, after the name of Dr. Hubert Marneffe, the Director of the Institut Pasteur d'Indochine. As repeatedly occurred in the history of the discovery of pathogens, Ségrétain became the first known human case of P. marneffei infection in 1959 as he accidentally inoculated himself with the fungus by a needle when transfering the organism to a hamster. While epidemiological studies have focused on the association of P. marneffei with bamboo rats, to date, no other animal besides man is known to naturally acquire an infection by this fungal pathogen. Despite the apparent relationship between the fungus and rodent, exposure to these animals has not been established as a risk factor for acquiring penicilliosis. Instead, exposure to soil appears to be the critical risk factor associated with acquisition of P. marneffei infection. This finding is perplexing since P. marneffei has rarely been isolated from nature. The environmental niche for P. marneffei is unknown although it is also assumed to be a soil organism.

The first documented case of natural human infection, however, was discovered much later in 1973 in a 61-year-old US visionary suffering from Hodgkin's disease. Subsequently, additional cases were reported from Southeast Asia in the early 1980s. One patient, an HIV-positive Congolese physician, was infected with P. marneffei at the Pasteur Institute after attending a course in tropical microbiology. The organism was not handled directly by the patient, but by other students and laboratory workers in the same building. Presumably, the patient acquired the infection from an aerosol containing P. marneffei spores. This case illustrates the possibility of airborne infection with this organism and points to a respiratory route of infection. Asymptomatic infections can occur in healthy individuals. One study reported serologic evidence of subclinical infection in two laboratory technicians. The likely route of infection in most cases is inhalation of P. marneffei spores. Patients with localized bronchopulmonary disease have also been reported. Bronchopneumonia with or without adenopathy and cavitary lung disease also occur. Chronic cervical lymphadenitis resembling tuberculosis has been described.

Late in 1996 more than 900 cases had already been diagnosed in the world, mostly from Southeast Asia. At present, the endemic areas cover all Southeast Asia: Burma, Cambodia, Southern China, Indonesia, Laos, Malaysia, Thailand, and Vietnam. In areas endemic for P. marneffei, systemic infections with this organism have become very common and now is among the top three, amongst Mycobacterium tuberculosis and Cryptococcus neoformans, as the indicator disease of AIDS in Southeast Asia, affecting up to 20% of patients in northern Thailand. For example, at Chiang Mai University Hospital in Northern Thailand between 1987 and 1992, there were 92 patients with documented systemic P marneffeii infection, of whom 86 were HIV positive. Since then, the number of cases among HIV-positive patients has increased dramatically.

The high incidence of penicilliosis among AIDS patients in Southeast Asia (10% of AIDS patients in Hong Kong) correlates with available evidence suggesting that there exists a significant number of symptomless individuals infected with P. marneffei. Because the AIDS pandemic is predicted to continue its explosive upsurge in this region, proportionate increases in the frequency of penicilliosis are anticipated. For instance, in China, where there is now at least one million HIV carriers, the incidence of penicilliosis is expected to increase dramatically in provinces endemic for this fungus.

A matter of much concern is that the organism also causes infection in persons who are apparently immunologically competent. However, disseminated infections occur much more frequently in immunosuppressed patients.

As is typical of Penicillium species, P. marneffei grows as a saprophytic mould bearing numerous conidia. However, in contrast to the filamentous pattern of growth exhibited by non-marneffei Penicillium species in vivo, P. marneffei assumes a yeast-like morphology upon tissue invasion. These yeast forms can also be observed in vitro when the organism is cultivated at 37ºC rather than room temperature.

The fungus in some way, therefore, is a bridge between the mould and the yeast. It is both far and near. It belongs to the generally non-pathogenic Penicillium genus, yet it is highly pathogenic. It is supposed to be a mould yet it becomes a yeast at body temperature. The genomic sequencing would bring an enormous understanding to all dimorphic fungus which have a very similar phenotype.

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