Thermal Dimorphism: Enabling Penicillium marneffei to Kill Since 1973

By MB

Figure 1. Emergence of HIV infections

and P. marneffei-associated penicilliosis for

the Chiang Mai region, northern Thailand 

The exploitation of secondary metabolites synthesized by Penicillium species has been a significant part of human history. The most well known use of these metabolites is in relation to antibiotic production. Several species of Penicillium, one being Penicillium chrysogenum, produces the antibiotic penicillin. For many years, penicillin has been a principal player in the treatment of skin, respiratory, and urinary tract infections. Other than antibiotics, many characteristics of various cheeses such as flavor, texture, and appearance can be attributed to Penicillium species. For example, Penicillium roqueforti gives rise to the ripening of blue-veined cheeses, such as Gorgonzola, and Roquefort. In addition to cheese production, the flavors of cured and fermented meat products are dependent on the species of Penicillium present (Ropars 2012). Much of the interest in Penicillium has stemmed from the consideration of additional products that could also prove useful to society, and it hasn’t been until recently that we discovered some species of Penicillium could have unfavorable effects.

Most species of Penicillium are generally non-pathogenic, but there’s a black sheep in every flock. Specifically, one species of Penicillium has acquired a more disturbing reputation than its antibiotic, cheese, and meat-producing relatives. This species is Penicillium marneffei, and it has emerged as an infectious beast in its current geographical residence. P. marneffei is a pathogenic fungus that can cause serious systemic mycoses in immunocompromised individuals. Currently, P. marneffei is geographically restricted with its infections endemic in Southeast Asia, India, and China (3). Previous studies have identified humidity as the most important environmental predictor of P. marneffei transmission. The predicted climatic conditions may provide insight on the possible areas where P. marneffei infections may emerge in the future (Bulterys 2013). Approximately thirty years ago, the occurrence of human penicillosis marneffei in the endemic areas was extremely rare, with the first reported natural case being in 1973. Although it was rare in the past, the prevalence has greatly increased with the rising number of HIV-infected individuals (Vanittanakom 2006). To validate this explaination, the UNAIDS/WHO working group reported a study in northern Thailand that evaluated the relationship between the prevalence of HIV infections and P. marneffei-associated penicilliosis. As seen in Figure 1, the dramatic incline and decline of the number of HIV infections appear to correspond to the number of P. marneffei infections.

Figure 2. A) Microscopic view of

P. marneffei conidiophores;

B) early stage hyphae formation

The pathogenicity of Penicillium marneffei is not the only aspect that contributes to this species’ distinctive nature. P. marneffei is the only identified Penicillium species that exhibits thermal dimorphism. Thermal dimorphism, also known as temperature-dependent dimorphic growth, can be defined as the growth of the fungus in two varying forms that is dependent on the microorganism’s environmental temperature (Vanittanakom 2006). At temperatures below 37°C, the microscopic morphology of P. marneffei is identical to the other species comprising the Penicillium genus, which is largely identified by the formation of conidiophores (Figure 2A). These structures are specialized stalks that produce asexual, non-motile spores called conidia (Vanittanakom 2006) As seen in Figure 2B, the early stages of P. marneffei growth at these lower temperatures consist of the formation of branched filaments called hyphae. Contrarily, P. marneffei exhibits very distinct characteristics at when grown at a temperature of 37°C. At this temperature, which is also normal human body temperature, P. marneffei resides in the yeast phase and exhibits yeast cell characteristics (Vanittanakom 2006). P. marneffei yeast-like cells are unicellular, have an oval shape, and divide by binary fission (Figure 3).

Figure 3. Photomicrograph

of P. marneffei yeast cells

Thermal dimorphism is largely accredited for the pathogenicity of P. marneffei. At temperatures in which the yeast-like cells are exhibited, P. marneffei is not only pathogenic but also parasitic. P. marneffei yeast-like cells live intracellularly in human macrophages, which enables them to both survive and disseminate to a variety of organs in the host (Vanittanakom 2006). How does this pathogenic fungi not only evade the host immune response, but also reside in one of the very cells responsible for killing such a pathogen? Unfortunately, the pathogenic mechanisms and processes enabling this parasitic fungus-host interaction are mostly unknown. One proposed mechanism responsible for the simultaneous invasion of macrophages and evasion of the host immune response is that P. marneffei inhibits the production of reactive oxygen species or neutralizes inhibitory host metabolites (Vanittanakom 2006). An alternative suggested mechanism for macrophage invasion is that a receptor consisting of a glycoprotein with exposed N-acetyl-b-glucosaminyl groups recognize the pathogen and allows entry into the cell. During infection, it has been shown that genes involved in glyoxylate bypass are highly expressed during the pathogenic yeast form of P. marneffei. The induction of the glyoxylate cycle is presumed to be a response to nutrient deprivation. Therefore, it is suggested that P. marneffei requires the glyoxylate cycle for growth as macrophages are considered an environment poor in nutrients (Cánovas 2006).

Once P. marneffei cells initiate the invasion of host immune cells, genes that are essential for pathogenesis are unregulated. A comprehensive understanding of the P. marneffei genome is currently non-existent, and therefore, the underlying cellular mechanisms responsible for the disease pathogenesis and thermal dimorphism of P. marneffei are yet to be discovered (Woo 2011). However, surface-level analysis of the genomic sequence of P. marneffei has lead to the exploration of the genes responsible for mold to yeast phase transition (Vanittanakom 2006). In addition, it has been determined that the genetic sequence of P. marneffei is more closely related to those of molds than to those of yeasts (Woo 2003). Further analysis of the genome may potentially provide insight on disrupting the ability of the fungus to invade host immune cells, and as a result, inhibiting the microorganism’s ability to cause disease.

References:

Bulterys, Philip L., Thuy Le, Vo Minh Quang, Kenrad E. Nelson, and James O. Lloyd-Smith. “Environmental Predictors and Incubation Period of AIDS-Associated Penicillium marneffei Infection in Ho Chi Minh City, Vietnam” Clin Infect Dis. (2013)56 (9): 1273-1279. doi:10.1093/cid/cit058

Cánovas, David, and Alex Andrianopoulos. “Developmental Regulation of the Glyoxylate Cycle in the Human Pathogen Penicillium Marneffei.” Molecular Microbiology 62, no. 6 (2006): 1725–1738. doi:10.1111/j.1365-2958.2006.05477.x.

Cao, Cunwei, Ruoyu Li, Zhe Wan, Wei Liu, Xiaohong Wang, Jianjun Qiao, Duanli Wang, Glenn Bulmer, and Richard Calderone. “The Effects of Temperature, pH, and Salinity on the Growth and Dimorphism of Penicillium Marneffei.” Medical Mycology 45, no. 5 (January 2007): 401–407. doi:10.1080/13693780701358600.

Ropars, Jeanne, Joëlle Dupont, Eric Fontanillas, Ricardo C. Rodríguez de la Vega, Fabienne Malagnac, Monika Coton, Tatiana Giraud, and Manuela López-Villavicencio. “Sex in Cheese: Evidence for Sexuality in the Fungus Penicillium Roqueforti.” PLoS ONE 7, no. 11 (November 21, 2012): e49665. doi:10.1371/journal.pone.0049665.

Vanittanakom, Nongnuch, Chester R. Cooper, Matthew C. Fisher, and Thira Sirisanthana. “Penicillium Marneffei Infection and Recent Advances in the Epidemiology and Molecular Biology Aspects.” Clinical Microbiology Reviews 19, no. 1 (January 1, 2006): 95–110. doi:10.1128/CMR.19.1.95-110.2006.

Woo, Patrick C. Y., Susanna K. P. Lau, Bin Liu, James J. Cai, Ken T. K. Chong, Herman Tse, Richard Y. T. Kao, Che-Man Chan, Wang-Ngai Chow, and Kwok-Yung Yuen. “Draft Genome Sequence of Penicillium Marneffei Strain PM1.” Eukaryotic Cell 10, no. 12 (December 1, 2011): 1740–1741. doi:10.1128/EC.05255-11.

Woo, Patrick C.Y., Hongjun Zhen, James J. Cai, Jun Yu, Susanna K.P. Lau, Jian Wang, Jade L.L. Teng, et al. “The Mitochondrial Genome of the Thermal Dimorphic Fungus Penicillium Marneffei Is More Closely Related to Those of Molds Than Yeasts.” FEBS Letters 555, no. 3 (December 18, 2003): 469–477. doi:10.1016/S0014-5793(03)01307-3.