Monday, December 5, 2011

Paracoccidioidomycosis: Men And Women Are Not Created Equal.

Figure 1. Skin lesions on a man infected with P. brasiliensis.Image from    
Paracoccidioidomycosis (PCM) is caused by a human fungal pathogen primarily infecting the lungs through inhalation of pathogenic conidia and can then disseminate throughout the rest of the body resulting in lesions in the skin, lymph nodes, mucous membranes, and adrenals (see Figure 1). It is the most common mycosal infection in Latin America, caused by the fungi Paracoccidioides brasiliensis. After inhalation, single nucleus conidia are transformed into multinucleated yeast at human temperature [4]. The natural habitat of P. brasiliensis is still unknown, but a case study by Calle et al. characterized environmental conditions in PCM endemic areas and found that a large number of endemic areas are located in coffee-growing areas in Colombia [3]. One of the most interesting clinical observations made about PCM is that incidence of symptomatic infection is not equal between males and females. There have been reports varying from a 13:1 up to 70.6:1 ratio of men-to-women incidence of infection [10]. What is the cause of this very extreme difference in infection rate between genders? Is it an environmental effect or is a physiological difference responsible for this huge difference in rate of infection?

Because P. brasiliensis’ natural habitat may be in close proximity to coffee plantations in Colombia and possibly other agricultural areas in Latin America, an initial hypothesis of the phenomenon that men contract PCM much more frequently than females may be that men interact more with the fungus through agriculture and therefore contract infection more often. However, skin tests in endemic areas have shown equal reaction to the fungal polysaccharide antigen, paracoccidioidin, indicating an equal presence of P. brasiliensis in males and females, suggesting that a biological difference between genders plays a role in the pathogenicity of Paracoccidioidomycosis [1, 8].

It is known that in order for initial infection to occur, P. brasiliensis must transition from its mycelial form to yeast form [8,9]. A study by Restrepo et al. found that the female sex hormone estrogen (specifically 17β-estradiol), and no other steroid hormones, suppresses this transition in vitro. P. brasiliensis isolates were also found to express a protein which binds estrogen, and is believed to be the molecular site of action for transition disruption [8]. This explains why paracoccidioidin skin tests on females return positive in equal frequency to men even when females are asymptomatic; the fungal cell is arrested in its mycelial form, preventing the spread of infection. Aristizabal et al. demonstrated these effects in vivo by castrating male and female mice and reconstituting some of the castrated males with β17-estradiol and some of the castrated females with testosterone. When infected with P. brasiliensis, normal female mice are able to control infection while normal males experience progressive disease. Castrated males, castrated females, and castrated females reconstituted with testosterone were unable to control infection, but castrated males reconstituted with β17-estradiol were able to restrict fungal multiplication [2]. This study shows the important role of β17-estradiol in host immunity that testosterone does not act equivalently.

This brings the question of how estrogen disrupts the morphological switch of P. brasiliensis and contributes to the host immune response during infection. It has been found that estrogen specifically binds to mycelial cytosolic extracts of P. brasiliensis, and the fungal binder is likely a protein that acts as an estradiol binding protein. Study of temporal gene expression during the morphological change from mycelium to yeast form demonstrated that treating mycelia with estrogen caused differential gene expression compared to controls and cells were arrested in the mycelial form [10]. Also, higher levels of the cytokines IL-2, IFN-γ, and TNF-α have been correlated with resistance to infection, and higher levels of IL-10 play a major role in the antigen-specific immunosuppression of PCM. Likewise, estrogens have been found to stimulate IL-12, IFN-γ, and TNF-α and down regulate IL-10, while testosterone is known to actually increase synthesis of IL-10 [7]. Estrogen’s ability to stimulate cytokines necessary to fight infection while down regulating cytokines with immunosuppressive activity may therefore contribute to females’ ability to resist PCM. It may also suggest that testosterone actually contributes to the male hosts’ susceptibility to infection with increased production of IL-10.

PCM isn’t the only microbial infection found to be more prevalent in males than females. Gastric cancer risk is two times greater in males than females, and one of the causes is from Helicobacter pylori colonized in the gastric epithelia [6]. H. pylori infected mice treated with 17β-estradiol have been found to develop less severe symptoms than control male mice, suggesting a similar effect in host immunity during H. pylori infection [5]. In contrast to P. brasiliensis and H. pylori, it’s been found that Candida albicans has an estrogen-binding protein with a high affinity for estradiol, which actually stimulates the dimorphic transition from yeast the hyphal form [10].

When it comes to PCM women fair better than men, and they have estrogen to thank for it. 17β-estradiol blocks the critical morphological transition of P. brasiliensis from mycelial to yeast form through stereospecific binding to fungal proteins and functions in the regulation of immune system cytokines. Though estrogen has been found to be beneficial in host immunity, it is also harmful during certain pathogenic infections. Sex hormones play an important role in host immunity and further study of their mechanisms of action may offer helpful insights in the battle against human pathogens.

by RH

1. Andc, M. O. K., Netto, F., Sciences, M., Abstract, B., Basin, U. A., America, L., Accepted, S., et al. (1978). PARACOCCIDIOIDIN AND HISTOPLASMIN IN COARI (STATE OF AMAZONAS), SENSITIVITY. Tropical Medicine, 27(4), 808-814.
2. Aristizábal, B. H., Clemons, K. V., Cock, a M., Restrepo, a, & Stevens, D. a. (2002). Experimental paracoccidioides brasiliensis infection in mice: influence of the hormonal status of the host on tissue responses. Medical mycology: official publication of the International Society for Human and Animal Mycology, 40(2), 169-78.
3. Calle, D., Rosero, D. S., Orozco, L. C., Camargo, D., Castañeda, E., & Restrepo, a. (2001). Paracoccidioidomycosis in Colombia: an ecological study. Epidemiology and infection, 126(2), 309-15.
4. Goldani, LZ.(2011). Gastrointestinal Paracoccidioidomycosis: An Overview. J Clin Gasteroenterol 45(2), 85-91.
5. Ohtani, M., Ge, Z., García, A., Rogers, A. B., Muthupalani, S., Taylor, N. S., Xu, S., et al. (2011). 17 β-estradiol suppresses Helicobacter pylori-induced gastric pathology in male hypergastrinemic INS-GAS mice. Carcinogenesis, 32 (8), 1244-50.
6. Parkin, D.M., et al. (2005). Global cancer statistics, 2002. CA Cancer J. Clin., 55, 74-108.
7. Pinzan, C. F., Ruas, L. P., Casabona-Fortunato, A. S., Carvalho, F. C., & Roque-Barreira, M.-C. (2010). Immunological basis for the gender differences in murine Paracoccidioides brasiliensis infection.
8. Restrepo, a, Salazar, M. E., Cano, L. E., Stover, E. P., Feldman, D., & Stevens, D. a. (1984). Estrogens inhibit mycelium-to-yeast transformation in the fungus Paracoccidioides brasiliensis: implications for resistance of females to paracoccidioidomycosis. Infection and immunity, 46(2), 346-53.
9. Rippon, J. W. (1980). Dimorphism in pathogenic fungi. Critical reviews in microbiology, 8(1), 49-97. 
10. Shankar, J., Restrepo, A., Clemons, K. V., & Stevens, D. a. (2011). Hormones and the resistance of women to paracoccidioidomycosis. Clinical microbiology reviews, 24(2), 296-313.

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