The ability of fungal pathogens to cause disease is dependent on the ability to grow within the human host environment. In general, the human host environment can be considered a slightly alkaline environment, and the ability of fungi to grow at this pH is essential for pathogenesis. The Rim101 signal transduction pathway is the primary pH sensing pathway described in the pathogenic fungi, and in Candida albicans, it is required for a variety of diseases. As more detailed analyses have been conducted studying pathogenesis at the molecular level, it has become clear that the Rim101 pathway, and pH responses in general, play an intimate role in pathogenesis beyond simply allowing the organism to grow.
The mammalian host environment can generally be considered to be at a pH slightly greater than neutral. The pH of human blood and tissues is 7.4 ± 0.1; the pH of murine blood and tissues is 7.2 ± 0.1. However, this represents a rather limited view of the host environment from a standpoint of pH, when mucosal and other sites exposed to the outside world are considered, dramatic variations from this slightly alkaline pH are found. One obvious example is the digestive track, which shows spatial variations in pH from extremely acidic (pH < 2.0) to more alkaline (pH > 8.0). Further, temporal changes in pH within a single site have been well documented, such as within the oral cavity following the fermentation of dietary sugar by endogenous microbes. The vaginal cavity is an acidic environment, pH 4; however, increases in vaginal pH occur in conjunction with menses. Thus, while fungi must be able to adapt to changes in pH within the host, most if not all pathogenic fungi must be able to thrive at neutral-alkaline pH within host tissues in order to cause disease. This paper discusses the signaling pathways required for growth and adaptation to host pH and the contributions these pathways make to pathogenesis.
Recent studies have found that the pathways responsible for sensing and responding to environmental pH have been co-opted for adaptation to the mammalian host. The pathogenic fungi, including C. albicans, C. neoformans, and A. nidulans, face physical and chemical stresses due to neutral-alkaline pH similarly to environmental fungi, such as S. cerevisiae, such as iron starvation. What has been somewhat surprising is that these pH sensing pathways also control expression of virulence traits not necessarily predicted to be associated with pH, including adhesion to host cells, tissue invasion, as well as other virulence attributes. This highlights the importance of continuing studies of these fundamental pH response pathways in pathogenic fungi in order to understand how these pathogens are adapted to the mammalian host and potentially identify new approaches for preventing or treating infections.
How human pathogenic fungi sense and adapt to pH: the link to virulence. Curr Opin Microbiol. 23 July 2009. doi:10.1016/j.mib.2009.05.006