Trends in Microbiology

Trends in Microbiology

Volume 15, Issue 4, April 2007, Pages 181-190
Journal home page for Trends in Microbiology

Review
MAP kinase pathways as regulators of fungal virulence

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MAP kinases are dual phosphorylated protein kinases, present in eukaryotes, which mediate differentiation programs and immune responses in mammalian cells. In pathogenic fungi, MAP kinases are key elements that control adaptation to environmental stress. Recent studies have shown that these pathways have an essential role in the control of essential virulence factors such as capsule biogenesis in Cryptococcus neoformans or morphogenesis, invasion and oxidative stress in Candida albicans. Although MAP kinases sense different activating signals, there is a considerable degree of crosstalk and/or overlap, which enables them to integrate, amplify and modulate the appropriate protective and adaptive response. MAP kinases behave as a ‘functional nervous system’ that controls virulence and influences the progression of the disease.

Section snippets

Fungi and human disease

Fungi are an important cause of human disease. Members of the genus Candida cause a variety of superficial and systemic infections depending on the immunological status of the individual. Superficial infections are relatively common, while systemic infections (called candidemias) only occur in patients with a severe immune defect. Candidemias are associated with significant morbidity and mortality among both paediatric and adult individuals and Candida albicans is the most common fungal species

Functional structure of MAP kinase pathways

MAP kinase pathways are used by eukaryotic cells to sense changes in the external and internal environment. There are several differences between higher mammalian cells and lower eukaryotic cells regarding the complexity and functionality of the elements involved. However, the core structure of the MAP kinase cascade is highly conserved. The structure comprises three kinases that function by sequential phosphorylation (Figure 2). Upon receiving a stimulatory signal, the MAP kinase kinase kinase

Fungal recognition

Fungal pathogenesis requires adhesion to host tissues. The fungal wall protects the cell against external injuries and provides the typical shape of the cell. In addition, it mediates adhesion to host tissues and is the primary structure recognized by the mammalian host cells. The cell wall is a dynamic structure, the architecture and composition of which are subjected to complex regulatory networks. Consequently, the cell wall is influenced by the phase of growth, the availability of nutrients

Colonization

The ability to grow and proliferate within the host tissue is essential to cause disease. Recent data indicate a role of the cell integrity pathway for growth inside the host. In Cr. neoformans, the cell integrity MAPKK Mpk1 is essential for proliferation at 37°C (the common body temperature) and mpk1 mutants are less virulent [33], demonstrating that this MAPK is important during infection. In C. albicans, the equivalent gene MKC1 is also important for proliferation at 42°C but not at 37°C, a

Coping with host immune defences

The ability to resist the action of immune cells is essential to all pathogens to establish themselves in the host. Macrophages carry out an essential function as antigen presenting cells, modulating and orchestrating the immune response. Upon ingestion by macrophages, nutrient deprivation, pH diminution and oxidative stress are important changes that the microbe senses within the phagocytic vacuole 40, 41. Recent evidence suggests that the HOG pathway participates in this process in at least

Morphogenesis

Fungal morphology is important both during invasion and during evasion from host cells. Pathogenic fungi display at least two morphologies, one mycelial and the other unicellular (yeast, conidia or spores). The cellular form seems to initiate infection but hyphae present some type of advantage at specific stages of the infectious process. Hyphae are more difficult to phagocytose (owing to their morphology and/or size) and they can eventually provoke the death of the macrophage (if hyphal

Concluding remarks

Although the structure of the MAP kinase pathways is relatively conserved among fungi, there are important differences that indicate a functional divergence arising from the different evolutionary histories of the species. Divergence is reflected by the diversity of genes and proteins involved in each pathway, but also in the type of stimuli that they sense, the kinetics of the response and, therefore, the functional specialization of the cascade. By linking environmental host signals to the

Acknowledgements

Work in our laboratory is supported by NIH grant RX4215–030 and BIO2006–036737.

Glossary

MAP kinase
A special type of kinase that is only present in eukaryotic cells. A MAP kinase is activated when it is simultaneously phosphorylated on a Thr and Tyr residue upon receiving a stimulatory environmental signal.
Dimorphism
An environmentally regulated differentiation program that enables a microbe to switch between two different morphologies, normally a unicellular yeast-like form and a mycelial form.
Virulence factor
Any cellular component whose quantitative or qualitative alteration

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