MicrobiologyBytes

A couple of articles about fungal infections captured my attention recently. The first is a good basic review/update:

Pathogenesis of invasive fungal infections. Curr Opin Infect Dis. 27 Feb 2013
Invasive fungal infection (IFI) is increasingly being recognized as a significant cause of morbidity and mortality in immunosuppressed patients. This review focuses on the latest literature reports concerning the pathogenesis of IFI in this population. New virulence factors of Candida and Aspergillus have recently been identified. The past few months have brought significant advances in our understanding of how the immune system acts against fungal infection, especially with regard to the role of mucosa in the innate immune system, the arsenal of innate immune recognition receptors and the pathways connecting innate and adaptive immunity. Knowledge of fungal pathogenesis and host immune response can help to optimize the management of fungal infections. Greater understanding of these processes may aid physicians in developing better prophylactic measures and antifungal or immunomodulatory therapies.

The second article discusses the influence of temperature on invasive fungi – something that is highly significant for organisms such as Cryptococcus neoformans, Histoplasma capsulatum, and Aspergillus fumigatus which normally grow in soil but can make the transition to invade the body:

Surviving the Heat of the Moment: A Fungal Pathogens Perspective. (2013) PLoS Pathog 9(3): e1003163. doi:10.1371/journal.ppat.1003163
Temperature is a critical parameter continually monitored by microorganisms. The dynamic environments inhabited by microorganisms evoke constant and effective environmental response strategies that have been elaborated over evolutionary time. For example, a significant rise or fall in ambient temperature initiates a stress response in the organism, commonly known as heat-shock or cold-shock responses, respectively. The phenomenon of temperature sensing has long been studied in microorganisms such as bacteria, but these mechanisms are only recently being translated to pathogenic fungi.

The ability of pathogenic microorganisms to assimilate nutrients from their host environment is one of the most fundamental aspects of infection. To counteract this, hosts attempt to withhold essential micro-nutrients from potentially harmful microbes to limit, or even prevent, their growth. This process is called nutritional immunity. For example, vertebrates, such as humans, express several iron-binding molecules to maintain extremely low free levels of this metal in the body. To overcome this restriction, successful pathogens have evolved sophisticated mechanisms to assimilate iron. These include high affinity transporters, siderophores, and transferrin-, ferritin-, and haem-binding proteins. Iron acquisition is considered a vital virulence factor for many pathogens. However, nutritional immunity does not begin and end with iron. Vertebrates have also developed mechanisms to sequester other essential metals, such as zinc. The importance of zinc sequestration and the strategies that successful pathogens employ to overcome this has only recently been realized.

Zinc Exploitation by Pathogenic Fungi. (2012) PLoS Pathog 8(12): e1003034. doi:10.1371/journal.ppat.1003034

Pneumocystis is an unusual fungus that is an opportunistic pathogen, causing an asymptomatic or mild infection in the normal host but pneumonia (PcP) in immunocompromised hosts. Untreated, the mortality rate from PcP approaches 100%. Even with treatment, mortality rates approach 10–20%. It is a ubiquitous organism infecting a wide array of mammalian species. Although the reservoir of infection for Pneumocystis has not been defined, direct airborne transmission from host to host has been proven under experimental conditions in rats.

The study of Pneumocystis has been problematic due to the inability to cultivate the organism or manipulate its cellular or molecular characteristics. As recently as the 1970s, a student studying Pneumocystis would have come away with the following understanding of its basic biology and function as a pathogen: Pneumocystis is an organism of low virulence found in many mammalian species. In humans, Pneumocystis pneumonia is a zoonosis resulting from reactivation of a latent infection acquired early in life. This concept of Pneumocystis arose largely through analogy to existing knowledge about other organisms to explain clinical observations, rather than through direct experimentation on the organism.

Over the past 25 years, we have learned more about Pneumocystis through controlled studies that have corrected some of the misconceptions contained in the “old” concept of Pneumocystis contagion stated above. This article is a brief summary of key research observations that give us a better, yet still incomplete, understanding of how Pneumocystis maintains its existence as an opportunistic pathogen.

Pneumocystis: Where Does It Live? (2012) PLoS Pathog 8(11): e1003025. doi:10.1371/journal.ppat.1003025

Invasive fungal infections are devastating. Despite state-of-the-art antifungal therapy, the mortality rates for invasive infections with the three most common species of human fungal pathogens are Candida albicans, 20%–40%; Aspergillus fumigatus, 50%–90%; and Cryptococcus neoformans, 20%–70%. Although invasive fungal infections can affect people with intact immune systems, the vast majority of disease occurs in the setting of an immunocompromised host.

The dismal outcomes for invasive fungal infections cannot be completely attributed to a lack of efficacious antifungal drugs. However, because most patients with invasive fungal infections are immunocompromised, the immune system cannot effectively assist in the clearance of the infection, and consequently, the success of treatment is more dependent on the efficacy of the antifungal agent than in the setting of an immunocompetent host. Unfortunately, our repertoire of antifungal agents is limited, particularly in comparison to the number of agents available for bacterial infections. In fact, it took 30 years for the newest class of antifungal drugs, the echinocandins, to progress from bench-to-beside. Furthermore, it is sobering to consider that the gold standard therapy for cryptococcal meningitis, a disease that kills more than 650,000 per year world-wide, is based on medications (amphotericin B and flucytosine) that were discovered nearly 50 years ago.

Antifungal Drug Discovery: Something Old and Something New. (2012) PLoS Pathog 8(9): e1002870. doi:10.1371/journal.ppat.1002870

MicrobiologyBytes likes a good hypothesis – one that really makes you think, even if there’s not much actual data to support it. So here’s one for you: fungi ate the reptiles?

“Here are two indisputable facts: we are living in the age of mammals, and immunologically intact mammals are highly resistant to fungal diseases, such that most human systemic fungal are considered “opportunistic”. Could these two facts be connected? The mammalian lifestyle is characterized by endothermy, homeothermy, and care for the young, including nourishment via lactation, all of which are energetically costly activities. In contrast, reptiles, which are ectotherms, require about one-tenth of the daily mammalian energy needs, and reptilian development is faster and requires less parental involvement. Given this energy handicap, how did mammals replace reptiles as the dominant land animals? This essay further develops the hypothesis originally proposed seven years ago that fungi contributed to the emergence of mammals by creating a fungal filter at the end of the Cretaceous that selected for the mammalian lifestyle and against reptiles.”

Fungi and the Rise of Mammals. (2012) PLoS Pathog 8(8): e1002808. doi:10.1371/journal.ppat.1002808

The fungi are angry. First it was the frogs, then it was the bats. Are humans next?

Fungal Disease and the Developing Story of Bat White-nose Syndrome. (2012) PLoS Pathog 8(7): e1002779. doi:10.1371/journal.ppat.1002779
Two recently emerged cutaneous fungal diseases of wildlife, bat white-nose syndrome (WNS) and amphibian chytridiomycosis, have devastated affected populations. Fungal diseases are gaining recognition as significant causes of morbidity and mortality to plants, animals, and humans, yet fewer than 10% of fungal species are known. Furthermore, limited antifungal therapeutic drugs are available, antifungal therapeutics often have associated toxicity, and there are no approved antifungal vaccines. The unexpected emergence of WNS, the rapidity with which it has spread, and its unprecedented severity demonstrate both the impacts of novel fungal disease upon naïve host populations and challenges to effective management of such diseases.

The continuing AIDS epidemic coupled with increased usage of immunosuppressive drugs to prevent organ rejection or treat autoimmune diseases has resulted in an increase in individuals at risk for acquiring fungal diseases. These concerns highlight the need to elucidate mechanisms of inducing protective immune responses against fungal pathogens. Consequently, several experimental models of human mycoses have been developed to study these diseases. The availability of transgenic animal models allows for in-depth analysis of specific components, receptors, and signaling pathways that elicit protection against fungal diseases. This review focuses on recent advances in our understanding of immune responses to fungal infections gained using animal models.

Immunology of fungal infections: lessons learned from animal models. Curr Opin Microbiol. 02 Jul 2012

Microorganisms are often covered by a proteinaceous surface layer that serves as a sieve for external molecular influx, as a shield to protect microbes from external aggression, or as an aid to help microbial dispersion. In bacteria, the latter is called the S-layer, in Actinomycetes, the rod-like fibrillar layer, and in fungi, the rodlet layer. The self-assembly properties and remarkable structural and physicochemical characteristics of hydrophobin proteins underlie the multiple roles played by these unique proteins in fungal biology.

Hydrophobins—Unique Fungal Proteins. (2012) PLoS Pathog 8(5): e1002700. doi:10.1371/journal.ppat.1002700

Biofilms are a principal form of microbial growth and are critical to development of clinical infection. They are responsible for a broad spectrum of microbial infections in the human host. Many medically important fungi produce biofilms, including Candida, Aspergillus, Cryptococcus, Trichosporon, Coccidioides, and Pneumocystis. This review emphasizes common features among fungal biofilms and points toward genes and pathways that may have conserved roles.

Fungal Biofilms. (2012) PLoS Pathog 8(4): e1002585. doi:10.1371/journal.ppat.1002585

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