LAUSR

This Special Issue deals with five systemic pathogenic fungi, all endemic in the Western Hemisphere, four of which are thermally dimorphic and the fifth is Cryptococcus neoformans, an important invasive yeast that can infect apparently immunocompetent hosts as well as immunocompromised people. The prevalence of asymptomatic cryptococcal infections is not known as there is no skin test antigen available, but using skin testing to diagnose prior infection with the dimorphic fungi revealed that the vast majority of infections with dimorphic fungi are asymptomatic [1]. Nevertheless, the overall economic and human cost of symptomatic invasive fungal infections is quite large. In 2014 in the United States, fungal infections resulted in ~75,000 hospitalizations with an estimated cost of $4.6 billion, and the four pathogens featured in this symposium that occur in the United States accounted for about 23% of those hospitalizations [2]. Paracoccidioidomycosis (PCM), which is endemic in Central and South America, is not a reportable disease in the endemic countries, so we do not have reliable incidence or prevalence figures from that region. However, in Brazil hospitalization rates for PCM vary from1.6 to 8.3/100,000 residents in different regions of the country, indicating the enormity of that problem in Brazil [3]. PCM is also endemic in the other northern countries in South America, and in Central America where the most cases are reported from Mexico, primarily from the rural southern states that have heavy rainfall and a lot of vegetation.Despite themillions of infections that are caused by thermally dimorphic fungi worldwide there are no vaccines and few if any drugs have been developed and FDA-approved to treat any of three dimorphic pathogens featured in this special issue. The invasive dimorphic fungi in the Western Hemisphere have many commonalities, which is to be expected since they are all members of the order Onygenales. Although it was originally believed that each of the diseases caused by those fungi was caused by a single species, genome sequencing and, in some cases, actual mating experiments have revealed that each disease can be caused by two or more different species [4–7]. The diseases they cause are with rare exceptions initiated by inhalation of asexual spores (or in the case of cryptococcosis, by inhaled desiccated yeast), and person to person transmission is almost unheard-of. The inhaled spores undergo a complex transformation into yeast that multiply inside macrophages in the host (Histoplasma, Paracoccidioides, Blastomyces), or transform into spherules (Coccidioides) that are primarily found extracellular because they only are small enough to be ingested while they are immature round cells. Pathogenic cryptococci are not dimorphic, but they are also facultative intracellular pathogens that multiply inside or are extruded by macrophages [8] but can grow extra-cellularly, which is most often seen in the cerebral spinal fluid. In all cases elevated temperature is a trigger for the morphological transformation from spores to the tissue invasive forms. The articles by Beyhan and Sil [9], McBride et al. [10], and Kirkland and Fierer [11] review what is known about the changes in gene expression that accompany the transition from spore to the pathogenic forms. The temperature-driven transformation in H. capsulatum is driven by four highly conserved factors, Ryp (Required for Yeast Phase)1, Ryp2, Ryn3, and Ryp4. Ryp factors belong to distinct families of proteins that control the developmental transitions in fungi. Ryp1, Ryp2, and Ryp3 are transcription factors that along with Ryp4 regulate their own and each other’s expression [9] and many of the known virulence genes in H capsulatum. These same transcription factors are conserved in Blastomyces and are required for yeast development and for the expression of multiple virulence factors [10]. The Ryp family of proteins is also present and expressed by spherules of C. immitis RS, but as yet their role in regulating the metamorphosis of spores into spherules is still unknown [12], and it is not yet known which of the differentially expressed genes in spherules are required for the transition from spores, the