New Models of Microsporidiosis: Infections in Zebrafish, C. elegans, and Honey Bee

Microsporidia comprise a large phylum of fungal-related pathogens that have been studied since the time of Louis Pasteur, who in 1870 found that they were responsible for silkworm disease that was decimating the silkworm industry [1,2]. These obligate intracellular microbes are ubiquitous, but have remained enigmatic because of the difficulties of culturing them in the lab. In the 1990s there was a surge of interest in microsporidia when it was found that they were responsible for severe diarrhea and death in AIDS patients, but most research on these parasites has been conducted in fish and insects [3]. A recent PLoS Pathogens Pearl focused on the phylogenetic placement of microsporidia and the compactness of their genomes [4]. In this review we will consider the interaction between microsporidia and their hosts, with a focus on three non-mammalian hosts: zebrafish, Caenorhabditis elegans, and honey bee (Figure 1). These hosts are relatively new systems for the study of microsporidia, with distinct reasons motivating interest in each of them as described below. These systems provide exciting new opportunities to obtain insights into the mechanisms of microsporidia pathogenesis. Microsporidia as a group are able to infect an astonishingly wide range of hosts, including all animal phyla as well as a few protists. But how specific is the host range for a particular species of microsporidia? Roughly 1,200 species of microsporidia have been described, and it is difficult to make a blanket statement about their host range. On one end of the spectrum is Antonospora locustae, which appears to have a very narrow host range. A. locustae infects and eventually kills locusts, and has been approved by the United States Environmental Protection Agency as a ‘‘green pesticide’’ for locust control. In the process of obtaining approval for agricultural use, it was shown that A. locustae did not infect mammals, birds, fish, aquatic invertebrates, or honey bees (http://www.epa.gov/). On the other end of the spectrum is Anncallia (formerly Brachiola or Nosema) algerae, which was originally isolated from mosquitoes, but can replicate in several different species of invertebrate and vertebrate cell lines [5]. Interestingly, A. algerae appears to have caused death in an immunocompromised patient, possibly from a mosquito bite [6]. Thus microsporidia may have narrow or wide host range, depending on the species. The determinants of this host range are likely to encompass both host and pathogen factors that allow microsporidia infection. How do microsporidia infect their hosts? Many microsporidia use a fecal-oral route of transmission, with some species restricted to intestinal cells and other species disseminating to a variety of tissues and organs. Very generally, microsporidia have two life stages: the actively replicating meront that develops inside of host cells, and the dormant spore form, which is the transmissible form that survives outside the host cell. In order to invade cells, spores contain a highly specialized infection apparatus called a polar tube. This tube is coiled inside the spore and then ‘‘fires’’ outside the spore to directly inject the parasite into host cells, although the exact details of this process are poorly understood in vivo. A variety of cues have been shown to induce polar tube firing in vitro, but no cue has been found that is universal [7]. Presumably the host environment encountered by each microsporidia species during infection differs, and thus each species may respond to a distinct set of conditions. Once inside the host cell, microsporidia are very dependent occupants. Microsporidian genomes are extremely reduced in size, having jettisoned functions that can be accomplished by the host cell. An example of this dependence is that microsporidia cannot make ATP (except perhaps through substrate level phosphorylation) and instead appear to steal this vital energy currency from the host. This strategy of dramatic invasion followed by extreme dependence on the host cell appears to be evolutionarily successful, since there are a large number of species and hosts for microsporidia. A lifestyle such as this may represent the ‘‘bare bones’’ of a eukaryotic pathogen and the closest lifestyle to a virus of any eukaryote. Thus, study of microsporidia may provide insight into what represents the minimal arsenal for a eukaryotic parasite.