Extraarticular Manifestations of Rheumatoid Arthritis in Patients under Anti-tumor Necrosis Factor-α Treatment.

Abstract

<h3>ABSTRACT</h3> Microsporidia are fungi-related intracellular pathogens that may infect virtually all animals, but are poorly understood. The nematode <i>Caenorhabditis elegans</i> has recently become a model host for studying microsporidia through the identification of its natural microsporidian pathogen <i>Nematocida parisii.</i> However, it was unclear how widespread and diverse microsporidia infections are in <i>C. elegans</i> or other related nematodes in the wild. Here we describe the isolation and culture of 47 nematodes with microsporidian infections. <i>N. parisii</i> is found to be the most common microsporidia infecting <i>C. elegans</i> in the wild. In addition, we further describe and name six new species in the <i>Nematocida</i> genus. Our sampling and phylogenetic analysis further identify two subclades that are genetically distinct from <i>Nematocida</i>, and we name them <i>Enteropsectra</i> and <i>Pancytospora.</i> Interestingly, unlike <i>Nematocida,</i> these two genera belong to the main clade of microsporidia that includes human pathogens. All of these microsporidia are horizontally transmitted and most specifically infect intestinal cells, except <i>Pancytospora epiphaga</i> that replicates mostly in the epidermis of its <i>Caenorhabditis</i> host. At the subcellular level in the infected host cell, spores of the novel genus <i>Enteropsectra</i> show a characteristic apical distribution and exit via budding off of the plasma membrane, instead of exiting via exocytosis as spores of <i>Nematocida.</i> Host specificity is broad for some microsporidia, narrow for others: indeed, some microsporidia can infect <i>Oscheius tipulae</i> but not its sister species, and conversely. We also show that <i>N. ausubeli</i> fails to strongly induce in <i>C. elegans</i> the transcription of genes that are induced by other <i>Nematocida</i> species, suggesting it has evolved mechanisms to prevent induction of this host response. Altogether, these newly isolated species illustrate the diversity and ubiquity of microsporidian infections in nematodes, and provide a rich resource to investigate host-parasite coevolution in tractable nematode hosts. <h3>Author Summary</h3> Microsporidia are microbial parasites that live inside their host cells and can cause disease in humans and many other animals. The small nematode worm <i>Caenorhabditis elegans</i> has recently become a convenient model host for studying microsporidian infections. In this work, we sample <i>Caenorhabditis</i> and other small nematodes and 47 associated microsporidian strains from the wild. We characterize the parasites for their position in the evolutionary tree of microsporidia and for their lifecycle and morphology. We find several new species and genera, especially some that are distantly related to the previously known <i>Nematocida parisii</i> and instead closely related to human pathogens. We find that some of these species have a narrow host range. We studied two species in detail using electron microscopy and uncover a new likely mode of exit from the host cell, by budding off the host cell plasma membrane rather than by fusion of a vesicle to the plasma membrane as in <i>N. parisii.</i> We also find a new species that infects the epidermis and muscles of <i>Caenorhabditis</i> rather than the host intestinal cells and is closely related to human pathogens. Finally, we find that one <i>Nematocida</i> species fails to elicit the same host response that other <i>Nematocida</i> species do. These new microsporidia open up many windows into microsporidia biology and opportunities to investigate host-parasite coevolution in the <i>C. elegans</i> system.