Modulation of innate antigen-presenting cell function by pre-patent schistosome infection.

Schistosomes are intravascular helminths that infect over 200 million people worldwide. Deposition of eggs by adult schistosomes stimulates Th2 responses to egg antigens and induces granulomatous pathology that is a hallmark of schistosome infection. Paradoxically, schistosomes require host immune function for their development and reproduction and for egress of parasite eggs from the host. To identify potential mechanisms by which immune cells might influence parasite development prior to the onset of egg production, we assessed immune function in mice infected with developing schistosomes. We found that pre-patent schistosome infection is associated with a loss of T cell responsiveness to other antigens and is due to a diminution in the ability of innate antigen-presenting cells to stimulate T cells. Diminution of stimulatory capacity by schistosome worms specifically affected CD11b(+) cells and did not require concomitant adaptive responses. We could not find evidence for production of a diffusible inhibitor of T cells by innate cells from infected mice. Rather, inhibition of T cell responsiveness by accessory cells required cell contact and only occurred when cells from infected mice outnumbered competent APCs by more than 3∶1. Finally, we show that loss of T cell stimulatory capacity may in part be due to suppression of IL-12 expression during pre-patent schistosome infection. Modulation of CD4(+) T cell and APC function may be an aspect of host immune exploitation by schistosomes, as both cell types influence parasite development during pre-patent schistosome infection.

Blood fluke exploitation of non-cognate CD4+ T cell help to facilitate parasite development.

Schistosoma blood flukes, which infect over 200 million people globally, co-opt CD4+ T cell-dependent mechanisms to facilitate parasite development and egg excretion. The latter requires Th2 responses, while the mechanism underpinning the former has remained obscure. Using mice that are either defective in T cell receptor (TCR) signaling or that lack TCRs that can respond to schistosomes, we show that naïve CD4+ T cells facilitate schistosome development in the absence of T cell receptor signaling. Concurrently, the presence of naïve CD4+ T cells correlates with both steady-state changes in the expression of genes that are critical for the development of monocytes and macrophages and with significant changes in the composition of peripheral mononuclear phagocyte populations. Finally, we show that direct stimulation of the mononuclear phagocyte system restores blood fluke development in the absence of CD4+ T cells. Thus we conclude that schistosomes co-opt innate immune signals to facilitate their development and that the role of CD4+ T cells in this process may be limited to the provision of non-cognate help for mononuclear phagocyte function. Our findings have significance for understanding interactions between schistosomiasis and other co-infections, such as bacterial infections and human immunodeficiency virus infection, which potently stimulate innate responses or interfere with T cell help, respectively. An understanding of immunological factors that either promote or inhibit schistosome development may be valuable in guiding the development of efficacious new therapies and vaccines for schistosomiasis.

Bidirectional transcription is an inherent feature of Giardia lamblia promoters and contributes to an abundance of sterile antisense transcripts throughout the genome.

A prominent feature of transcription in Giardia lamblia is the abundant production of sterile antisense transcripts (Elmendorf et al. The abundance of sterile transcripts in Giardia lamblia. Nucleic Acids., 29, 4674-4683). Here, we use a computational biology analysis of SAGE data to assess the abundance and distribution of sense and antisense messages in the parasite genome. Sterile antisense transcripts are produced at approximately 50% of loci with detectable transcription, yet their abundance at a given locus does not correlate to the abundance of the complementary sense transcripts at that locus or to transcription levels at neighboring loci. These data suggest that sterile antisense transcripts are not simply a local effect of open chromatin structure. Using 5'RACE, we demonstrate that Giardia promoters are a source of antisense transcripts through bidirectional transcription, producing both downstream coding sense and upstream sterile antisense transcripts. We use a dual reporter system to explore roles of specific promoter elements in this bidirectional initiation of transcription and suggest that the degenerate AT-rich nature of TATA and Inr elements in Giardia permits them to function interchangeably. The phenomenon of bidirectional transcription in G. lamblia gives us insight into the interaction between transcriptional machinery and promoter elements, and may be the prominent source of the abundant antisense transcription in this parasite.