Blood Fluke Exploitation of Non-Cognate CD4+ T Cell Help to Facilitate Parasite Development

Abstract

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.

Eosinophils Preserve Parasitic Nematode Larvae by Regulating Local Immunity

“…Parasite growth modulation by the immune system has been shown in other helminth infections. For example, T cells facilitate growth of S. mansoni by exerting non-cognate influence on MHC class II + antigen presenting cells (32). In addition, development of the filarial nematode L. sigmodontis is transiently delayed in the absence of IL-5 or eosinophils, and B. malayi development improves in the presence of T cells and NK cells(33–35).…”

Regulation of Innate Responses during Pre-patent Schistosome Infection Provides an Immune Environment Permissive for Parasite Development

“…Although chronic LPS stimulation, administered twice weekly during the first six weeks of infection [4], can restore schistosome development in recombination activating gene-deficient (RAG −/− ) mice, this stimulus is unlikely to be present at high concentrations in mouse plasma during pre-patent infection. We therefore sought to identify other inflammatory processes occurring during the pre-patent stage of schistosome infection in normal mice, as these might be candidates for a physiological stimulus for parasite development.…”

“…Previously, CD4 + T cells were shown to play a fundamental role in schistosome development [1]–[3], as significant impairment of parasite growth and reproductive activity occurred in mice that lack CD4 + T cells. While the precise mechanism by which CD4 + T cells mediate this effect is unclear, the mechanism is indirect, as chronic stimulation of innate immune responses with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) agonist, during pre-patent infection was able to restore parasite development in the absence of CD4 + T cells [4]. Thus, all the host factors necessary for schistosome development are present, or at least can be induced, independently of CD4 + T cells.…”

The helminth parasite proteome at the host–parasite interface – Informing diagnosis and control

“…Several experimental studies have indicated that once established the parasites do not have a passive existence in the host. Apart from obtaining nutrients, the parasites rely on cues from the host for reproduction and development (Babayan et al, 2010;Davies et al, 2001;Cheng et al, 2008;Tang et al, 2013;Lamb et al, 2010). Growth and development of schistosomes can be positively influenced by the host immune cells.…”

“…Growth and development of schistosomes can be positively influenced by the host immune cells. In several studies it appeared that absence of CD4 þ T cells retarded the development and growth of S. japonicum and S. mansoni in early infections in mice (Davies et al, 2001;Cheng et al, 2008;Tang et al, 2013;Lamb et al, 2010). In addition, Davies et al (2001) observed in mice deficient in B and T cells a reduced accumulation of eggs in the liver.…”