CD4 T Cell Responses in Lung Tissue and Their Role in Th2 Protective Immunity

The acquisition of protective immunity is a critical feature of the immune system. It is the unique ability of the adaptive immune response to generate and maintain long-lived antigen specific memory cells, which is the key to preventing reinfection and achieving the goal of protective immunity. The importance of secondary lymphoid tissue (such as lymph nodes) as a site of effector CD4 T cell responses and the generation, dissemination and maintenance of memory CD4 T cells is well accepted. However, a key research area needing investigation is the basic biology of the CD4 T cell, particularly the recirculation, distribution and maintenance of CD4 T cells at sites throughout the body. To address these issues we used Nippostrongylus brasiliensis as a model of CD4 mediated protective immunity, combined with G4/IL-4 reporter mice. We show that the lung environment is critical for the priming of CD4 T cells and conferring protective immunity. In contrast to others we find no protective role for the CD4 T cell population of the skin and only a minor role for the population within the gut. In a separate study we used the drug fingolimod (FTY720) to block the cellular trafficking between lymph node and lung tissue during immune responses. Interestingly, our findings show that protection against N. brasiliensis infection is maintained when CD4 T cell recirculation between the lung and lymph node is blocked. Furthermore, we reveal that peripheral lung residing CD4 T cells are sufficient for conferring protective immunity in the N. brasiliensis model, generating support for the model of effector lymphoid tissue. When N. brasiliensis experienced CD4 T cells were localised to the lung by intranasal adoptive transfer they were able to confer protection against infection in otherwise naive animals, as early as 48 hours post infection. The most striking finding of this work is the discovery that memory CD4 T cells residing in the lung that are sufficient to confer protection against reinfection. Identifying the factors in the lung and lymph node that induce and support this CD4 T cell subset will be an important area of future research given its high relevance to the design of vaccines against parasite infections

Field Testing Integrated Interventions for Schistosomiasis Elimination in the People\u27s Republic of China: Outcomes of a Multifactorial Cluster-Randomized Controlled Trial

Despite significant progress, China faces the challenge of re-emerging schistosomiasis transmission in currently controlled areas due, in part, to the presence of a range of animal reservoirs, notably water buffalo and cattle, which can harbor Schistosoma japonicum infections. Environmental, ecological and social-demographic changes in China, shown to affect the distribution of oncomelanid snails, can also impact future schistosomiasis transmission. In light of their importance in the S. japonicum, lifecycle, vaccination has been proposed as a means to reduce the excretion of egg from cattle and buffalo, thereby interrupting transmission from these reservoir hosts to snails. A DNA-based vaccine (SjCTPI) our team developed showed encouraging efficacy against S. japonicum in Chinese water buffaloes. Here we report the results of a double-blind cluster randomized trial aimed at determining the impact of a combination of the SjCTPI bovine vaccine (given as a prime-boost regimen), human mass chemotherapy and snail control on the transmission of S. japonicum in 12 selected administrative villages around the Dongting Lake in Hunan province. The trial confirmed human praziquantel treatment is an effective intervention at the population level. Further, mollusciciding had an indirect ~50% efficacy in reducing human infection rates. Serology showed that the SjCTPI vaccine produced an effective antibody response in vaccinated bovines, resulting in a negative correlation with bovine egg counts observed at all post-vaccination time points. Despite these encouraging outcomes, the effect of the vaccine in preventing human infection was inconclusive. This was likely due to activities undertaken by the China National Schistosomiasis Control Program, notably the treatment, sacrifice or removal of bovines from trial villages, over which we had no control; as a result, the trial design was compromised, reducing power and contaminating outcome measures. This highlights the difficulties in undertaking field trials of this nature and magnitude, particularly over a long period, and emphasizes the importance of mathematical modeling in predicting the potential impact of control intervention measures. A transmission blocking vaccine targeting bovines for the prevention of S. japonicum with the required protective efficacy would be invaluable in tandem with other preventive intervention measures if the goal of eliminating schistosomiasis from China is to become a reality

Vaccination to protect against infection of the female reproductive tract

Infection of the female genital tract can result in serious morbidities and mortalities from reproductive disability, pelvic inflammatory disease and cancer, to impacts on the fetus, such as infant blindness. While therapeutic agents are available, frequent testing and treatment is required to prevent the occurrence of the severe disease sequelae. Hence, sexually transmitted infections remain a major public health burden with ongoing social and economic barriers to prevention and treatment. Unfortunately, while there are two success stories in the development of vaccines to protect against HPV infection of the female reproductive tract, many serious infectious agents impacting on the female reproductive tract still have no vaccines available. Vaccination to prevent infection of the female reproductive tract is an inherently difficult target, with many impacting factors, such as appropriate vaccination strategies/mechanisms to induce a suitable protective response locally in the genital tract, variation in the local immune responses due to the hormonal cycle, selection of vaccine antigen(s) that confers effective protection against multiple variants of a single pathogen (e.g., the different serovars of Chlamydia trachomatis) and timing of the vaccine administration prior to infection exposure. Despite these difficulties, there are numerous ongoing efforts to develop effective vaccines against these infectious agents and it is likely that this important human health field will see further major developments in the next 5 years

An Ex Vivo Model for Studying Hepatic Schistosomiasis and the Effect of Released Protein from Dying Eggs

BACKGROUND:We report the use of an ex vivo precision cut liver slice (PCLS) mouse model for studying hepatic schistosomiasis. In this system, liver tissue is unfixed, unfrozen, and alive for maintenance in culture and subsequent molecular analysis. METHODS AND FINDINGS:Using thick naive mouse liver tissue and sterile culture conditions, the addition of soluble egg antigen (SEA) derived from Schistosoma japonicum eggs, followed 4, 24 and 48 hrs time points. Tissue was collected for transcriptional analysis and supernatants collected to quantitate liver enzymes, cytokines and chemokines. No significant hepatotoxicity was demonstrated by supernatant liver enzymes due to the presence of SEA. A proinflammatory response was observed both at the transcriptional level and at the protein level by cytokine and chemokine bead assay. Key genes observed elevated transcription in response to the addition of SEA included: IL1-α and IL1-β, IL6, all associated with inflammation. The recruitment of antigen presenting cells was reflected in increases in transcription of CD40, CCL4 and CSF1. Indications of tissue remodeling were seen in elevated gene expression of various Matrix MetalloProteinases (MMP3, 9, 10, 13) and delayed increases in TIMP1. Collagen deposition was significantly reduced in the presence of SEA as shown in COL1A1 expression by qPCR after 24 hrs culture. Cytokine and chemokine analysis of the culture supernatants confirmed the elevation of proteins including IL6, CCL3, CCL4 and CXCL5. CONCLUSIONS:This ex vivo model system for the synchronised delivery of parasite antigen to liver tissue provides an insight into the early phase of hepatic schistosomiasis, corresponding with the release of soluble proteins from dying schistosome eggs

Kunitz-type protease inhibitor as a vaccine candidate against schistosomiasis mansoni

Objective: The aim of this study was to develop a vaccine against schistosomiasis, which is a major challenge due to the complex lifecycle of the causative schistosome parasite. Methods: SmKI-1 is a 16-kDa Kunitz-type protease inhibitor present in the excretory–secretory products and tegument of adult worms and eggs of Schistosoma mansoni. Two independent vaccine trials were performed in mice to determine the efficacy of rSmKI-1 in developing protective immunity. Results: The results obtained showed reductions of 23–33% in adult worms, 28–31% in intestinal eggs, 33–39% in faecal eggs, and 20–43% in liver eggs. Furthermore, rSmKI-1 significantly increased the production of interferon gamma, interleukin (IL)-10, and IL-6 in vaccinated mice, maintaining a Th1/Th2-type balanced protective response. Conclusions: rSmKI-1 generated partial protection against schistosomiasis mansoni in the murine model of infection and could be developed as part of a combination vaccine with other vaccine candidates to provide an even more solid level of protection

Schistosomiasis protects against multiple sclerosis

The incidences of schistosomiasis and multiple sclerosis (MS) are mutually exclusive worldwide suggesting that schistosomiasis may offer protection against the induction of the immune-mediated disease, MS. Recent studies using the mouse model of MS, experimental autoimmune encephalomyelitis, support a direct suppression of the onset of MS by chronic Schistosoma mansoni infection. Self-reactive Th1 but not Th2 responses develop in infected mice immunized with myelin oligodendrocyte glycoprotein albeit at reduced levels indicating that the induction of auto-reactive T cells is not abolished nor phenotypically altered. CNS infiltration by inflammatory cells, particularly macrophages, is significantly reduced in S. mansoni-infected, immunized mice compared to uninfected, immunized mice. Because activated macrophages are crucial to the induction of clinical disease, these findings support the hypothesis that differences in macrophage activation may contribute to the reduced incidence and delayed progression of experimental autoimmune encephalomyelitis during schistosomiasis

T cell-mediated immunity in CBA mice during Schistosoma japonicum infection

Characterisation of the cellular immune response to schistosomiasis is well established for Schistosoma mansoni but a comprehensive description of T cell-mediated immune responses against S. japonicum infection is lacking. Accordingly, 20 CBA mice were infected with cercariae of S. japonicum and the immune response at different time points was determined. Mouse spleen and liver lymphocytes were isolated from the mice and stimulated with schistosomal adult worm antigen preparation (SWAP) and schistosomal soluble egg antigen (SEA). There was a relatively higher Th1 immune response to SWAP compared to SEA at the early phase of infection (up to week 5 post challenge). However, a Th2 immune response directed against SEA was dominant at week 6 post-infection, a time point when the highest IgG response against both SWAP and, especially, SEA was generated. The regulatory immune response was highest at the early phase of the immune response (up to week 5 post challenge) followed by a rapid decline at week 6-post infection. Before egg-laying, S. japonicum induced a regulatory T cell immune response which may limit the early Th1-mediated immune response that is believed to be protective in murine schistosomiasis. Following egg laying, the immune response was polarized to a Th2 immune response mainly directed against the eggs and this may contribute to parasite survival