Innate and adaptive immunity to the nematode Strongyloides stercoralis in a mouse model.

Mice have been used to the study the mechanisms of protective innate and adaptive immunity to larval Strongyloides stercoralis. During primary infection, neutrophils and eosinophils are attracted by parasite components and kill the larvae by release of granule products. Eosinophils also function as antigen-presenting cells for the induction of a Th2 response. B cells produce both IgM and IgG that collaborate with neutrophils to kill worms in the adaptive immune response. Vaccine studies have identified a recombinant diagnostic antigen that induced high levels of immunity to infection with S. stercoralis in mice. These studies demonstrate that there are redundancies in the mechanisms used by the immune response to kill the parasite and that a vaccine with a single antigen may be suitable as a prophylactic vaccine to prevent human strongyloidiasis

Macrophages and neutrophils from humans and mice kill larval Strongyloides stercoralis during innate immunity

The parasitic nematode Strongyloides stercoralis (Ss) infects 30-100 million people worldwide, yet little is known about the immune response in humans. Previous studies on innate immunity to Ss in mice have demonstrated a role for eosinophils, neutrophils (PMN) and complement activation in the protective immune response

Extracellular traps are associated with human and mouse neutrophil and macrophage mediated killing of larval Strongyloides stercoralis.

Neutrophils are multifaceted cells that are often the immune system\u27s first line of defense. Human and murine cells release extracellular DNA traps (ETs) in response to several pathogens and diseases. Neutrophil extracellular trap (NET) formation is crucial to trapping and killing extracellular pathogens. Aside from neutrophils, macrophages and eosinophils also release ETs. We hypothesized that ETs serve as a mechanism of ensnaring the large and highly motile helminth parasite Strongyloides stercoralis thereby providing a static target for the immune response. We demonstrated that S. stercoralis larvae trigger the release of ETs by human neutrophils and macrophages. Analysis of NETs revealed that NETs trapped but did not kill larvae. Induction of NETs was essential for larval killing by human but not murine neutrophils and macrophages in vitro. In mice, extracellular traps were induced following infection with S. stercoralis larvae and were present in the microenvironment of worms being killed in vivo. These findings demonstrate that NETs ensnare the parasite facilitating larval killing by cells of the immune system

Vaccines to combat river blindness: expression, selection and formulation of vaccines against infection with Onchocerca volvulus in a mouse model.

Human onchocerciasis is a neglected tropical disease caused by Onchocerca volvulus and an important cause of blindness and chronic disability in the developing world. Although mass drug administration of ivermectin has had a profound effect on control of the disease, additional tools are critically needed including the need for a vaccine against onchocerciasis. The objectives of the present study were to: (i) select antigens with known vaccine pedigrees as components of a vaccine; (ii) produce the selected vaccine antigens under controlled conditions, using two expression systems and in one laboratory and (iii) evaluate their vaccine efficacy using a single immunisation protocol in mice. In addition, we tested the hypothesis that joining protective antigens as a fusion protein or in combination, into a multivalent vaccine, would improve the ability of the vaccine to induce protective immunity. Out of eight vaccine candidates tested in this study, Ov-103, Ov-RAL-2 and Ov-CPI-2M were shown to reproducibly induce protective immunity when administered individually, as fusion proteins or in combination. Although there was no increase in the level of protective immunity induced by combining the antigens into one vaccine, these antigens remain strong candidates for inclusion in a vaccine to control onchocerciasis in humans

Strongyloides stercoralis - Immunological basis for susceptibility and resistance in mice and humans

Strongyloides stercoralis is a parasitic nematode of humans that causes chronic disease resulting in significant morbidity and mortality. Several studies in mice have defined the protective innate and adaptive immune response to the parasite. The objective of this thesis was to determine: 1) the capacity of macrophages to kill larvae, 2) the ability of neutrophils to release extracellular traps and 3) to examine hyperinfection in mice. The use of the diffusion chamber system in mice and the development of an in vitro killing assay have enabled the examination of both mouse and human immune components. We demonstrate that macrophages, like neutrophils and eosinophils have the ability to kill the larvae of S. stercoralis. Interestingly, the larval killing process in vitro required cooperation of human or mouse macrophages, neutrophils and complement. In mice, infection with the parasite results in the induction of alternatively activated macrophages which demonstrated an enhanced capacity to kill the parasite over naïve macrophages. Together these studies validate the concept that immunity to S. stercoralis is comprised of redundant killing mechanisms. In order for larval killing to occur the host immune response must first seize the large and highly motile parasite. Here we show that human and mouse neutrophils release neutrophil extracellular traps (NETs) that serve as a mechanism for ensnaring the parasite. Furthermore, NET formation was required but not sufficient for larval killing. Therefore, functional immune components are integral to trapping and parasite elimination, which ultimately lead to resistance. These findings were further substantiated by the observation that infected immunodeficient and humanized mice developed high parasite burdens. Although these mice were highly susceptible to infection they failed to generate hyperinfection. The occurrence of hyperinfection in severely immunodeficient mice following corticosteroid administration reveals a direct role for steroids in the development of autoinfective larvae. This thesis validates the utility of mice as a model of S. stercoralis infection and hyperinfection. Furthermore, we propose that these findings will help address current drawbacks in the diagnosis and treatment of strongyloidiasis in humans