Vaccination of mice with chitosan nanogel-associated recombinant NcPDI against challenge infection with Neospora caninum tachyzoites

P>The effects of nanogel encapsulation of recombinant NcPDI (recNcPDI) following vaccination of mice by intranasal or intraperitoneal routes and challenge infection with Neospora caninum tachyzoites were investigated. Nanogels were chitosan based, with an alginate or alginate-mannose surface. None of the mice receiving recNcPDI intraperitoneal (i.p.) (without nanogels) survived, whereas intranasal (i.n.) application protected 9 of 10 mice from disease. Association of recNcPDI with nanogels improved survival of i.p. vaccinated mice, but nanogels without recNcPDI gave similar protection levels. When nanogels were inoculated via the i.n. route, 80% of the mice were protected. Association of recNcPDI with the alginate-coated nanogels protected all mice against disease. Quantification of the cerebral parasite burden showed a significant reduction of parasite numbers in most experimental groups vaccinated i.n., except those vaccinated with alginate-mannose nanogels with or without recNcPDI. For i.p. vaccinated groups, no significant differences in cerebral infection densities were measured, but there was a reduction in the groups vaccinated with recNcPDI associated with both types of nanogels. Analysis of the immune responses of infected mice indicated that association of recNcPDI with nanogels altered the patterns of cytokine mRNA expression profiles, but had no major impact on the antibody subtype responses. Nevertheless, this did not necessarily relate to the protection.

The microbiota provides colonisation resistance against intestinal helminths by regulating intestinal physiology

Luc Xavier Marie Lebon

Intestinal helminth infections are a global health problem affecting particularly people living in poor countries. Heavy worm burdens can lead to nutritional and cognitive deficiencies. Type-two immunity plays a crucial role in promoting tissue repair and limiting parasite burdens; however, our knowledge as to how these responses lead to protection is limited. Moreover, intestinal helminths have co-evolved with their mammalian hosts and are well known to possess potent immuno-modulatory capacities allowing them to establish chronic and repeated infections. As adult worms reside in the gut, we asked whether the presence of intestinal bacterial communities (commonly referred to as the microbiota) impacted on worm burdens or type-two immunity following infection. For this purpose, we infected germ-free (living in a sterile environment) or antibiotic-treated mice with the natural murine parasite Heligmosomoides polygyrus bakeri. As worms are normally hatched from faecal cultures and carry their own microbiota, we first developed a system to generate bacteriologically-sterile (axenic) infective larvae. In germ-free and antibiotic-treated mice, the number of adult worms and their egg production were both increased, despite the presence of a slightly increased helminth-elicited type-two immune response, as shown by cytokine and antibody responses. The increased worm fitness in the absence of microbiota was already detected early following infection and was associated with a more anterior distribution of larvae along the intestinal tract. Thus, we hypothesised that the microbiota may impact on parasite burdens through observed alterations of intestinal physiology, such as increased bile acid production and deregulated smooth muscle cell contractility. To test the importance of these factors, we performed experiments in which we treated mice with an excess of bile acids or altered intestinal transit through drug treatment. Both interventions lead to changes in worm infectivity or location, mirroring different observations generated in our germ-free and antibiotic-treated mice. In summary, our data indicate that a complex microbiota affords 'colonisation resistance' against intestinal helminths, in a manner that is independent of the immune response but dependent on changes to intestinal physiology.

EPFL2017

Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors

Michel Aguet

Alpha/beta interferon (IFN) and gamma IFN exert widely overlapping biological effects. Still, mice with individually inactivated alpha/beta or gamma receptors exhibit variably severely reduced resistance to infection and altered immune responses. To investigate to what extent the two IFN systems are functionally redundant, we generated mice with a combined receptor defect (AG129 mice). Like mice with individual mutations, AG129 mice had no apparent anomalies, confirming that in the mouse the IFN system is not essential for normal development. These mice showed an additive phenotype with respect to antiviral defense and exhibited an increased susceptibility to lymphocytic choriomeningitis virus (LCMV) and notably vaccinia virus infection. Because of unlimited replication and subsequent rapid exhaustion of cytotoxic T lymphocyte (CTL) precursors, these mice were unable to mount a CTL response to LCMV. CD8(+)-mediated immunopathology was absent in LCMV-infected mice, and virus persisted. Vaccinia virus replicated much faster in AG129 mice, and a 10(4)-fold lower dose of vaccinia virus was sufficient to prime these mice. With the normal priming dose of 10(6) PFU, cytopathic effects and overwhelming infection possibly causing partial exhaustion of CTL interfered with the anti-vaccinia virus response. Even though global antiviral immunoglobulin G (IgG) titers were within normal ranges, the IgG subclass distribution was heavily biased toward IgG1.

1995

Immune defence in mice lacking type I and/or type II interferon receptors

Michel Aguet

Mice lacking the receptor for type I interferon (IFN-alpha beta, A129 mice), for type II interferon (IFN-gamma, G129 mice) or for both receptors (AG129 mice) have been generated by embryonic stem cell mediated gene targeting and inter-crossing A129 x G129, respectively. The role of the two IFN systems in controlling a range of infections has been studied using these mice. Type I IFN is shown to be responsible for the immune defence against most viral infections tested (Lymphocytic Choriomeningitis Virus, Semliki Forest Virus, Theiler's Virus, Vesicular Stomatitis Virus), type II IFN seems to be of little importance. In Vaccinia Virus and Theiler's Virus infection, however, both IFN systems were found to play a nonredundant role. IFN-gamma was critical for the defence against intracellular bacteria (Mycobacterium, Listeria) and parasites (Leishmania), whereas IFN-alpha beta was not. IFN-alpha beta is produced by virus-infected cells within hours and plays an important role in preventing virus spread early. Production of IFN-gamma on the other hand needs activation of the immune system and plays a major role later, i.e. mostly during the immune response. Data obtained with the mice described here show that both IFN systems seem to have evolved to complement each other in the host defence against a wide variety of infectious agents.

1995

The microbiota provides colonisation resistance against intestinal helminths by regulating intestinal physiology

Luc Xavier Marie Lebon

EPFL2017