Toxolasma gondii and modulation of the susceptibility to develop allergic lung inflammations

FENOY I; ALEJANDRA GOLDMAN

Buenos Aires

Mesa redonda; XXVII Reunión Anual Sociedad Argentina de Protozoología; 2015

SAP

Allergic asthma is an airway chronic inflammatorydisease characterized by increased allergen specific IgE production,predominant eosinophilic airway inflammation, increased mucus secretion anddevelopment of in vivohyperreactivity dependent on increased production of Th2 cytokines. In lastdecades, the incidence of asthma and other allergic diseases has dramaticallyincreased particularly in developed countries. The reasons for the increasedincidence of allergy are still not well understood. The pathogenesis of asthmareflects the influences of multiple risk factors including geneticsusceptibility and environmental factors such as pollution, diet and a lack ofsome infectious stimuli arising from modern sanitary practices and thewidespread use of antibiotics. Certainly, these last three would be mainlyresponsible for the growing prevalence. Within the epidemiological studies, itwas shown that respiratory allergy is less frequent in people exposed toorofecal and foodborne microbes such as the intracellular protozoan Toxoplasmagondii. However, despite the existing epidemiological data and thecharacteristics of the immune response associated with toxoplasmosis showing T. gondii as a possible candidate to beincluded in that modulate infections allergies, the study of the effect ofinfection on T. gondii thedevelopment of these diseases had not been previously addressed. Infection withthe parasite, through stimulation of TLR2, TLR4, TLR-11, TLR12 and CCR5receptors, induces a strong Th1-type immune response, particularly during theacute phase of infection. In turn, as a result of the response and in order toprevent the imbalance of the strong Th1 response resulting in immunopathology,anti-inflammatory cytokines including IL-10 and TGF-β that inhibit IFN-g production and impair macrophage activation areproduced.  Using a well-known mouse modelof experimental asthma, we investigated the consequences of T. gondii infection on the developmentof pulmonary allergic inflammation. Bothacute and chronic infection with T. gondii before allergic sensitizationsubstantially blocked the development ofairway inflammation in adult BALB/c mice as shown by a decrease in bronchoalveolar lavage (BAL) eosinophilia,cell infiltration around airways and vessels and goblet cell hyperplasia. Lowlevels of allergen-specific immunoglobulin IgE and IgG1 and high levels ofallergen-specific IgG2a serum antibodies were detected. A decreased IL-4 andIL-5 production by lymph node cells was observed. The high levels of IFN-ginduced by the parasite along with the reduction of allergen specificTh2-associated cytokines and IgG isotypes suggested that the protective effectmight be related to the high concentrations of Th1 cytokines associated withthe immune response against T. gondii. Nevertheless, othermechanisms could also be participating, particularly when sensitizing duringchronic toxoplasmosis when lower levels of IFN-gare present in response to infection. The possibility that regulatory T cellsnormally prevent and control the development of atopic disorders is supportedfrom research in murine models and humans. Hence, we investigated the cellularmechanisms involved in T. gondii induced protection against allergy. Ourresults show for the first time that thoracic lymph node cells from micesensitized during chronic parasiteinfection have suppressor activity. Suppression was detected both in vitro, on allergen specific Tcell proliferation and in vivo, on allergic lung inflammation afteradoptive transference from infected/sensitized mice to previously sensitizedanimals. This ability was found to be contact- independent and correlated withan expansion of CD4+FoxP3+ cells. Experiments withIL-10-deficient mice suggested that IL-10 is not mediatingthe protection from allergic inflammation. High levels of TGF-b wereonly detected in mice sensitized only during chronic infection. In addition to lung airwayinflammation, T. gondii infection cansuppress allergic responses at systemic level. Sensitization during both acuteand chronic phases of infection resulted in a decreased anaphylaxis reaction.These results open the possibility that this protozoan infection could modulateother allergic disorders such as atopic dermatitis or oral allergies. Our workshows for the first time the ability of aprotozoan to prevent the development of allergic inflammations. Understandingthe mechanisms by which different microorganisms regulate inflammation maypotentially lead to the development of strategies aimed to control atopicdiseases.