Targeting nucleic acid receptors to improve filarial vaccination in the <em>Litomosoides sigmodontis</em> model

Abstract

Lymphatic filariasis and onchocerciasis (river blindness) are human filarial diseases, which put a high socio-economic burden on endemic countries. Until now no vaccination is available, which could greatly aid elimination goals. Protective immunity is not yet well understood and has been linked to Th2-dominated immune responses. However also Th1-associated immune responses were shown to be protective and the need for a balanced immune response to clear the infection has been suggested. An unexplored field during filarial infections is the contribution of nucleic acid sensing to protective immunity.<br /> In this thesis it was shown that nucleic acids derived from the rodent-pathogenic filaria <em>Litomosoides sigmodontis</em> induced the secretion of type I interferon by human and murine cells. Further IFN- β production in the pleural cavity was increased during the course of infection with <em>L. sigmodontis</em>, which correlated with the worm burden. At the same time there was no impact on larval migration to the pleural cavity in nucleic acid receptor MDA5-, TLR7-, TLR9- or STING-deficient mice.<br /> However, the stimulation with the nucleic acid receptor agonist 3pRNA or poly(I:C) reduced larval counts in the pleural cavity and therefore the agonists were analyzed further as potential vaccine adjuvants.<br /> In the immunization setting with irradiated <em>L. sigmodontis</em> L3 larvae the adjuvants enhanced the local immune activation. Two weeks after the last immunization parasite-specific antibodies were detected in the serum and the serum was potent in inhibiting the motility of L3 larvae <em>in vitro</em>. This was enhanced by the use of poly(I:C) or 3pRNA as adjuvant during immunization.<br /> The immunization was followed by a challenge infection. There the use of transfected poly(I:C) or 3pRNA as adjuvant reduced the adult worm burden in the pleural cavity by 73% and 57%, respectively, while the immunization without adjuvant resulted in a reduction of 45%.<br /> Overall, the data suggest that type I interferons may have a protective role in filarial infections and the nucleic acid receptor agonists poly(I:C) and 3pRNA may be promising adjuvant candidates for the development of an effective filarial vaccine.