Therapeutic role of Filarial HSP70 in murine models of polymicrobial sepsis and H1N1 Influenza

Abstract

Nematodes characteristically modulate effector immune responses by synthesizing and releasing both anti-inflammatory as well as proinflammatory molecules in infected hosts. Pre-clinical studies suggest that immuno-modulatory molecules and synthetic small molecules that mimic parasite products could have therapeutic value to ameliorate tissue damage found in inflammatory diseases. We report here identification of a glycoprotein from filarial parasite, a homologue of mammalian Heat Shock Protein 70 with immunostimulatory attributes. The purified native glycoprotein designated as FHSP70 and its recombinant protein moiety, WFL were found to be TLR2 and TLR4 agonists in vitro in human myeloid cells and induce systemic inflammatory cytokines in vivo. Cecal ligation and puncture (CLP) performed in mice which leads to onset of poly microbial sepsis and mortality could be treated by therapeutic administration of a single dose of FHSP70, along with antibiotics, suggesting its potential as a immunotherapeutic adjuvant for clinical management of Sepsis. Intra-nasal administration of WFL to mice followed by challenge with virulent human Influenza-A virus resulted in decreased viral growth as well as improved survival. The protective effect was demonstrable by both prophylactic as well as therapeutic intranasal administration of WFL. Further, therapeutic administration of WFL by intraperitoneal route 5 days post viral challenge also resulted in significant decrease in viral load in the respiratory tract. One sentence SummarySystemic administration of a Filarial HSP70 acts as an adjuvant therapy, through immuno-modulation, for improved survival against murine Polymicrobial Sepsis and Viral Infection while its intra nasal administration protects mice prophylactically as well as therapeutically against H1N1 Influenza viral challenge.