Inhibition of Activin A suppressed tumor necrosis factor-α secretion and improved histopathological conditions in malarial mice

Malaria Infection still remains as one of the most prominent parasitic diseases afflicting mankind in tropical and subtropical regions. The severity of malaria Infection has often been associated to exuberant host immune inflammatory responses that could possibly lead to severe immunopathological conditions and subsequent death of host tissues. Activin A is a protein belonging to the transforming growth factor-beta (TGF-β) family that regulates multiple physiological processes and pathological-associated diseases. The biological roles of Activin A have been associated with manipulation of inflammation-related processes and modulation of host immune responses. This implies that Activin A protein could play a role in malaria pathogenesis since malaria Infection has been closely linked to severe immune responses leading to death, However, the actual in vivo role of Activin A in malaria Infection remains elusive. Hence, this study was undertaken to investigate the involvement of Activin A in malaria Infection as well as to assess the modulating effects of Activin A on the cytokine releases (TNF-α, IFN-γ and IL-10) and histopathological changes in major affected organs (kidney, liver, lung, brain and spleen) in malarial mice infected with Plasmodium berghei ANKA. Our results showed that the concentrations of plasma Activin A were significantly increased in malarial mice throughout the study periods. Also. the systemic Activin A level was positively correlated with malaria parasitemia. This indicates that Activin A could play a role in malaria pathogenesis and malaria parasitemia development. Plasma TNF-α, IFN-γ and IL-10 cytokine levels were significantly increased in malarial mice at day-5 post Infection, suggesting that these cytokines attributed to severe malaria pathogenesis. Histopathological features such as sequestration of parasitized red blood cells (pRBCs) and hemozoin formation were amongst the most common pathological conditions observed in tissues of major affected organs (kidney, liver, lung, brain and spleen) in malarial mice. Neutralization of Activin A production via recombinant mouse activin RIIA Fc chimera (rmActivin RIIA Fc chimera) had significantly reduced the parasitemia levels in malarial mice. The release of TNF-α cytokine was significantly reduced as well as the sequestration of parasitized pRBCs and hemozoin formation in major affected organs in malarial mice were also alleviated following inhibition of Activin A production. Overall, this preliminary study suggests that Activin A could play an immune modulation role in malaria pathogenesis through modulation of TNF-α release that benefits host from severe pathological destructions provoked by intensified inflammatory responses. Further studies are warranted to elucidate the precise mechanism of immune modulation mediated by Activin A and its associated immune-modulation mediators in regulating the inflammatory responses elicited during the course of malaria Infection.