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Plasmodium infection inhibits the induction of adaptive immunity to heterologous antigens by …

Biology Articles » Parasitology » Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function » Background

- Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function

Malaria is the major parasitic disease of humans throughout the tropics and subtropics, mainly affecting children under 5 years of age and causing 500 million clinical cases and up to 2.7 million deaths each year [1]. In addition to infection-induced mortality, malaria is also associated with public-health problems resulting from impairment of immune responses. Although this immunosuppression may have evolved as a mechanism by which the parasite can prevent immune-mediated clearance [2-8], it leaves malaria-infected individuals or experimental animals more susceptible to secondary infections, such as non-typhoidal Salmonella [9], herpes zoster virus [10], hepatitis B virus [11], Moloney leukemia virus [12] and nematode infection [13], as well as Epstein-Barr virus reactivation [14-17]. Because the efficacy of heterologous vaccines can also be suppressed in malaria-infected patients [18-21], children showing clinical signs of malaria are rarely immunized until after anti-malarial chemoprophylaxis, which can improve the response to vaccination [22]. In a recent study of a new conjugate vaccine against pneumococci, efficacy was reduced during the malaria transmission season [23], demonstrating the possible impact of malaria infection on large-scale vaccine regimes. Certain vaccines, however, seem to induce protective responses irrespective of malaria status and the immunosuppressive effect of malaria infection might thus not extend to all antigens [20]; studies in vivo are required to investigate this controversy further. Several animal studies have described suppression of immune function by Plasmodium parasites in vitro and in vivo [24-34], but the mechanisms involved remain unclear.

Dendritic cells (DCs) have a crucial role in the activation of T cells and consequently in the induction of adaptive immune responses and immunity [35,36]. There is evidence that many pathogens have evolved mechanisms that subvert DC function, thereby modulating the host's immune response to their advantage [37,38]. Recent studies have revealed that DCs are important in malaria infection, particularly during the early events of induction of the protective immune response to infection [39,40]. It has been reported that red blood cells (RBCs) infected with schizont-stage Plasmodium falciparum activate plasmacytoid DCs as detected by increased expression of the antigen CD86 and the cytokine interferon-α (IFN-α) in vitro [41]. In contrast, the asexual erythrocytic stages of P. falciparum were shown to impair the ability of human DCs to undergo maturation in vitro [42]. Indeed, peripheral blood DCs of P. falciparum-infected children showed reduced levels of the major histocompatibility complex (MHC) molecule HLA-DR compared with uninfected controls [43], suggesting a reduced activation state. Thus, the ability of malaria parasites to inhibit maturation of DCs could be involved not only in parasite-specific immunosuppression but also in the suppression of responses to heterologous antigens such as vaccines and unrelated pathogens [2,19,20]. As human malaria parasites are host-specific, however, observations on the effect of human malaria on DCs are largely limited to studies in vitro.

Here, we describe the mechanism underlying this suppression of immunity in vitro and in vivo. DC activation is dynamically altered by parasitized erythrocytes (pRBCs), partly because of deposition of the malarial pigment hemozoin (HZ) within these cells. Following presentation of heterologous antigen by pRBC-exposed DCs, there is less expansion of CD4+ 'helper' T cells that are essential for the induction of adaptive immunity. Subsequently, migration of T cells to lymphoid follicles is abrogated, leading to defective B-cell expansion and differentiation and a failure of the antibody response. These studies explain why immunity to malaria is slow to develop and why protection against secondary infections is reduced in Plasmodium-infected individuals.

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