Children living in endemic countries are constantly exposed to STH infections as soon as they start to crawl. Reinfection with the same or different STH species is common leading to co-infection of helminth species. Plasmodium species being a common parasitic disease among children living in the tropical and subtropical countries including Tanzania, its coexistence with STH is not uncommon. Recently, a number of conflicting results have been published and other scientific work ongoing to explore the interactions between Plasmodium and STH (Nacher, 2011, Adegnika and Kremsner, 2012). This is not a new field in such as for many years scientists have been considering that worms are somehow good for our health, which of course questions the public health benefit, and hence relevance of the deworming (Bundy et al., 2000, Nacher, 2002, Nacher, 2011, Wammes et al., 2014). Experiences from industrialized developed countries shows an increment of inflammatory diseases and allergies (atopy and asthma) as per “hygiene hypothesis theory” (Strachan, 1989). Success stories from case reports and clinical trials on using a porcine whipworm (Trichuris suis), hookworm (Necator americanus) and E. vermicularis for treatment of inflammatory bowel diseases (IBD) have been documented (Elliott and Weinstock, 2012) and many other clinical trials are in the pipeline (Wammes et al., 2014). Here we summarize the possible mechanisms of interaction between STH and Plasmodium, either directly or mediated through the host.
13 1.3.1 Direct interaction and resource competition
STH are macroparasites mostly occupying the human intestinal lumen (Jackson et al., 2009). Generally, the outcome of pathogenesis to the host varies depending on the co-infected species as outlined by Petney & Andrew (Petney and Andrews, 1998), and summarized in Table 2. The pathological damage caused by one parasite could influence the susceptibility of the host to a different species. Competition between parasite species can either limit population size or can cause changes in the anatomical site of the infection in the host (change in the occupied niche) (Petney and Andrews, 1998). This is a characteristic of most of the parasite within the host, for example hookworm, A. lumbricoides and S. stercoralis with visceral migration as compared to E. vermicularis and T. trichiura which are mostly localized in the lumen of gastrointestinal tract. Different mechanism of interaction occurs most likely at different stages of the life cycles (Churcher et al., 2006, Yakob et al., 2013). The rate and multiplicity of species observed as disease progression process for example with Plasmodium species could be influenced by other co- infecting species. Factors triggering the progression of Plasmodium infection from the liver stage to a blood stage or from asymptomatic Plasmodium infection to a clinical disease state are still vague (Stanisic et al., 2013). Complex mechanisms are involved in structuring the interactions which could be synergistic, antagonistic or neutral depending on external and internal factors shaping the co-infection (Petney and Andrews, 1998). Both interference and exploitation competition can occur depending on the co-infecting species virulence, abundance, over-dispersion within the host and sequence in which the host acquired the infections (Fakae et al., 1994, May and Nowak, 1995, Petney and Andrews, 1998).
Table 2. The possible outcomes of the two species parasite infection on the pathogenicity to the host
14 1.3.2 Immune mechanisms
Different immunological mechanisms induced by helminth infection have been highlighted as potentially protective against Plasmodium infection or increasing the risk. Infection with helminth has a profound effect on the immune system resulting in polarisation towards T helper 2 (Th2) responses, characterized by high levels of cytokines such as interleukin-4 (IL-4), IL-5, IL-13 and high serum levels of immunoglobulin E (IgE) (Maizels and Yazdanbakhsh, 2003, Jackson et al., 2009). Despite these strong Th2 responses, adult helminth often survives in the human host, sometimes for decades. The mechanisms include the induction of regulatory T (Treg) cells and modulation of cells of the innate immune system (Wammes et al., 2014), such as alternatively activated macrophages (AAMφ), myeloid depressed suppressor cells (MDSC)(Gabrilovich and Nagaraj, 2009), regulatory dendritic cells (DCreg) and regulatory natural killer cells (NKreg)(Jewett et al., 2013), which results in an anti-inflammatory environment, characterized by increased levels of IL-10 and transforming growth factor-β (TGF-β). The excretory and secretory products of helminth causing immune-regulatory activities have been documented (McSorley et al., 2013). This regulatory network prevents the elimination of the helminth and at the same time protects the host against pathology that would otherwise result from excessive inflammation. The hypo-responsiveness also termed as “modified Th2 immune response” is not only directed towards helminth antigens, but appears to extend to third party antigens. These includes Plasmodium infection, allergies and inflammatory conditions such as autoimmune diseases and IBD (Jackson et al., 2009, Nacher, 2011, Elliott and Weinstock, 2012). The immune correlates of protection for the Plasmodium are not well characterized. Cytophilic antibodies immunoglobulin-G1 (IgG1) and IgG3 are probably the major effectors of Plasmodium parasite clearance during the blood stage (Cohen et al., 1961). The role of CD4 T-cells against blood-stage malaria has been investigated in rodent models and indicates that Th1 cells are involved during the acute phase through the production of pro-inflammatory cytokines such as IFN- and TNF- while Th2 cells are important for the clearance of the parasite, involving active cooperation of innate immunity including monocytes/macrophages, dendritic cells, natural killer (NK) cells, natural killer T (NKT) cells and δT cells (Bouharoun-Tayoun et al., 1990, Achtman et al., 2005, Stanisic et al., 2013). Figure 7 summarizes A. the immune response to malaria infection and B. the immune response to helminth infection.
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Figure 7. A. The immune response to malaria infection. 7. B. The immune response to helminth infection.
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The Th2/Treg response is presumed to modify the malaria immunity in two main hypotheses which support either the protective or the enhancing role of helminths for severe malaria. First, the helminth could protect through an increase in IgE complexes that activate high affinity Fc receptors FceRII (CD23) and the anti-inflammatory IL-10 which activate the nitric oxide synthase releasing the nitric oxide leading to reduced sequestration of parasited red blood cells (Nacher, 2002). Additionally, T cells with regulatory function (Treg) in helminth co-infected children may lead to suppression of Th1 and pro-inflammatory responses which are key for Plasmodium parasite clearance within the host (Hartgers et al., 2009). Secondly, the helminths are presumed to decrease cytophilic IgG1 and IgG3 and increase non-cytophilic IgG2, IgG4 and IgM antibodies. This alters antibody dependent cellular inhibition (ADCI) leading to increase in incidence and severity of malaria (Druilhe et al., 2005, Roussilhon et al., 2010).
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