The Seriousness Of Malaria Biology Essay

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Malaria is a febrile illness, clinically characterized by recurrent episodes of high fever (36.9-37.8oC) (Marcovitch, 2005). P. falciparum malaria ranges from asymptomatic, mild and uncomplicated (UM) to severe and complicated malaria (CM) (Laishram et al. 2012). Asymptomatic malaria or chronic malaria is prevalent in malaria endemic areas, characterized by sub-patent (sub-microscopic) parasetemia with no clinical manifestations (Dharmeshkumar et al., 2003). UM is characterized by fever & chills, sweats, headache, vomiting, watery diarrhea, anemia, jaundice and/or spleen enlargement, which can develop into severe & complicated malaria if not treated (Laishram et al. 2012). Severe P. falciparum malaria affects various body systems and presentations include cerebral malaria, hypoglycemia, adult respiratory distress syndrome (ARDS), acute renal failure, disseminated intravascular coagulation, hypotension & shock, and warrants blood transfusion and fluid-electrolyte balance (Dharmeshkumar et al.,, 2003). Severe malarial anemia (SMA) is the most common presentation of CM in young children and is associated with high infant and child (6 months-3years) mortality, in malaria holoendemic areas of Western Kenya, regardless of the parasite densities (Ong'echa et al. 2006).

This range of disease severity is witnessed in children lacking exposure-related immunity in holoendemic areas, where malaria transmission is high throughout the year. For this reason, major efforts are continuously being directed towards early diagnosis, treatment and management of clinical manifestations, in order to avert high malaria-related mortality resulting from severe & complicated malaria (Laishram et al. 2012).

Falciparum malaria pathogenesis and immunity is complex and multi-factorial, dictated by parasite attributes such as density, rosetting & sequestration, genetic diversity, to human factors including genetic susceptibility of the immune system, erythrocyte polymorphisms, nutritional status, complexity of infection, and significantly the circulating antibodies and cytokines (Moormann 2009; Laishram et al. 2012). Antibodies have been evidently shown to play a major role in protection against malaria, especially against blood-stages that lead to clinical malaria, though their correlation to protection has not always been easy to gauge (Langhorne et al. 2008; Moormann 2009). This was supported by experiments in which purified IgG from malaria immune adults resolved high fever and reduced parasetemia in children (Laishram et al. 2012).

Acute uncomplicated P. falciparum malaria in children living in malaria holoendemic areas of Western Kenya, was reported to influence peripheral blood lymphocytes, and resulted in perturbation of B cell homeostasis (Asito et al., 2008). Immune perturbations in malaria infections include polyclonal B cell activation (PBA) (Fesel et al. 2005; Sfriso et al. 2010; Laishram et al. 2012) culminating in polyclonal antibody production hypothesized to protect against P. falciparum erythrocytic stages, by reducing their density thus a reduction in clinical manifestations (Laishram et al. 2012). However, these Abs are also self-reactive and react with host cells and tissues (Baker et al., 2008).

Various studies hypothesize different causal agents and/or mechanisms involved in inducing and perpetuating autoimmune response, and subsequent production of autoantibodies (aAb) in Plasmodium infections. Most studies implicate PBA leading to production of antibodies lacking specificity to parasitic antigens (Sfriso et al. 2010). Other studies credited this to parasite molecular mimicry, mitogens, cryptic and superantigens, polyclonal T cell activation, 'by-stander' T cell activation and autoreactive B/T cells (Phanuphak et al. 1983; Pied et al. 1997; Sfriso et al. 2010).

Human malaria results in production of various aAb, notably rheumatoid factor (RF), anti-nuclear (ANA), anti-ss/dsDNA, anti-ribonucleoprotein (RNP), anti-phospholipids (PL), anti-erythrocyte, anti-lymphocyte, anti-mitochondria (anti-mt) and anti-smooth muscle (SMA); typical of several autoimmune diseases of unknown etiology such as systemic lupus erythmatosus (SLE) (Yaffe 2001; Cainelli, Betterle, and Vento 2004). The degree of exposure to malaria, Plasmodium species, strain and parasetemia determines the array and quantity of aAb produced, and their autoreactivity (Daniel-Ribeiro 2000). However, their mechanistic role(s) in malaria has been uncertain, with some studies suggesting that they have pathological and protective roles (Ermann and Fatman 2001; Cainelli, Betterle, and Vento 2004). Clinical outcomes during acute or chronic malaria have been hypothesized to be as a result of autoimmunity (Daniel-Ribeiro 2000). A possible role of aAb in aggravating UM to severe manifestations such as SMA, due to destruction of uninfected erythrocytes was reported using semi-immune mice having low parasetemia (Helegbe et al. 2009). Anemia is hypothesized to result from an autoimmune response as there is no correlation with parasetemia during malaria infections (Daniel-Ribeiro 2000). Protective role of natural aAb against primary erythrocytic infection has also been hypothesized by several studies (Facer et al.,, 1979; Jayawadena, 1979; Lloyd et al.,, 1994; Daniel-Ribeiro & Zanini, 2001). In vitro studies using monoclonal aAb (MoAb) having different specificities reported inhibited growth of different strains of P. falciparum (Zanini et al., 2009; Brahimi et al., 2011). In addition, studies using sera from patients with autoimmune disease reacted with various P. falciparum antigens, and against young trophozoites of P. yoelii 17XNL strain in experimental murine malaria (Brahimi et al. 2011). These latter studies emphasize that pathological autoimmunity and malaria inhibit rather than enhance each other. Further support comes from epidemiological survey and studies using model organisms, that suggest malaria protection against autoimmune disease development in the malaria endemic areas, despite inducing an autoimmune response (Moore 2007; Farias et al. 2011).

The quantity and quality of functionally active, antigen-specific antibodies reveal the degree of protection against P. falciparum malaria (Courtin et al. 2009). Several studies have reported conflicting results concerning the aAb prevalence, titers, specificity and autoreactivity in asymptomatic and symptomatic malaria infections in malaria-endemic areas. High aAb titers and reactivity were reported in asymptomatic than acute symptomatic malaria subjects (Fesel et al. 2005), while others reported similar levels between the two groups (Yaffe 2001), in women and men alike, as well as young children; although with a lower incidence (Cainelli et al., 2004)). High titers of ANA and anti-SM Abs were reported in immune/chronic and acute malaria infections respectively using murine models (Daniel-Ribeiro 2000), while others reported low ANAs titers and reactivity in 'healthy' individuals being a common observation (Tozzoli et al. 2002). However, data depicting these parameters in children under the age of 5 years in malaria holoendemic areas is scarce.

1.1. Problem statement

Malaria continues to be a deadly life-threatening tropical parasitic disease in Kenya (WHO 2012) with more than 70% of the population living in malaria transmission areas (Douglis 2012). P. falciparum is the most common etiological agent in malaria holoendemic areas of Kenya; the coastal regions, around Lake Victoria region in Nyanza province and Western Kenya, associated with a lot of morbidity and mortality (WHO 2012). Mostly affected are children under the age of 5 years lacking protective acquired malaria immunity (Crawley et al.,, 2010), with more than 34,000 malaria-related deaths being reported annually and 3.5 million being highly at risk of infection and developing severe malaria illness (Douglis 2012).

Due to the (underestimated) burden of malaria in Kenya, malaria control interventions including indoor residual spraying (IRS), insecticide-treated bed nets (ITNs) and early treatment with Artemisinin-based combination therapy (ACT) have been scaled-up in the affected areas hence reduced morbidity and mortality (Crawley et al. 2010; WHO 2012). In spite of 50% reduction in malaria deaths being reported across the country; 36% and 31% reduced child and infant mortality respectively, malaria deaths are still high in Nyanza and Western Kenya attributed to environmental factors favoring mosquito vector population (MOH, 2011). In these areas, malaria prevalence in children aged 1-4 years is 83% out of the estimated 90% prevalence in the overall population, with SMA being the most common presentation of severe malaria and leading cause of malaria-related deaths (Ong'echa et al. 2006).

Malaria control interventions that initially promised a possibility of malaria control, and even elimination in Africa, face challenges including the development of multi-drug resistant P. falciparum strains, mosquito vector insecticide resistance, in addition to the fact that an effective malaria vaccine is still farfetched (Crawley et al. 2010; WHO 2012).The development of RTS,S vaccine, currently in phase III clinical trials in Kenya and other African countries, is promising to protect young children and infants against P. falciparum malaria (30-50% efficacy during phase II trials), though unforeseen challenges cannot be ruled out (Crompton et al., 2010). This warrants continued need for better understanding of mechanisms behind natural acquired immunity to malaria, to boost ideas in vaccine development that can be used to confer protection in children aged <5 years.

1.2. Research Justification

Studies in malaria holoendemic areas of Western Kenya have shown that P. falciparum is associated with a lot of morbidity, hospitalization and mortality in young children aged below 5 years, as a result of severe & complicated malaria, presenting mostly as SMA, developing from untreated uncomplicated malaria (Laishram et al. 2012;Ong'echa et al. 2006).). P. falciparum malaria spectrum (asymptomatic, mild & uncomplicated to severe & complicated) is witnessed in children living in malaria holoendemic areas of Western Kenya, and lack of naturally acquired immunity to malaria lead to severe malaria illnesses and mortality (Laishram et al.,, 2012). Hence, there is need to avert severe malaria manifestations by early diagnosis, treatment and management of clinical uncomplicated malaria.

Autoantibody (aAb) production, a common feature of autoimmunity, has been observed in P. falciparum malaria infections (Daniel-Ribeiro, 2000), mostly associated with polyclonal B cell activation (PBA) (Pied et al.,, 1993; Sfriso et al.,, 2010). However, their mechanistic role(s) in malaria pathogenesis have been widely debated, with protective and pathological role taking centre stage. Clinical outcomes during acute or chronic malaria have been hypothesized to result from autoimmunity (Daniel-Ribeiro, 2000), while other specific clinical manifestations such as malarial anemia has also been evidently suggested using semi-immune malaria-infected mice (Helegbe, 2009). Protective role against malaria has also been suggested by in vitro studies in which monoclonal autoantibodies (MoAb), inhibited parasite growth (Brahimi et al.,, 2011) while sera from autoimmune disease patients, containing an array of autoantibodies previously demonstrated in P. falciparum infections, reacted with a variety of Plasmodium antigens and was specific against young trophozoites of P. yoelii strain (Brahimi et al.,, 2011). This contrasting report has been supported by other discordant results on aAb prevalence, titers and autoreactivity in asymptomatic and symptomatic P. falciparum malaria infections in malaria endemic areas in the tropics (Fessel et al., 2005; Daniel-Ribeiro, 2000; Yaffe, 2001; Cainelli et al., 2004). Thus there is need to gain insight into the probable role(s) of aAb in P. falciparum malaria and possible use in curbing malaria in children.

Malaria immunity is complex and multi-factorial, yet most studies done to understand the mechanisms in P. falciparum malaria pathogenesis during uncomplicated and complicated malaria in children, use adult populations (Crawley et al., 2010). In addition, knowledge of the roles of such immune responses to malaria pathogenesis aids in demarcating protective against pathological responses (Langhorne et al., 2008). Therefore, this study is designed to look at aAb profile and titers, and correlate findings with parasetemia and activated B cell subsets, with focus being to augment knowledge of autoimmunity in malaria pathogenesis in children aged 1-5 years, in a malaria holoendemic area in Western Kenya.

1.3. Null Hypotheses

There are no differences in autoantibody profile and titers in children aged 1-5 years, during and after acute uncomplicated P. falciparum malaria, in Chulaimbo Sub-District hospital in Western Kenya.

1.4. Objectives of the study

1.4.1. General objective

To determine the autoantibody profile and titers in children aged of 1-5 years during acute malaria and post-recovery from Chulaimbo Sub-District hospital in Western Kenya

1.4.2. Specific objectives

To determine the aAb profile and titers in children aged 1-5years during acute malaria and post-recovery from Chulaimbo Sub-District hospital in Western Kenya

To determine the correlation between aAb titers and P. falciparum parasite density in children aged 1-5 years during acute uncomplicated malaria and post-recovery in Chulaimbo Sub-District hospital in Western Kenya

To determine the activated B-cell subsets (IgM+IgD+CD27+CD38+) in children aged 1-5 years during acute uncomplicated malaria and post-recovery in Chulaimbo Sub-District hospital in Western Kenya

To determine the correlation between aAb titers and activated B-cell subsets in children aged 1-5 years during acute uncomplicated malaria and post-recovery in Chulaimbo Sub-District hospital in Western Kenya

1.5. Significance of the study

Autoimmune-mediated protection in malaria could be an invaluable strategy to curb malaria in children, in the event of evidence of a possibility of aAb protection against severe malaria without leading to clinical autoimmunity and autoimmune disease in the future. This would be by using monoclonal auto-antibody (MoAb) against important P. falciparum antigens used by invasive erythrocytic blood stages (young trophozoites), as a complement course of therapy to anti-malarial drugs, currently experiencing challenges due to P. falciparum multi-drug resistant in the region. In addition, more efficacious vaccines could be designed and developed in a manner that can elicit an autoimmune response towards various parasite antigens and offer clinical immunity in non/semi-immune. This would warrant re-evaluation of vaccine development strategies.

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