Malaria infection caused by Plasmodium parasites remains a major health burden worldwide especially in the tropics and subtropics. Plasmodium exhibits a complex life cycle whereby it undergoes a series of developmental stages in the Anopheles mosquito vector and the vertebrate human host. Malaria severity is mainly attributed to the genetic complexity of the parasite which is reflected in the sophisticated mechanisms of invasion and evasion that allow it to overcome the immune responses of both its invertebrate and vertebrate hosts. In this review, we aim to provide an updated, clear and concise summary of the literature focusing on the interactions of the vertebrate innate immune system with Plasmodium parasites, namely sporozoites, merozoites, and trophozoites. The roles of innate immune factors, both humoral and cellular, in anti-Plasmodium defense are described with particular emphasis on the contribution of key innate players including neutrophils, macrophages, and natural killer cells to the clearance of liver and blood stage parasites. A comprehensive understanding of the innate immune responses to malaria parasites remains an important goal that would dramatically help improve the design of original treatment strategies and vaccines, both of which are urgently needed to relieve the burden of malaria especially in endemic countries.
The two major intestinal α-glycosidases, sucrase-isomaltase (SI) and maltase-glucoamylase (MGAM), are active towards α-1,4 glycosidic linkages that prevail in starch. These enzymes share striking structural similarities and follow similar biosynthetic pathways. It has been hypothesized that starch digestion can be modulated via “toggling” of activities of these mucosal α-glycosidases, suggesting a possible interaction between these two enzyme complexes in the intestinal brush border membrane (BBM). Here, the potential interaction between SI and MGAM was investigated in solubilized BBMs utilizing reciprocal pull down assays, i.e., immunoprecipitation with anti-SI antibody followed by Western blotting with anti-MGAM antibody and vice versa. Our results demonstrate that SI interacts avidly with MGAM concomitant with a hetero-complex assembly in the BBMs. This interaction is resistant to detergents, such as Triton X-100 or Triton X-100 in combination with sodium deoxycholate. By contrast, inclusion of sodium deoxycholate into the solubilization buffer reduces the enzymatic activities towards sucrose and maltose substantially, most likely due to alterations in the quaternary structure of either enzyme. In view of their interaction, SI and MGAM regulate the final steps in starch digestion in the intestine, whereby SI assumes the major role by virtue of its predominant expression in the intestinal BBMs, while MGAM acts in auxiliary supportive fashion. These findings will help understand the pathophysiology of carbohydrate malabsorption in functional gastrointestinal disorders, particularly in irritable bowel syndrome, in which gene variants of SI are implicated.
Sucrase isomaltase (SI) is the most prominent disaccharidase in the small intestine responsible for the final steps of carbohydrate digestion. Mutations in the SI gene can lead to a drastic reduction or loss of the catalytic activity required for digestion of disaccharides, and thus can be associated with maldigestion and malabsorption of carbohydrates. Carbohydrate malabsorption is one of the most common gastrointestinal problems, where 70% of the population are affected. Congenital sucrase‐isomaltase deficiency (CSID) is an autosomal recessive disorder caused by defective SI activity; and it is clinically characterized by abdominal pain, flatulence, bloating, and diarrhea. Recently, a homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), was identified in the Inuit population with an observed allele frequency of 17.2%. In this study, Cos‐1 cells were transiently transfected with cDNA encoding the Gly92Leufs*8 mutation or SI wild‐type (SI‐WT) as a control. The assessment of this new variant phenotype was investigated through enzymatic activity measurements, cellular localization and trafficking behavior. The truncation is associated with the elimination of all N‐glycosylation sites, whereas the Ser/Thr‐rich stalk region is retained pointing to a potential O‐glycosylation. In fact, treatment with benzyl 2‐acetamido‐2‐deoxy‐α‐D‐galactopyranoside, an inhibitor of O‐glycosylation in the Golgi, resulted in a substantial shift in the size of the mutant concomitant with transport competence of the mutant to O‐glycosylation in the Golgi Apparatus. The mutant is further trafficked to the cell surface as assessed by the detection of biotinylated forms of the mutant at the cell surface. This result was also corroborated by immunofluorescence images, which revealed the mutant at the cell surface. However, this mutant does not exhibit SI activity due to the absence of the sucrase and isomaltase domains. While our data unraveled the molecular basis for the onset of the clinical symptoms in patients homozygous to this mutation, further work is needed to determine whether heterozygotes with this mutation are also affected and to which extent.
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