Malaria is one of the main health problems facing developing countries today. At present, preventative and treatment strategies are continuously hampered by the issues of the ever-emerging parasite resistance to newly introduced drugs, considerable costs and logistical problems. The main hope for changing this situation would be the development of effective malaria vaccines. An important part of this process is understanding the mechanisms of naturally acquired immunity to malaria. This review will highlight key aspects of immunity to malaria, about which surprisingly little is known and which will prove critical in the search for effective malaria vaccines.

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Immunity to malaria: more questions than answers.

Cerebral malaria is the most severe neurological complication of Plasmodium falciparum malaria. Even though this type of malaria is most common in children living in sub-Saharan Africa, it should be considered in anybody with impaired consciousness that has recently travelled in a malaria-endemic area. Cerebral malaria has few specific features, but there are differences in clinical presentation between African children and non-immune adults. Subsequent neurological impairments are also most common and severe in children. Sequestration of infected erythrocytes within cerebral blood vessels seems to be an essential component of the pathogenesis. However, other factors such as convulsions, acidosis, or hypoglycaemia can impair consciousness. In this review, we describe the clinical features and epidemiology of cerebral malaria. We highlight recent insights provided by ex-vivo work on sequestration and examination of pathological specimens. We also summarise recent studies of persisting neurocognitive impairments in children who survive cerebral malaria and suggest areas for further research.

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Pathogenesis, clinical features, and neurological outcome of cerebral malaria.

Malaria is a serious parasitic disease in the developing world, causing high morbidity and mortality. The pathogenesis of malaria is complex, and the clinical presentation of disease ranges from severe and complicated, to mild and uncomplicated, to asymptomatic malaria. Despite a wealth of studies on the clinical severity of disease, asymptomatic malaria infections are still poorly understood. Asymptomatic malaria remains a challenge for malaria control programs as it significantly influences transmission dynamics. A thorough understanding of the interaction between hosts and parasites in the development of different clinical outcomes is required. In this review, the problems and obstacles to the study and control of asymptomatic malaria are discussed. The human and parasite factors associated with differential clinical outcomes are described and the management and treatment strategies for the control of the disease are outlined. Further, the crucial gaps in the knowledge of asymptomatic malaria that should be the focus of future research towards development of more effective malaria control strategies are highlighted.

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The complexities of malaria disease manifestations with a focus on asymptomatic malaria.

Greater than 80% of malaria-related mortality occurs in sub-Saharan Africa due to infections with Plasmodium falciparum. The majority of P. falciparum-related mortality occurs in immune-naive infants and young children, accounting for 18% of all deaths before five years of age. Clinical manifestations of severe falciparum malaria vary according to transmission intensity and typically present as one or more life-threatening complications, including: hyperparasitemia; hypoglycemia; cerebral malaria; severe malarial anemia (SMA); and respiratory distress. In holoendemic transmission areas, SMA is the primary clinical manifestation of severe childhood malaria, with cerebral malaria occurring only in rare cases. Mortality rates from SMA can exceed 30% in pediatric populations residing in holoendemic transmission areas. Since the vast majority of the morbidity and mortality occurs in immune-naive African children less than five years of age, with SMA as the primary manifestation of severe disease, this review will focus primarily on the innate immune mechanisms that govern malaria pathogenesis in this group of individuals. The pathophysiological processes that contribute to SMA involve direct and indirect destruction of parasitized and non-parasitized red blood cells (RBCs), inefficient and/or suppression of erythropoiesis, and dyserythropoiesis. While all of these causal etiologies may contribute to reduced hemoglobin (Hb) concentrations in malaria-infected individuals, data from our laboratory and others suggest that SMA in immune-naive children is characterized by a reduced erythropoietic response. One important cause of impaired erythroid responses in children with SMA is dysregulation in the innate immune response. Phagocytosis of malarial pigment hemozoin (Hz) by monocytes, macrophages, and neutrophils is a central factor for promoting dysregulation in innate inflammatory mediators. As such, the role of P. falciparum-derived Hz (PfHz) in mediating suppression of erythropoiesis through its ability to cause dysregulation in pro- and anti-inflammatory cytokines, growth factors, chemokines, and effector molecules is discussed in detail. An improved understanding of the etiological basis of suppression of erythropoietic responses in children with SMA may offer the much needed therapeutic alternatives for control of this global disease burden.

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Severe Malarial Anemia: Innate Immunity and Pathogenesis

Resolution of infections depends on the host's ability to mount a protective immune response. However, an exacerbated response to infections may result in deleterious lesions. Consequently, immunoregulatory mechanisms are needed to control immune response and prevent infection-associated lesions. Interleukin 10 may be a major regulator of innate and adaptive immunity in vitro and in animals, but its role in human infections is still unclear. Review of the published work reveals wide involvement of interleukin 10 in two major features of infectious diseases. On one hand, interleukin 10 prevents the development of immunopathological lesions that result from exacerbated protective immune response to acute and chronic infections. On the other hand, it is critically involved in persistence of bacteria and viruses by interfering with innate and adaptive protective immunity. Moreover, infections induce the expansion of interleukin-10-producing regulatory cells that are involved in protection against allergic diseases.

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The two faces of interleukin 10 in human infectious diseases

Inflammatory cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. A total of 248 cases of severe Plasmodium falciparum malaria among children aged 3 months to 14 years residing in Bandiagara, Mali, were matched to cases of uncomplicated malaria and healthy controls. Using modified World Health Organization criteria for defining severe malaria, we identified 100 cases of cerebral malaria (coma, seizure, and obtundation), 17 cases of severe anemia (hemoglobin, 500,000/mm3). Significantly elevated levels (given as geometric mean concentrations in picograms/milliliter) of interleukin-6 (IL-6; 485.2 versus 54.1; P = 5 g/dl. Hyperparasitemia was associated with significantly lower levels of IL-6 (336.6 versus 602.1; P = 0.002). These results illustrate the complex relationships between inflammatory cytokines and disease in P. falciparum malaria.

https://iai.asm.org/content/iai/72/10/5630.full.pdf

Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1β), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls

M. Dao

Papers

Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1β), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls

Seroprevalence of Borrelia, Rickettsia and Hantaviruses in North Vietnam