Interplay Between the Immune and Nervous Cognitive Systems in Homeostasis and in Malaria

Abstract

The immune and nervous systems can be thought of as cognitive and plastic systems, since they are both involved in cognition/recognition processes and can be architecturally and functionally modified by experience, and such changes can influence each other's functioning. The immune system can affect nervous system function depending on the nature of the immune stimuli and the pro/anti-inflammatory responses they generate. Here we consider interactions between the immune and nervous systems in homeostasis and disease, including the beneficial and deleterious effects of immune stimuli on brain function and the impact of severe and non-severe malaria parasite infections on neurocognitive and behavioral parameters in human and experimental murine malaria. We also discuss the effect of immunization on the reversal of cognitive deficits associated with experimental non-severe malaria in a model susceptible to the development of the cerebral form of the illness. Finally, we consider the possibility of using human vaccines, largely exploited as immune-prophylactics for infectious diseases, as therapeutic tools to prevent or mitigate the expression of cognitive deficits in infectious and chronic degenerative diseases.

Keywords: homeostasis; immune system; malaria; nervous system; neurocognitive impairment..

Figure 1

Effects of malaria and immune system stimuli on the nervous system performance. Immune events are involved in brain function and neurocognitive homeostasis. T cells and microglia are classically described as important for the maintenance of neurogenesis in the hippocampus, being associated with the capacity for learning and spatial memory in adulthood . The immune system influence is dependent upon the nature and intensity of the (activating or suppressing) stimuli it applies on the nervous system, benefitting or impairing its function. Infectious agents, such as malaria parasite, while promoting immune learning, may also exert signals perceived as disruptive to the immune response, differently from the positive properties of non-infectious stimuli, such as vaccines inducing type 2 immune responses. High levels of cytokines in the peripheral circulation and intracerebroventricular space, such as Interferon (IFN) and Tumor Necrosis Factor (TNF), produced by T cells in response to red blood cell infection (pRBC) and rupture, can impair the brain function and the cognitive ability . On the other hand, the presence of T cells that produce anti-inflammatory cytokines, such as the interleukin 4 (IL-4), has been associated with improved cognitive ability and learning through the induction of brain-derived neurotrophic factor (BDNF) expression by astrocytes . Neurocognitive impairment (learning and memory deficits and anxiety-like behavior) caused by a single episode of non-severe experimental murine malaria can be attenuated or even avoided by exposure to anti-inflammatory immune stimuli that included the largely used diphtheria tetanus human vaccine (Td) . Increased numbers of regulatory T cells (Treg) in the spleen and interleukin 10 (IL-10) levels in the peripheral circulation observed in experimental studies may be involved in such effect .

Figure 2

Main features of severe and non-severe malaria in C57BL/6 mice infected by Plasmodium berghei ANKA. On the fourth day of infection, when the disease can still be characterized as a non-severe malaria, low inflammatory response (few leukocytes adhered to blood vessels) in the brain are recorded, along with low parasitemia (about 2.5%) and oedema . Between the fifth and sixth days of infection, murine cerebral malaria may start to establish. On the fifth day, such events expand throughout the brain and an increase in parasitaemia occurs . Although parasitized red blood cells can also be observed in the brain microenvironment , there is a predominance of leukocyte accumulation, mainly T cells, in the cerebral microvasculature . Generalized and severe bleeding, elevated levels of edema and leukocyte adhesion throughout the brain, and damage to the BBB occur from the sixth day of infection on . Long-term cognitive and behavioral deficits, such as learning and memory difficulties and anxiety-like behavior, are observed as sequelae using this model of infection, including in mice treated the day before the onset of cerebral malaria establishment, the fourth day of infection ,. These sequelae are also evident after cerebral malaria along with motor system impairment ,.