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However, when a foreign agent such as a parasite establishes in the CNS, a set of immune defences is mounted and several immune molecules are released to promote an array of responses, which ultimately would control the infection and associated damage. Instead, a host\u2013parasite relationship is established, in the context of which a close biochemical coevolution and communication at all organization levels between two complex organisms have developed. The ability of the parasite to establish in its host is associated with several evasion mechanisms to the immune response and its capacity for exploiting host-derived molecules. In this context, the CNS is deeply involved in modulating immune functions, either protective or pathogenic, and possibly in parasitic activity as well,<jats:italic>via<\/jats:italic>interactions with evolutionarily conserved molecules such as growth factors, neuropeptides and hormones. This review presents available evidence on some examples of CNS parasitic infections inducing different morbi-mortality grades in low- or middle-income countries, to illustrate how the CNS microenvironment affect pathogen establishment, growth, survival and reproduction in immunocompetent hosts. 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