MyD88-Deficient Mice Exhibit Decreased Parasite-Induced Immune Responses but Reduced Disease Severity in a Murine Model of Neurocysticercosis

The symptomatic phase of neurocysticercosis (NCC), a parasitic disease of the central nervous system (CNS) in humans, is characterized by inflammatory responses leading to neuropathology and, in some cases, death. In an animal model of NCC in which mice were intracranially inoculated with the parasite Mesocestoides corti, the infection in mice lacking the myeloid differentiation primary response gene 88 (MyD88^−/−) resulted in decreased disease severity and improved survival compared with that in wild-type (WT) mice. The CNS of MyD88^−/− mice was more quiescent, with decreased microgliosis and tissue damage. These mice exhibited substantially reduced primary and secondary microglial nodule formations and lacked severe astrogliotic reactions, which were seen in WT mice. Significantly reduced numbers of CD11b⁺ myeloid cells, αβ T cells, γδ T cells, and B cells were present in the brains of MyD88^−/− mice in comparison with those of WT mice. This decrease in cellular infiltration correlated with a decrease in blood-brain barrier permeability, as measured by reduced fibrinogen extravasation. Comparisons of cytokine expression indicated a significant decrease in the CNS levels of several inflammatory mediators, such as tumor necrosis factor alpha, gamma interferon, CCL2, and interleukin-6, during the course of infection in MyD88^−/− mice. Collectively, these findings suggest that MyD88 plays a prominent role in the development of the hyperinflammatory response, which in turn contributes to neuropathology and disease severity in NCC.Neurocysticercosis (NCC) is the most common parasitic disease of the central nervous system (CNS), occurring as a result of infection of the brain with the larval stage of the tape worm parasite Taenia solium (56). In humans, the disease has a long asymptomatic phase, typically 3 to 5 years, followed by the symptomatic phase, consisting of clinical signs such as epilepsy (43), increased intracranial (i.c.) pressure, obstructive hydroencephalus, stroke, and encephalitis (55, 56). More than 25% of all epileptic cases diagnosed in adults worldwide are due to NCC (19). The sequential progression from asymptomatic to symptomatic NCC depends upon the degeneration of larvae, caused by either therapeutic treatment or normal attrition. This leads to the induction of a strong inflammatory response, causing a chronic granulomatous reaction and the manifestation of symptoms of the disease (41, 57). The immune response in the CNS of symptomatic patients consists of an overt TH1 phenotype (39) or a mixed TH1, TH2, and TH3 phenotype, depending upon the absence or presence of granuloma formation (38). Specifically, the TH1 hyperinflammatory response prevailing in the CNS during the symptomatic phase is thought to be responsible for the severe neuropathology and mortality associated with NCC (55). Direct evidence that the inflammatory/TH1 response contributes to the neuropathology and severity of NCC, however, is limited. Nevertheless, along with antiparasitic drugs, the treatment of NCC patients with immunosuppressive/anti-inflammatory factors such as corticosteroids helps to control the host inflammatory response and associated neuropathology (32). Long-term treatments with steroids, however, lead to problematic side effects that may become life-threatening. Therefore, despite recent advances made in detection and therapy, effective treatment of NCC remains a major challenge, as cysticidal treatment itself results in the symptoms that one is trying to control and/or the manifestation of other complications. Therefore, it is important to understand the pathophysiological basis of the CNS inflammatory response in NCC and to identify critical molecules responsible for such responses.The myeloid differentiation primary response gene 88 (MyD88) is an important regulator of the host inflammatory response (50, 51). The protein produced by the MyD88 gene is an adaptor molecule necessary for signal transductions originating from the interleukin-1 receptor (IL-1R)/IL-18R family of receptors and the Toll-like receptor (TLR) family of proteins (35). Once engaged, TLRs signal through a common pathway involving MyD88 (42), leading to the subsequent downstream activation of the NF-κB and mitogen-activated protein (MAP) kinase pathways and inducing a TH1 proinflammatory response (28). Previous studies have demonstrated that MyD88 knockout mice exhibit defective proinflammatory responses and display dramatic defects in antimicrobial immunity in a variety of infectious disease models, highlighting the importance of this molecule in influencing a wide array of host responses and disease control (2, 8, 18, 45, 52). A contrasting situation occurs in onchocerciasis, an infection of the eye caused by another helminth parasite, Onchocerca volvulus. In this case, MyD88 plays a pivotal role in the development of a persistent hyperinflammatory response eventuating in corneal haze and hence contributing to the development of river blindness (22, 26). An important unanswered question, therefore, is whether MyD88-dependent mechanisms are involved in inflammatory responses that contribute to the observed pathology and severity of NCC or play an essential role in the containment of this disease.The goal of this study was to identify the overall effect of the absence of the MyD88-dependent signaling pathway, using a well-characterized murine model of NCC developed in our laboratory (14). In the present study, we compared the susceptibilities and immunopathology of MyD88^−/− and wild-type (WT) mice infected i.c. with Mesocestoides corti. The contribution of MyD88 signaling to CNS inflammation was assessed by measuring infiltration of various immune cells into the brain, blood-brain barrier (BBB) permeability, and proinflammatory cytokine responses in the CNS of MyD88^−/− and WT mice.