Biomarkers and host-parasite interactions in neurocysticercosis and other parasitic infections

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

In neurocysticercosis (NCC), the larval form of the tapeworm, Taenia solium, infects the central nervous system (CNS). Most commonly, the parasite is in the substance of the brain ("parenchymal disease") which clinically manifests as seizures most commonly. When the parasite is located in the subarachnoid space, particularly the basilar cisterns of the brain, Sylvian fissures, or around the spinal cord, the cells lining the tegument of the parasite have the ability to self renew like stem cells. This form of the disease, also known as racemose NCC is relapsing and highly recalcitrant to treatment. We have developed and utilized 2 highly sensitive and specific tests (qPCR and Ag testing) for detection of Taenia solium, the causative organism, We have demonstrated the utility in NCC in predicting cure in those with subarachnoid and ventricular NCC. We perform both the antigen and qPCR assays under a Clinical Laboratory Improvements Amendment Certificate for the clinical reporting out of these results to clinicians from around the country. Given the relapsing nature of this disease without a proven end point in treatment previously, this provides some guidance to clinicians as to when to stop treatment. In collaboration with 15 other clinical sites across the US, we led a retrospective study describing a large cohort of SANCC across the country. Use of CSF T. solium biomarkers (antigen [TsAg] and/or qPCR) to guide length of anthelmintic therapy decreased the risk of SANCC recurrence on follow-up imaging, whereas use of brain MRI to guide treatment length did not. A delay in SANCC diagnosis or initial management without anthelmintics was associated with a significant increase in subsequent SANCC-related Emergency Department visits or hospital admissions. This manuscript is awaiting collaborator review and will be submitted for publication soon. Much remains unknown about the inflammation in subarachnoid NCC, yet it is the main driver of morbidity and mortality in this population. We have previously described the cytokine and chemokine milieu of the CSF early in subarachnoid NCC, and how it changes with treatment. In the past year we submitted and have had a manuscript accepted probing the origins of IL-10 in archived CSF cell samples in SANCC patients. We identified three sources of IL-10 within a large CD4+ T cell population: natural regulatory T cells (nTregs), induced regulatory T cells (iTregs), and Th17 cells. The abundance and phenotype of IL-10 producing populations differed between CSF and blood, but iTregs were the single most productive population in the CSF. During treatment, these IL-10 producers persisted in consistent proportions despite decreases in parasite antigen over time (Tang NL, Schaughency P, Gazzinelli-Guimaraes P, Lack J, Thumm L, Miltenberger E, Nash TE, Nutman TB, O'Connell EM. Immunologic Profiling of CSF in Subarachnoid Neurocysticercosis Reveals Specific Interleukin-10-Producing Cell Populations During Treatment. Neurol Neuroimmunol Neuroinflamm. 2024 Nov;11(6):e200320. PMID: 39475624; PMCID: PMC11527482.). The pathogenesis of disease in SANCC remains less than clear. To explore the role of autoantibody mediated pathology in SANCC, we identified 2 CNS-expressed human proteins to which patients with SANCC have marked elevated levels of antibodies to. Further, each of these has highly similar Taenia orthologues suggesting that Taenia infection induces antibodies that cross-react to the human proteins and may drive neurotoxic, pro-inflammatory reactions. We found that Taenia-derived annexin and metabolic enzymes contain epitopes that likely drive local CSF antibody production that cross-reacts with human ANXA8 and BAP18 and may contribute to the pathology underlying SANCC (Guzmán JJ, Bah A, Bennuru S, Harrison S, Nash TE, Sciurba J, Thumm L, Nutman TB, O'Connell EM. Molecular Mimicry Drives Locally Produced Autoantibodies in Subarachnoid Neurocysticercosis. Open Forum Infect Dis. 2025 May 8;12(5):ofaf276. PMID: 40406372; PMCID: PMC12096073). We previously developed an ELISA for Taenia-specific antibody detection. In collaboration with a group at Baylor Medicine, we conducted a cross-section serosurvey of Mexican-American adults residing along the Texas-Mexico border (Starr County, Texas) and identified an overall seroprevalence of 7.4% (45/605) for cysticercosis. Brain imaging studies conducted on seropositive study participants identified lesions consistent with calcified neurocysticercosis in 2 of the 45 seropositive individuals. Female sex (p = 0.021), employment in healthcare, caregiving, or social service (p = 0.002), and indoor occupation (p < 0.001) were found to be significantly associated with seropositivity. (Duffey MM, O'Connell EM, Jibowu M, Moron FE, Leining LM, Tang NL, Hanis CL, Brown EL, Gunter SM. Seroprevalence and Risk Factors for Cysticercosis in Mexican Americans in Starr County, Texas. Pathogens. 2024 Nov 12;13(11):988. PMID: 39599541; PMCID: PMC11597702.)