Biomarkers and host-parasite interactions in neurocysticercosis and other helminths

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

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 now 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. We have demonstrated the usefulness of targeting GP50, Ts24, and Ts18var3 proteins in ELISA format (Triplex assay) to detect Taenia-specific antibodies in patients, with nearly the same sensitivity as EITB. We examined the serologic responses in our cohort of patients, with a median follow up time of 8 years. The duration of seropositivity following disease cure was highly dependent on the classification of disease, with subarachnoid disease patients having a longer time to sero-reversion compared with parenchymal disease (Emerg Infect Dis. 2023. 7:1340-1348). We have converted this assay into multiplexed bead assay (single tube) and will be organizing to make a lateral flow point of care test for NCC diagnosis. 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. Over the past year we have delved into further understanding the inflammatory response through single cell sequencing and flow cytometry of CSF cells over the course of disease treatment. We have now identified the cellular sources of the pro- and anti-inflammatory cytokines in the CSF using cryopreserved CSF cells. We now are prospectively sampling fresh CSF cells by multiparameter flow cytometry and single-cell RNAseq. The pathogenesis of disease in SANCC remains less than clear. To explore the role of autoantibody mediated pathology in SANCC, we identified 3 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. Further work is now being pursued to understand the mechanisms underlying this autoantibody-mediated disease process. Our clinical protocol has enabled us to further understand that the factors that put patients at risk for one neglected tropical disease (i.e. neurocysticercosis) are also likely to blame for increased risk of a secondary NTD. Specifically, in our NCC cohort of patients we found in those from areas endemic for Chagas disease, there was a Chagas prevalence of 3%, which is more than other general Latin American communities in the US. As a result of these findings, we advocate for screening of all patients with NCC for Chagas upon hospital presentation. (McAleese KR, Guzman JJ, Thumm L, Nutman TB, Showler A, O'Connell EM. Chagas Disease Prevalence in a Cohort of Neurocysticercosis Patients in a Non-Endemic Setting. Clin Infect Dis. 2022). Emerging cestode infections are also of interest to our group. We have developed a highly sensitive and specific qPCR assay for detection of Echinococcus multilocularis. In collaboration with a group in Virginia, we have described the emergence of Em in the fox population along the East Coast of the US, with isolate genetics similar to 2 human infections that have not travelled outside the US. Thus, it appears the epidemiology of Em is changing and that the more virulent European haplotypes have now become endemic in the US. (N Engl J Med. 2022 387(20):1902-1904)