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      Identification and validation of host biomarkers for leprosy: A step forward to establish point-of-care tests

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      EBioMedicine
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          Abstract

          For infectious diseases in which direct detection of the pathogen is challenging, the discovery, validation and implementation of host biomarkers can be crucial for fast and reliable diagnosis, to monitor responses of treatment and help to optimize treatment regimes. In addition, biomarkers can be helpful in reducing transmission by early identification of cases and contact screening. These factors are also critical to avoid further spreading of pathogens in mycobacterial diseases including tuberculosis caused by Mycobacterium tuberculosis as well as for Buruli ulcer disease caused by M. ulcerans and leprosy caused by M. leprae both classified as neglected tropical diseases (NTDs). Tuberculosis is the classical example for a disease, in which a biomarker assay has been successfully implemented. Interferon-gamma (IFN-γ) release assays (IGRAs) are a standard diagnostic tool in high-income countries with low incidence rates. However, limited sensitivity of IGRAs in young children and immune-compromised individuals as well as potentially in some high-endemic countries highlight the need for additional assays and/or more complex biomarker signatures [1,2]. For many diseases, candidates for promising biomarkers have been identified, but validation and implementation remains a major obstacle [3]. This is especially a problem in NTDs (such as Buruli ulcer disease and leprosy) which are common in low-income countries [4]. Here large-scale approaches to verify biomarkers face huge logistic and financial restrictions and implementation is only achievable if biomarkers are applicable for rapid point-of-care (POC) testing. Furthermore, some NTDs are characterised by a low incidence requiring multi-national long-term approaches for validation. This is the case for Buruli ulcer disease and leprosy where the search for biomarkers is ongoing [5,6]. Leprosy is a highly contagious chronic disease mainly affecting the skin and peripheral nerves. Whereas leprosy has been largely eliminated globally, it remains a serious public health problem in few endemic countries with around 200,000 cases annually [8]. The course of the disease is largely determined by host immune responses involving immune polarisation. A mixed T helper type-1 (TH1) /TH17 response is associated with bacterial control and characteristic for tuberculoid leprosy [7]. In contrast, an immune-regulatory/TH2 response (typically induced in helminth infections), inducing an antibody-mediated immune response, is associated with uncontrolled bacteria (multibacillary) characteristic for Lepromatous leprosy [7]. There are several potential biomarkers for the detection of leprosy described with IgM-antibodies against M. leprae phenolic glycolipid I (anti-PGL-I IgM) being the most promising [6]. In combination with CCL4, IL-10, IP-10 and CRP may help to cover different disease outcomes [9]. However, the performance and validation of these biomarkers is, particularly for paucibacillary disease, still unsatisfactory hindering implementation. In a recent article in EBioMedicine, van Hooij and colleagues present a study using a comprehensive approach to identify new biomarkers, validate candidates and test applicability for POC testing [10]. This study uses a funnel approach including a discovery cohort and two validation cohorts. In the discovery cohort, supernatants of whole blood cultures in the presence of antigens (comparable to IGRAs) were screened using a multiplex bead array testing for 60 proteins focusing on cytokines, chemokines and growth factors. Six proteins were selected potentially identifying both the paucibacillary and multibacillary form of the disease and applied in a validation cohort. That comprises previously identified biomarkers such as CCL4, IL-10 and an IP-10 as well as the new marker IL-1Rα. In addition, authors selected additional 11 biomarkers with known or assumed diagnostic potential and all together were measured by ELISA. The first validation cohort confirmed eight of the candidates of which seven were detected in 24 h culture even without specific stimulus rendering potential analysis in plasma. The direct use of plasma specimens has the advantage that it omits the requirement of an overnight culture. Hence candidates were tested in plasma samples of validation cohort II in which five were detectable. Those, namely S100A12, CRP, ApoA1, IP-10 and anti-PGL-I IgM, were further tested using a lateral flow assay, which is applicable for POC and even larger field screening approaches. All five markers showed differences comparing multibacillary patients and controls, whereas ApoA1 could additionally identify paucibacillary forms. However, apart from anti-PGL-I IgM, which had sufficient sensitivity and specificity to distinguish multibacillary patients from controls as reported earlier [6], none of the other biomarkers showed satisfactory results in terms of sensitivity and specificity prompting authors to analyse a combined five-marker signature. Using this approach, 86% of leprosy patients were identified with comparable results in both paucibacillary and multibacillary patients. This elegant study by van Hooij and colleagues proves that new biomarkers can be identified using a funnel approach. Of the identified marker, two candidates (ApoA1 and S100A12) were even suitable to use in lateral flow assays and therefore applicable for use in POC testing and for larger screening approaches. Furthermore, the study indicates the power of biomarker signatures and it already provides a certain degree of validation of identified markers. Further studies are required to prove that this specific signature is useful in other endemic areas with a different genetic background of the affected population. In addition, the exposure to other infections including other mycobacteria and/or helminth parasites influencing host immune responses may differ in different areas affecting the outcome. To analyse the value of these markers in identifying potentially infected contacts of leprosy patients and individuals at particular risk of developing disease would be an additional long-term goal. This study is a step forward heading towards implementations of according POC tests and also nicely shows that even for a NTD with overall low incidence rates, long-term committed projects can bring advances for improved management. Declaration of Competing Interest The authors declare that they have no conflict of interest.

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          The influence of innate and adaptative immune responses on the differential clinical outcomes of leprosy

          Leprosy is a chronic infectious disease caused by Mycobacterium leprae. According to official reports from 121 countries across five WHO regions, there were 213 899 newly diagnosed cases in 2014. Although leprosy affects the skin and peripheral nerves, it can present across a spectrum of clinical and histopathological forms that are strongly influenced by the immune response of the infected individuals. These forms comprise the extremes of tuberculoid leprosy (TT), with a M. leprae-specific Th1, but also a Th17, response that limits M. leprae multiplication, through to lepromatous leprosy (LL), with M. leprae-specific Th2 and T regulatory responses that do not control M. leprae replication but rather allow bacterial dissemination. The interpolar borderline clinical forms present with similar, but less extreme, immune biases. Acute inflammatory episodes, known as leprosy reactions, are complications that may occur before, during or after treatment, and cause further neurological damages that can cause irreversible chronic disabilities. This review discusses the innate and adaptive immune responses, and their interactions, that are known to affect pathogenesis and influence the clinical outcome of leprosy. Electronic supplementary material The online version of this article (doi:10.1186/s40249-016-0229-3) contains supplementary material, which is available to authorized users.
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            Field-friendly serological tests for determination of M. leprae-specific antibodies

            Early detection of leprosy is key to reduce the ongoing transmission. Antibodies directed against M. leprae PGL-I represent a useful biomarker for detecting multibacillary (MB) patients. Since efficient leprosy diagnosis requires field-friendly test conditions, we evaluated two rapid lateral flow assays (LFA) for detection of Mycobacterium leprae-specific antibodies: the visual immunogold OnSite Leprosy Ab Rapid test [Gold-LFA] and the quantitative, luminescent up-converting phosphor anti-PGL-I test [UCP-LFA]. Test performance was assessed in independent cohorts originating from three endemic areas. In the Philippine cohort comprising patients with high bacillary indices (BI; average:4,9), 94%(n = 161) of MB patients were identified by UCP-LFA and 78%(n = 133) by Gold-LFA. In the Bangladeshi cohort, including mainly MB patients with low BI (average:1), 41%(n = 14) and 44%(n = 15) were detected by UCP-LFA and Gold-LFA, respectively. In the third cohort of schoolchildren from a leprosy hyperendemic region in Brazil, both tests detected 28%(n = 17) seropositivity. Both rapid tests corresponded well with BI(p < 0.0001), with a fairly higher sensitivity obtained with the UCP-LFA assay. However, due to the spectral character of leprosy, additional, cellular biomarkers are required to detect patients with low BIs. Therefore, the UCP-LFA platform, which allows multiplexing with differential biomarkers, offers more cutting-edge potential for diagnosis across the whole leprosy spectrum.
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              Evaluation of Immunodiagnostic Tests for Leprosy in Brazil, China and Ethiopia

              Leprosy remains persistently endemic in several low- or middle income countries. Transmission is still ongoing as indicated by the unabated rate of leprosy new case detection, illustrating the insufficiency of current prevention methods. Therefore, low-complexity tools suitable for large scale screening efforts to specifically detect M. leprae infection and diagnose disease are required. Previously, we showed that combined detection of cellular and humoral markers, using field-friendly lateral flow assays (LFAs), increased diagnostic potential for detecting leprosy in Bangladesh compared to antibody serology alone. In the current study we assessed the diagnostic performance of similar LFAs in three other geographical settings in Asia, Africa and South-America with different leprosy endemicity. Levels of anti-PGL-I IgM antibody (humoral immunity), IP-10, CCL4 and CRP (cellular immunity) were measured in blood collected from leprosy patients, household contacts and healthy controls from each area. Combined detection of these biomarkers significantly improved the diagnostic potential, particularly for paucibacillary leprosy in all three regions, in line with data obtained in Bangladesh. These data hold promise for the use of low-complexity, multibiomarker LFAs as universal tools for more accurate detection of M. leprae infection and different phenotypes of clinical leprosy.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                17 October 2019
                October 2019
                17 October 2019
                : 48
                : 9-10
                Affiliations
                Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
                Author notes
                Article
                S2352-3964(19)30632-2
                10.1016/j.ebiom.2019.09.028
                6838452
                31631045
                3c8c77da-455f-4335-86b7-4562434c7d42
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 16 September 2019
                : 16 September 2019
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