A multiplex serologic platform for diagnosis of tick-borne diseases

Tokarz, Rafal; Mishra, Nischay; Tagliafierro, Teresa; Sameroff, Stephen; Caciula, Adrian; Chauhan, Lokendrasingh; Patel, Jigar; Sullivan, Eric; Gucwa, Azad L; Fallon, Brian A.; Golightly, Marc G.; Molins, Claudia R.; Schriefer, Martin E.; Marques, Adriana; Briese, Thomas; Lipkin, W. Ian

doi:10.1038/s41598-018-21349-2

Cited by 80 publications

(79 citation statements)

References 63 publications

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“…In addition to B. miyamotoi peptides, we examined the reactivity to peptides from other tick-borne agents. In 2 samples, we detected IgG reactivity to specific epitopes of B. burgdorferi that were identified in our previous work (40). Subsequent examination of clinical history of these 2 individuals revealed that both had previously been diagnosed with Lyme disease.…”

Section: Resultssupporting

confidence: 51%

“…The TBD-Serochip is a peptide array that consists of approximately 170,000 12-mer linear peptides designed from the protein sequence of the primary antigens of Anaplasma phagocytophilum , B. burgdorferi , B. miyamotoi , Babesia microti , Rickettsia rickettsii , Ehrlichia chaffeensis , Powassan virus and Heartland virus (40). The 12-mer peptides tile the sequence of each antigen with an 11 amino acid (aa) overlap to the preceding 12-mer peptide in a sliding window pattern.…”

Section: Methodsmentioning

confidence: 99%

“…All sera were tested at a 1:50 dilution. We used de-identified human sera from our previous work with the TBD-Serochip, and additional samples acquired form the National Institutes of Health (40). These samples were obtained under clinical protocols (ClinicalTrials.gov Identifier NCT00028080 and NCT00001539) approved by the institutional review board of the National Institute of Allergy and Infectious Diseases, and all participants signed informed consent.…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we employed the Tick-borne disease Serochip (TBD-Serochip), a novel serologic peptide array platform, to examine the antibody response in human patients with BMD to a wide array of B. miyamotoi antigens. Our work identified linear epitopes that could be applied in the development of improved diagnostic tests (40).…”

Section: Introductionmentioning

confidence: 99%

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Identification of immunoreactive linear epitopes ofBorrelia miyamotoi

Tokarz

Tagliafierro

Caciula

et al. 2019

Preprint

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27Borrelia miyamotoi is an emerging tick-borne spirochete transmitted by Ixodid ticks. 28Current serologic assays for B. miyamotoi are impacted by genetic similarities to other 29 Borrelia and limited understanding of optimal antigenic targets. In this study, we 30 employed the TBD-Serochip, a peptide array platform, to identify new linear targets for 31 serologic detection of B. miyamotoi. We examined a wide range of suspected B. 32miyamotoi antigens and identified 352 IgM and 91 IgG reactive peptides, with the 33 majority mapping to variable membrane proteins. These included peptides within 34 conserved fragments of variable membrane proteins that may have greater potential for 35 differential diagnosis. We also identified reactive regions on FlaB, and demonstrate 36 crossreactivity of B. burgdorferi C6 with a B. miyamotoi C6-like peptide. The panel of 37 linear peptides identified in this study can be used to enhance serodiagnosis of B.38 miyamotoi. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 miyamotoi was discovered in 1995; however, the link to disease was first established in 56 2011 when it was implicated in an outbreak of tick-borne illness in Russia (1, 6). B. 57 miyamotoi is primarily transmitted by I. scapularis and I. pacificus in North America, and 58 I. ricinus and I. persulcatus in Europe and Asia (6-9). These tick species also transmit 59 Borreliae that cause Lyme borreliosis (10). Lyme borreliosis is the most common vector-60 borne disease in the United States, where most infections are caused by Borrelia 61 burgdorferi and transmitted by Ixodes scapularis. Despite sharing the same vectors, B. 62 miyamotoi differs from B. burgdorferi in a number of ecological aspects, including the 63 ability for transovarial transmission, quicker transmission during tick feeding, and lower 64 infection rates in vector ticks. The prevalence of B. miyamotoi in nymphs is typically 1% 65 to 5% versus 15% to 25% for B. burgdorferi (11-15). Nonetheless, B. miyamotoi and B. 66 burgdorferi can occasionally infect the same tick, and concurrent human infections have 67 been reported (5, 15, 16). 68 69 Symptomatic infections with B. miyamotoi (Borrelia miyamotoi disease; BMD) usually 70 present with fever and other non-specific symptoms including fatigue, headache, chills 71 and nausea (17, 18). Bouts of relapsing fever may occur in untreated patients. In the 72 United States, reports of BMD are rare with less than 200 cases identified between 2011 73 and 2017 (3, 19, 20). This is considerably less than would be expected based on the 74 high incidence of other tick-borne diseases and suggests a substantial underreporting of 75 B. miyamotoi infections (21). A portion of infections may be asymptomatic while 76 symptomatic infections may not be identified because of a similar presentation to certain 77 other tick-borne illnesses and the lack of optimal diagnostic tests (22-24). Patients with 78 4 BMD may test positive on the C6 ELISA, a serologic assay used in the diagnosis of 79 Lyme disease (20, 25, 26). Current methods of BM...

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Section: Resultssupporting

confidence: 51%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification of immunoreactive linear epitopes ofBorrelia miyamotoi

Tokarz

Tagliafierro

Caciula

et al. 2019

Preprint

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“…The peptide microarray technology we use in this study allows for one serum sample to be assayed against six million unique 16-residue peptides, or for 12 samples to each be assayed against 392,000 peptides, on a single chip (Roche Sequencing Solutions, Madison, WI). The technology has been used in proteome-wide epitope mapping [30], profiling of antibody responses in autoimmune disease [31], profiling venom toxin epitopes [32], determining functions of cellular enzymes [33], de novo binding sequence discovery [34], epitope validation following phage display screening [35], and screening for tick-borne disease seroprevalence [36]. We previously used this tool to examine antibody responses in simian pegivirus (SPgV) and simian immunodeficiency virus (SIV) infections [37].…”

Section: Introductionmentioning

confidence: 99%

Antibody responses to Zika virus proteins in pregnant and non-pregnant macaques

Mohr

Heffron

Baker

et al. 2018

Preprint

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24The kinetics and specificity of antibody responses against Zika virus (ZIKV) are not well-25 characterized. This is due, in part, to the antigenic similarity between ZIKV and closely 26 related Dengue virus (DENV) serotypes. Since these and other similar viruses co-27 circulate and are spread by the same mosquito species, it is difficult to disentangle 28 ZIKV-specific antibody responses from responses to closely-related arboviruses in 29 humans. Here we use high-density peptide microarrays to differentiate ZIKV from DENV 30 antibody reactivity in pregnant and non-pregnant macaque monkeys with known 31 exposure histories. We independently confirm a ZIKV-specific IgG antibody response 32 targeting ZIKV nonstructural protein 2B (NS2B) that was recently reported in ZIKV-33 infected people and show that antibody reactivity in pregnant animals can be detectable 34 as late as 113 days post-infection (dpi). We also show, however, these responses wane 35 over time, and in one case the response was elicited following DENV infection in a 36 previously ZIKV-exposed animal. The generally weak and short-lived antibody 37 responses to this NS2B epitope, the only reliably ZIKV-specific epitope identified to date 38 to our knowledge, suggest epidemiologic studies assessing seroprevalence specifically 39 to ZIKV using linear epitope-based strategies may be prone to false negative or 40 otherwise confounded results. These results additionally indicate some antibodies 41 produced in response to ZIKV infection are in circulation for only a short period of time. 42 43 IMPORTANCE 44Infection with ZIKV during pregnancy can lead to congenital ZIKV infection and 45 associated birth defects. The vulnerability of communities to future ZIKV outbreaks will 46 . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/352880 doi: bioRxiv preprint first posted online 3 depend, in part, on the prevalence of immunity, which is thought to be mediated 47 principally by antibodies. We currently lack diagnostic assays to differentiate ZIKV-48 specific antibodies from antibodies directed against closely related DENV and we do not 49 know how long anti-ZIKV responses persist. Here we profile antibodies recognizing 50 linear epitopes throughout the entire ZIKV and DENV polyproteins and show that while 51 ZIKV-specific antibody responses can be detected, these responses are generally weak 52 and ephemeral. This may complicate efforts to identify people previously infected with 53 ZIKV and to determine ZIKV seroprevalence, and it raises questions about the utility of 54 linear epitope-based technologies in defining ZIKV infection history. 55 56 INTRODUCTION 57

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Informative array testing with multiplex assays

Bilder

Tebbs

McMahan

2021

Statistics in Medicine

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High‐volume testing of clinical specimens for sexually transmitted diseases is performed frequently by a process known as group testing. This algorithmic process involves testing portions of specimens from separate individuals together as one unit (or “group”) to detect diseases. Retesting is performed on groups that test positively in order to differentiate between positive and negative individual specimens. The overall goal is to use the least number of tests possible across all individuals without sacrificing diagnostic accuracy. One of the most efficient group testing algorithms is array testing. In its simplest form, specimens are arranged into a grid‐like structure so that row and column groups can be formed. Positive‐testing rows/columns indicate which specimens to retest. With the growing use of multiplex assays, the increasing number of diseases tested by these assays, and the availability of subject‐specific risk information, opportunities exist to make this testing process even more efficient. We propose specific specimen arrangements within an array that can reduce the number of retests needed when compared with other array testing algorithms. We examine how to calculate operating characteristics, including the expected number of tests and the SD for the number of tests, and then subsequently find a best arrangement. Our methods are illustrated for chlamydia and gonorrhea detection with the Aptima Combo 2 Assay. We also provide R functions to make our research accessible to laboratories.

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A multiplex serologic platform for diagnosis of tick-borne diseases

Cited by 80 publications

References 63 publications

Identification of immunoreactive linear epitopes ofBorrelia miyamotoi

Identification of immunoreactive linear epitopes ofBorrelia miyamotoi

Antibody responses to Zika virus proteins in pregnant and non-pregnant macaques

Informative array testing with multiplex assays

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