Adriana Marques - Academia.edu (original) (raw)

Papers by Adriana Marques

Clinical and Vaccine Immunology, 2006

The American Journal of Pathology, 2007

Relapsing fever is an infection characterized by peaks of spirochetemia attributable to antibody ... more Relapsing fever is an infection characterized by peaks of spirochetemia attributable to antibody selection against variable serotypes. In the absence of B cells, serotypes cannot be cleared, resulting in persistent infection. We previously identified differences in spirochetemia and disease severity during persistent infection of severe combined immunodeficiency mice with isogenic serotypes 1 (Bt1) or 2 (Bt2) of Borrelia turicatae. To investigate this further, we studied pathogen load, clinical disease, cytokine/chemokine production, and inflammation in mice deficient in B (Igh6 ؊/؊ ) or B and T (Rag1 ؊/؊ ) cells persistently infected with Bt1 or Bt2. The results showed that Igh6 ؊/؊ mice, despite lower spirochetemia, had a significantly aggravated disease course compared with Rag1 ؊/؊ mice. Measurement of cytokines revealed a significant positive correlation between pathogen load and interleukin (IL)-10 in blood, brain, and heart. Bt2-infected Rag1 ؊/؊ mice harbored the highest spirochetemia and, at the same time, displayed the highest IL-10 plasma levels. In the brain, Bt1, which was five times more neurotropic than Bt2, caused higher IL-10 production. Activated microglia were the main source of IL-10 in brain. IL-10 injected systemically reduced disease and spirochetemia. The results suggest IL-10 plays a protective role as a downregulator of inflammation and pathogen load during infection with relapsing fever spirochetes. (Am J

Journal of Clinical Microbiology, Dec 1, 1999

VlsE, the variable surface antigen of Borrelia burgdorferi, contains an immunodominant conserved ... more VlsE, the variable surface antigen of Borrelia burgdorferi, contains an immunodominant conserved region named IR 6 . In the present study, the diagnostic performance of a peptide enzyme-linked immunosorbent assay (ELISA) based on a 26-mer synthetic peptide (C 6 ) with the IR 6 sequence was explored. Sensitivity was assessed with serum samples (n ‫؍‬ 210) collected from patients with clinically defined Lyme disease at the acute (early localized or early disseminated disease), convalescent, or late disease phase. The sensitivities for acute-, convalescent-, and late-phase specimens were 74% (29 of 39), 85 to 90% (34 of 40 to 35 of 39), and 100% (59 of 59), respectively. Serum specimens from early neuroborreliosis patients were 95% positive (19 of 20), and those from an additional group of patients with posttreatment Lyme disease syndrome yielded a sensitivity of 62% (8 of 13). To assess the specificity of the peptide ELISA, 77 serum samples from patients with other spirochetal or chronic infections, autoimmune diseases, or neurologic diseases and 99 serum specimens from hospitalized patients in an area where Lyme disease is not endemic were examined. Only two potential false positives from the hospitalized patients were found, and the overall specificity was 99% (174 of 176). Precision, which was assessed with a panel of positive and negative serum specimens arranged in blinded duplicates, was 100%. Four serum samples with very high anti-OspA antibody titers obtained from four monkeys given the OspA vaccine did not react with the C 6 peptide. This simple, sensitive, specific, and precise ELISA may contribute to alleviate some of the remaining problems in Lyme disease serodiagnosis. Because of its synthetic peptide base, it will be inexpensive to manufacture. It also will be applicable to serum specimens from OspA-vaccinated subjects.

The Journal of Infectious Diseases, Mar 15, 2006

Toll-like receptors (TLRs) trigger innate immune responses via the recognition of conserved patho... more Toll-like receptors (TLRs) trigger innate immune responses via the recognition of conserved pathogen-associated molecular patterns. Lipoproteins from Borrelia burgdorferi, the agent of Lyme disease, activate inflammatory cells through TLR2 and TLR1. We show that stimulation of human monocytes with B. burgdorferi lysate, lipidated outer surface protein A, and triacylated lipopeptide Pam 3 CysSerLys 4 results in the up-regulation of both TLR2 and TLR1 but the down-regulation of TLR5, the receptor for bacterial flagellin, and that this effect is mediated via TLR2. TLR4 stimulation had no effect on TLR2, TLR1, and TLR5 expression. Human monocytes stimulated with TLR5 ligands (including p37 or flaA, the minor protein from B. burgdorferi flagella) up-regulated TLR5. In addition, TLR2 stimulation rendered cells hyporesponsive to a TLR5 agonist. These results indicate that diverse stimuli can cause differential TLR expression, and we hypothesize that these changes may be useful for either the pathogen and/or the host.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 28, 2015

Endothelial cell growth factor has been recently proposed as a potential autoantigen in manifesta... more Endothelial cell growth factor has been recently proposed as a potential autoantigen in manifestations of Lyme disease that are thought to involve immune-mediated mechanisms. Our findings indicate that a humoral immune response to this protein is not associated with posttreatment Lyme disease syndrome.

Background: Lyme disease is associated with a robust B cell response to the VlsE lipoprotein of B... more Background: Lyme disease is associated with a robust B cell response to the VlsE lipoprotein of Borrelia burgdorferi. Epitope mapping analyses have shown the IR6 region within the variable domain and specific sequences in the N- and C-terminal invariable domains of VlsE to contain the major immunogenic regions. However, antibody reactivity against immunodominant epitopes of VlsE has not been systematically analyzed during the various stages of infection. Methods: Here, we examined serum samples from 90 patients with a range of early to late manifestations of Lyme borreliosis for antibody reactivity to the three major epitope sequences of VlsE. These included amino acid sequences 274-298 (IR6 epitope), 21-44 (N-terminal epitope), and 336-349 (C-terminal epitope) of the VlsE protein from B. burgdorferi B31. In addition, antibody response to a recombinantly generated protein containing the entire membrane-proximal domain of VlsE and its associated epitopes as a contiguous sequence was ...

Background: Lyme disease is caused by spirochetes of the Borrelia burgdorferi species complex. So... more Background: Lyme disease is caused by spirochetes of the Borrelia burgdorferi species complex. Some of the symptoms of Lyme disease are thought to result from the body’s immune response during infection. Recently, immune reactivity to endothelial cell growth factor (ECGF), a self-antigen, has been reported to be elevated in patients with Lyme disease. As such, the ECGF protein has been proposed as an autoantibody target in manifestations that are thought to involve infection-induced immune-mediated mechanisms, including refractory Lyme arthritis and post-Lyme disease syndrome (PLDS). Methods: We aimed to evaluate this hypothesis through analysis of antibody response to recombinant human ECGF in serum from 90 individuals with a range of early to late manifestations of Lyme disease, including single EM, multiple EM, early neurologic, late neurologic, arthritis, and refractory arthritis, as well as 93 PLDS patients, 25 post-Lyme healthy individuals, and 30 healthy individuals without a...

Clinical and Vaccine Immunology

Severe chronic active Epstein-Barr virus disease (SCAEBV) is characterized by elevated EBV DNA le... more Severe chronic active Epstein-Barr virus disease (SCAEBV) is characterized by elevated EBV DNA levels in the blood and EBV DNA, RNA, or proteins in tissues with lymphocytic infiltration. Patients present with fever, adenopathy, and splenomegaly and complications include cytopenias, hepatitis, and neurological disorders. Most patients we studied developed progressive immunodeficiency and died of infections or progressive lymphoproliferation. We report here on two men with SCAEBV. The first presented with fever, pancytopenia, adenopathy, and splenomegaly, followed by hepatitis, neuropathy, encephalomyelitis, and uveitis. Lymph node and spleen showed abundant EBV RNA and hemophagocytosis. Treatment with corticosteroids and azathioprine controlled symptoms for several years, but he developed clonal T cell infiltration of the bone marrow and liver which progressed despite chemotherapy. After receiving a matched unrelated bone marrow transplant his disease resolved and he remains asymptom...

Infectious Disease Clinics of North America, 2015

The majority of laboratory tests performed for the diagnosis of Lyme disease are based on detecti... more The majority of laboratory tests performed for the diagnosis of Lyme disease are based on detection of the antibody responses against B burgdorferi in serum. The sensitivity of antibody-based tests increases with the duration of the infection. Patients early in their illness are more likely to have a negative result. There is a need to simplify the testing algorithm for Lyme disease, improving sensitivity in early disease while still maintaining high specificity and providing information about the stage of infection. The development of a point of care assay and biomarkers for active infection would be major advances for the field.

Journal of clinical microbiology, 2000

We evaluated the new MPM medium for the growth of Borrelia burgdorferi. All 18 blood samples from... more We evaluated the new MPM medium for the growth of Borrelia burgdorferi. All 18 blood samples from 17 patients with Lyme disease were negative. Growth studies showed that by day 4, most organisms in MPM were not viable. Our results reinforce the use of BSK medium as the primary choice for growing B. burgdorferi.

Nature medicine, 1999

Elucidating the cellular immune response to infectious agents is a prerequisite for understanding... more Elucidating the cellular immune response to infectious agents is a prerequisite for understanding disease pathogenesis and designing effective vaccines. In the identification of microbial T-cell epitopes, the availability of purified or recombinant bacterial proteins has been a chief limiting factor. In chronic infectious diseases such as Lyme disease, immune-mediated damage may add to the effects of direct infection by means of molecular mimicry to tissue autoantigens. Here, we describe a new method to effectively identify both microbial epitopes and candidate autoantigens. The approach combines data acquisition by positional scanning peptide combinatorial libraries and biometric data analysis by generation of scoring matrices. In a patient with chronic neuroborreliosis, we show that this strategy leads to the identification of potentially relevant T-cell targets derived from both Borrelia burgdorferi and the host. We also found that the antigen specificity of a single T-cell clone...

Journal of clinical microbiology, 1999

Ear and hearing, 2003

The purpose of this study was to characterize auditory function in patients diagnosed with post-t... more The purpose of this study was to characterize auditory function in patients diagnosed with post-treatment Lyme disease syndrome (PTLDS). Eighteen patients with PTLDS were evaluated and compared to a normal population. Evaluations consisted of pure tone and speech thresholds, word recognition (WRS), acoustic immittance battery, auditory brain stem response (ABR), and loudness discomfort level (LDL). Both seropositive and seronegative patients were evaluated. Audiologists were blinded to patient status. Forty four percent of the patients had one or more abnormal pure tone thresholds compared to gender- and age-adjusted norms. Thirty-one percent showed abnormally reduced LDLs, and 17% had abnormal acoustic reflexes at one or more frequencies. This paper catalogs previously unstudied long-term auditory system sequelae resulting from PTLDS. Our most significant finding was the dramatically reduced loudness tolerance in the presence of either normal or minimally impaired hearing. The clin...

Journal of immunology (Baltimore, Md. : 1950), 2008

During relapsing fever borreliosis, a high pathogen load in the blood occurs at times of peak bac... more During relapsing fever borreliosis, a high pathogen load in the blood occurs at times of peak bacteremia. Specific IgM Abs are responsible for spirochetal clearance so in absence of B cells there is persistent high-level bacteremia. Previously, we showed that B cell-deficient mice persistently infected with Borrelia turicatae produce high levels of IL-10 and that exogenous IL-10 reduces bacteremia. This suggested that IL-10 helps reduce bacteremia at times of high pathogen load by a B cell-independent mechanism, most likely involving innate immunity. To investigate this possibility, we compared B. turicatae infection in RAG2/IL-10(-/-) and RAG2(-/-) mice. The results showed that IL-10 deficiency resulted in significantly higher bacteremia, higher TNF levels, and early mortality. Examination of the spleen and peripheral blood showed markedly increased apoptosis of immune cells in infected RAG2/IL-10(-/-) mice. Neutralization of TNF reduced apoptosis of leukocytes and splenocytes, inc...

Expert review of anti-infective therapy, 2014

Whether Borrelia burgdorferi, the causative agent of Lyme disease, can persist after antibiotic t... more Whether Borrelia burgdorferi, the causative agent of Lyme disease, can persist after antibiotic therapy is an area of ongoing controversy. In animal models, B. burgdorferi DNA can be detected in tissues after antibiotic therapy as well as by using the natural tick vector to acquire the organism through feeding (xenodiagnosis). Vector arthropods have been successfully used in xenodiagnosis to describe the etiology of infections such as malaria, typhus and Chagas disease. Our recent safety trial of xenodiagnosis demonstrates that ticks may be successfully fed on patients and may help determine the biological basis for post-treatment Lyme disease syndrome.

Current Allergy and Asthma Reports, 2001

Lyme disease is a multisystem illness caused by the spirochete Borrelia burgdorferi, and it is th... more Lyme disease is a multisystem illness caused by the spirochete Borrelia burgdorferi, and it is the most common vector-borne illness in the United States. Lyme disease is also endemic in Europe and Asia. There have been major advances in the field since the disease was first described, including the sequencing of the B. burgdorferi genome; an increase in understanding of the interactions among the spirochete, the tick, and the mammalian host; new and improved laboratory tests; and a vaccine for prevention of the disease. Still, the diagnosis of Lyme disease remains based on history and clinical findings, supplemented by careful use of laboratory tests, and requires that the physician be familiar with the disease&amp;#39;s clinical manifestations and the shortcomings of the available diagnostic tests.

Current Allergy and Asthma Reports, 2010

Lyme disease is the most common vector-borne illness in the United States and is also endemic in ... more Lyme disease is the most common vector-borne illness in the United States and is also endemic in Europe and Asia. It is caused by the spirochete Borrelia burgdorferi and transmitted by the bite of the Ixodes (deer) tick. It occurs most frequently during spring and summer and may involve the skin, nervous system, heart, and joints. This article reviews the pathogenesis, epidemiology, clinical manifestations, diagnosis, treatment, and prevention of Lyme disease.