|
|
Recent Lyme & TBD Abstracts
Cell Host Microbe. 2009 Nov 19;6(5):482-92.
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Traditionally, vaccines directly target a pathogen or microbial toxin. Lyme disease, caused by Borrelia burgdorferi, is a tick-borne illness for which a human vaccine is not currently available. B. burgdorferi binds a tick salivary protein, Salp15, during transmission from the vector, and this interaction facilitates infection of mice. We now show that Salp15 antiserum significantly protected mice from B. burgdorferi infection. Salp15 antiserum also markedly enhanced the protective capacity of antibodies against B. burgdorferi antigens, such as OspA or OspC. Mice actively immunized with Salp15 were also significantly protected from tick-borne Borrelia. In vitro assays showed that Salp15 antiserum increased the clearance of Salp15-coated B. burgdorferi by phagocytes, suggesting a mechanism of action. Vaccination with a vector molecule that a microbe requires for infection of the mammalian host suggests a new strategy for the prevention of Lyme disease, and this paradigm may be applicable to numerous arthropod-borne pathogens of medical importance.
N Engl J Med. 2009 May 14;360(20):2099-107.
C
Wadsworth Center, New York State Department of Health and the Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York, USA. norma.tavakoli@wadsworth.org
Deer tick virus is related to Powassan virus, a tickborne encephalitis virus. A 62-year-old man presented with a meningoencephalitis syndrome and eventually died. Analyses of tissue samples obtained during surgery and at autopsy revealed a widespread necrotizing meningoencephalitis. Nucleic acid was extracted from formalin-fixed tissue, and the presence of deer tick virus was verified on a flavivirus-specific polymerase-chain-reaction (PCR) assay, followed by sequence confirmation. Immunohistochemical analysis with antisera specific for deer tick virus identified numerous immunoreactive neurons, with prominent involvement of large neurons in the brain stem, cerebellum, basal ganglia, thalamus, and spinal cord. This case demonstrates that deer tick virus can be a cause of fatal encephalitis. 2009 Massachusetts Medical Society
Vector Borne Zoonotic Dis. 2009 Sep 2. [Epub ahead of print]
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY.
|
Ixodes scapularis ticks are clinically important hematophagous vectors. A single tick bite can lead to a polymicrobial infection. We determined the prevalence of polymicrobial infection with Borrelia burgdorferi, Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi, and Powassan virus in 286 adult ticks from the two counties in New York State where Lyme disease is endemic, utilizing a MassTag multiplex polymerase chain reaction assay. Seventy-one percent of the ticks harbored at least one organism; 30% had a polymicrobial infection. Infections with three microbes were detected in 5% of the ticks. One tick was infected with four organisms. Our results show that coinfection is a frequent occurrence in ticks in the two counties surveyed.
Pediatrics. 2009 May;123(5):e835-41.
Harvard Medical School, Division of Cardiac Intensive Care, Department of Cardiology, Children's Hospital Boston, 300 Longwood Ave, Bader 600, Boston, MA 02115, USA. john.costello@cardio.chboston.org
OBJECTIVES: We sought to identify predictive factors for Lyme carditis in children and to characterize the clinical course of these patients. METHODS: We reviewed all cases of early disseminated Lyme disease presenting to our institution from January 1994 through July 2008, and summarized the presentation and course of those patients with carditis. A case-control study was used to identify predictive factors for carditis. Controls were patients with early disseminated Lyme disease without carditis. RESULTS: Of 207 children with early disseminated Lyme disease, 33 (16%) had carditis, 14 (42%) of whom had advanced heart block, including 9 (27%) with complete heart block. The median time to recovery of sinus rhythm in these 14 patients was 3 days (range: 1-7 days), and none required a permanent pacemaker. Four (12%) of 33 patients with carditis had depressed ventricular systolic function, 3 (9%) of whom required mechanical ventilation, temporary pacing, and inotropic support. Complete resolution of rhythm disturbances and myocardial dysfunction occurred in 24 (89%) of 27 patients for whom follow-up data were available. Most patients with carditis also had other systemic Lyme involvement. By using multivariate logistic regression analysis, we found that children >10 years of age, those with arthralgias, and those with cardiopulmonary symptoms were more likely to have carditis. CONCLUSIONS: The spectrum of presentation for children with Lyme carditis is broad, ranging from asymptomatic, first-degree heart block to fulminant myocarditis. Variable degrees of heart block are the most common manifestation and occasionally require temporary pacing. Transient myocardial dysfunction, although less common, can be life-threatening. Advanced heart block resolves within 1 week in most cases. In children with early disseminated Lyme disease, older age, arthralgias, and cardiopulmonary symptoms independently predict the presence of carditis.
Pediatrics. 2009 May;123(5):e829-34.
Rhode Island Hospital, Pediatric Emergency Medicine, Claverick Building, 2nd Floor, Providence, RI 02906, USA. agarro@lifespan.org
OBJECTIVE: Lyme meningitis is difficult to differentiate from other causes of aseptic meningitis in Lyme disease-endemic regions. Parenteral antibiotics are indicated for Lyme meningitis but not viral causes of aseptic meningitis. A clinical prediction model was developed to distinguish Lyme meningitis from other causes of aseptic meningitis. Our objective was to prospectively validate this model. METHODS: Children between 2 and 18 years of age presenting to Hasbro Children's Hospital from April through October of 2006 and 2007 were enrolled if a lumbar puncture for meningitis showed a cerebrospinal fluid white blood cell count of >8 cells per microL. Cerebrospinal fluid was sent for Lyme antibody testing. The probability of Lyme meningitis was calculated by using the percentage of cerebrospinal fluid mononuclear cells, duration of headache, and presence of cranial neuropathy by using the prediction model. Definite Lyme meningitis cases were defined as cerebrospinal fluid pleocytosis with (1) positive Lyme serology confirmed by immunoblot or (2) erythema migrans rash. Possible Lyme meningitis cases were defined as cerebrospinal fluid pleocytosis with positive cerebrospinal fluid Lyme antibody. Sensitivity, specificity, and likelihood ratios for definite and possible Lyme meningitis were determined by using 10% increments of calculated probability of Lyme meningitis. RESULTS: Fifty children were enrolled, including 14 children with definite Lyme meningitis, 6 with possible Lyme meningitis, and 30 with aseptic meningitis. A calculated probability of <10% for Lyme meningitis had a negative likelihood ratio of 0.006 for definite and possible Lyme meningitis cases. A calculated probability of >50% for Lyme meningitis had a positive likelihood ratio of 100 using these definitions. CONCLUSIONS: A clinical prediction model using the percentage of cerebrospinal fluid mononuclear cells, headache duration, and presence of cranial neuropathy can differentiate children with Lyme meningitis from children with aseptic meningitis. Our findings suggest categories of low (<10%), indeterminate (10%-50%), and high (>50%) probability of Lyme meningitis.
Arch Gen Psychiatry. 2009;66(5):554-563.
Columbia University, 1051 Riverside Drive, Unit 69, New York, NY 10032, USA. baf1@columbia.edu
Context There is controversy regarding whether objective neurobiological abnormalities exist after intensive antibiotic treatment for Lyme disease. Objectives To determine whether patients with a history of well-characterized Lyme disease and persistent cognitive deficit show abnormalities in global or topographic distributions of regional cerebral blood flow (rCBF) or cerebral metabolic rate (rCMR).
Design Case-controlled study. Setting A university medical center. Participants A total of 35 patients and 17 healthy volunteers (controls). Patients had well-documented prior Lyme disease, a currently reactive IgG Western blot, prior treatment with at least 3 weeks of intravenous cephalosporin, and objective memory impairment. Main Outcome Measures Patients with persistent Lyme encephalopathy were compared with age-, sex-, and education-matched controls. Fully quantified assessments of rCBF and rCMR for glucose were obtained while subjects were medication-free using positron emission tomography. The CBF was assessed in 2 resting room air conditions (without snorkel and with snorkel) and 1 challenge condition (room air enhanced with carbon dioxide, ie, hypercapnia). Results Statistical parametric mapping analyses revealed regional abnormalities in all rCBF and rCMR measurements that were consistent in location across imaging methods and primarily reflected hypoactivity. Deficits were noted in bilateral gray and white matter regions, primarily in the temporal, parietal, and limbic areas. Although diminished global hypercapnic CBF reactivity (P < .02) was suggestive of a component of vascular compromise, the close coupling between CBF and CMR suggests that the regional abnormalities are primarily metabolically driven. Patients did not differ from controls on global resting CBF and CMR measurements. Conclusions Patients with persistent Lyme encephalopathy have objectively quantifiable topographic abnormalities in functional brain activity. These CBF and CMR reductions were observed in all measurement conditions. Future research should address whether this pattern is also seen in acute neurologic Lyme disease.
J Infect Dis. 2009 May 1;199(9):1379-88.
The Antibiotics Doxycycline and Minocycline Inhibit the Inflammatory Responses to the Lyme Disease Spirochete Borrelia burgdorferi.
Bernardino AL, Kaushal D, Philipp MT.
Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, Covington, Louisiana.
Tetracyclines moderate inflammatory responses of various etiologies. We hypothesized that tetracyclines, in addition to their antimicrobial function, could exert control over the inflammation elicited by Borrelia burgdorferi. To model systemic effects, we used the human monocytic cell line THP-1; to model effects in the central nervous system, we used rhesus monkey brain astrocytes and microglia. Cells were stimulated with live or sonicated B. burgdorferi or with the lipoprotein outer surface protein A in the presence of increasing concentrations of doxycycline or minocycline. Both antibiotics significantly reduced the production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8 in a dose-dependent manner in all cell types. Microarray analyses of the effect of doxycycline on gene transcription in spirochete-stimulated monocytes revealed that the NFKB and CHUK (alias, IKKA) genes were down-regulated. Functionally, phosphorylation of IkappaBalpha and binding of NF-kappaB to target DNA were both reduced in these cells. Our results suggest that tetracyclines may have a dual therapeutic effect in Lyme disease.
Arthritis Rheum. 2009 Apr;60(4):1179-86.
Center for Biologics Evaluation and Research, FDA, Rockville, Maryland, USA.
Robert.Ball@fda.hhs.gov
OBJECTIVE: To investigate whether persons with treatment-resistant Lyme arthritis-associated HLA alleles might develop arthritis as a result of an autoimmune reaction triggered by Borrelia burgdorferi outer surface protein A (OspA), the Lyme disease vaccine antigen. METHODS: Persons in whom inflammatory arthritis had developed after Lyme disease vaccine (cases) were compared with 3 control groups: 1) inflammatory arthritis but not Lyme disease vaccine (arthritis controls), 2) Lyme disease vaccine but not inflammatory arthritis (vaccine controls), and 3) neither Lyme disease vaccine nor inflammatory arthritis (normal controls). HLA-DRB1 allele typing, Western blotting for Lyme antigen, and T cell reactivity testing were performed. RESULTS: Twenty-seven cases were matched with 162 controls (54 in each control group). Odds ratios (ORs) for the presence of 1 or 2 treatment-resistant Lyme arthritis alleles were 0.8 (95% confidence interval [95% CI] 0.3-2.1), 1.6 (95% CI 0.5-4.4), and 1.75 (95% CI 0.6-5.3) in cases versus arthritis controls, vaccine controls, and normal controls, respectively. There were no significant differences in the frequency of DRB1 alleles. T cell response to OspA was similar between cases and vaccine controls, as measured using the stimulation index (OR 1.6 [95% CI 0.5-5.1]) or change in uptake of tritiated thymidine (counts per minute) (OR 0.7 [95% CI 0.2-2.3]), but cases were less likely to have IgG antibodies to OspA (OR 0.3 [95% CI 0.1-0.8]). Cases were sampled closer to the time of vaccination (median 3.59 years versus 5.48 years), and fewer cases had received 3 doses of vaccine (37% versus 93%). CONCLUSION: Treatment-resistant Lyme arthritis alleles were not found more commonly in persons who developed arthritis after Lyme disease vaccination, and immune responses to OspA were not significantly more common in arthritis cases. These results suggest that Lyme disease vaccine is not a major factor in the development of arthritis in these cases.
Pediatrics. 2009 Mar;123(3):959-65.
Acute pediatric monoarticular arthritis: distinguishing lyme arthritis from other etiologies.
Thompson A, Mannix R, Bachur R.
Children's Hospital Boston, Division of Emergency Medicine, 300 Longwood Ave, Boston, MA 02115, USA. amy.thompson@childrens.harvard.edu
OBJECTIVE: Identify clinical predictors of Lyme arthritis among patients with acute monoarticular arthritis. METHODS: A medical chart review was conducted of children </=18 years of age with monoarticular arthritis who underwent arthrocentesis in a pediatric emergency department located in the northeast United States. Patients were classified into 3 categories of arthritis: septic, Lyme, or nonseptic non-Lyme arthritis. Historical, clinical, and laboratory data were compared to identify distinguishing features of Lyme arthritis. RESULTS: One hundred seventy-nine patients were studied: 46 (26%) patients with septic arthritis, 55 (31%) patients with Lyme arthritis, and 78 (43%) patients with nonseptic non-Lyme arthritis. Compared with those with septic arthritis, patients with Lyme disease were more likely to have a tick-bite history, knee involvement, and less likely to have a history of fever or elevated temperature at triage. Erythrocyte sedimentation rate, C-reactive protein, joint white blood cell count, and joint neutrophil percentage were also statistically lower. In comparison to nonseptic non-Lyme arthritis, knee involvement and tick-bite history were predictors of Lyme. Erythrocyte sedimentation rate, joint white blood cell count, and joint neutrophil percentage were also statistically different. Multivariate analysis comparing Lyme to septic arthritis demonstrated fever history and elevated C-reactive protein level to be negative predictors of Lyme arthritis and knee involvement to be a positive predictor (model sensitivity: 88%; specificity: 82%). CONCLUSIONS: Lyme arthritis shares features with both septic and nonseptic non-Lyme arthritis. This overlap prevents the creation of a clinically useful predictive model for Lyme arthritis. In endemic areas, Lyme testing should be performed on all patients presenting with acute monoarticular arthritis.
Scand J Immunol. 2009 Jan;69(1):64-9.
International Lyme and Associated Diseases Society, Bethesda, MD, USA. rstricker@usmamed.com
Complement split products C3a and C4a are reportedly elevated in patients with acute Lyme disease. We have now examined these immunologic markers in patients with chronic Lyme disease compared to appropriate disease controls. The study population consisted of 29 healthy controls, 445 patients with chronic Lyme disease, 11 patients with systemic lupus erythematosus (SLE) and six patients with AIDS. The Lyme disease patients were divided according to predominant musculoskeletal symptoms (324 patients) or predominant neurologic symptoms (121 patients). C3a and C4a levels were measured by radioimmunoassay. All patients with chronic Lyme disease and AIDS had normal C3a levels compared to controls, whereas patients with SLE had significantly increased levels of this marker. Patients with predominant musculoskeletal symptoms of Lyme disease and AIDS patients had significantly increased levels of C4a compared to either controls, patients with predominant neurologic symptoms of Lyme disease or SLE patients. Response to antibiotic therapy in chronic Lyme disease was associated with a significant decrease in the C4a level, whereas lack of response was associated with a significant increase in this marker. In contrast, AIDS patients had persistently increased C4a levels despite antiretroviral therapy. Lyme patients with positive single-photon emission computed tomographic (SPECT) scans had significantly lower C4a levels compared to Lyme patients with normal SPECT scan results. Patients with predominant musculoskeletal symptoms of Lyme disease have normal C3a and increased C4a levels. This pattern differs from the increase in both markers seen in acute Lyme disease, and C4a changes correlate with the response to therapy in chronic Lyme disease. C4a appears to be a valuable immunologic marker in patients with persistent symptoms of Lyme disease.
J Med Entomol.
2009 Jan;46(1):131-8.
University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Lyme disease in the United States is caused by the bacterial spirochete Borrelia burgdorferi s.s. (Johnson, Schmid, Hyde, Steigerwalt, and Brenner), which is transmitted by tick vectors Ixodes scapularis (Say) and I. pacificus (Cooley and Kohls). Borrelia lonestari, transmitted by the tick Amblyomma americanum L., may be associated with a related syndrome, southern tick-associated rash illness (STARI). Borrelia lonestari sequences, reported primarily in the southeastern states, have also been detected in ticks in northern states. It has been suggested that migratory birds may have a role in the spread of Lyme disease spirochetes. This study evaluated both migratory waterfowl and nonmigratory wild turkeys (Meleagris gallopavo silvestris, Eastern wild turkey) for B. burgdorferi and B. lonestari DNA sequences. A total of 389 avian blood samples (163 migratory birds representing six species, 125 wild turkeys harvested in habitats shared with migratory birds, 101 wild turkeys residing more distant from migratory flyways) were extracted, amplified, and probed to determine Borrelia presence and species identity. Ninety-one samples were positive for Borrelia spp. Among migratory birds and turkeys collected near migration routes, B. burgdorferi predominated. Among turkeys residing further away from flyways, detection of B. lonestari was more common. All A. americanum ticks collected from these areas were negative for Borrelia DNA; no I. scapularis were found. To our knowledge, this represents the first documentation of B. lonestari among any birds.
Pediatr Infect Dis J. 2008 Dec;27(12):1089-94.
Lyme neuroborreliosis in children: a prospective study of clinical features, prognosis, and outcome.
Skogman BH, Croner S, Nordwall M, Eknefelt M, Ernerudh J, Forsberg P.
Pediatric Clinic at the University Hospital, Division of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. hedinskogman@ltdalarna.se
BACKGROUND: Evaluation of children with clinically suspected neuroborreliosis (NB) is difficult. With a prospective study design we wanted to characterize children with signs and symptoms indicative for NB, investigate clinical outcome and, if possible, identify factors of importance for recovery. MATERIAL/METHODS: Children being evaluated for NB (n = 177) in southeast Sweden were categorized into 3 groups: "confirmed neuroborreliosis" (41%) with Borrelia antibodies in the cerebrospinal fluid, "possible neuroborreliosis" (26%) with pleocytosis but no Borrelia antibodies in the cerebrospinal fluid, and "not determined" (33%) with no pleocytosis and no Borrelia antibodies in the cerebrospinal fluid. Antibiotic treatment was given to 69% of children. Patients were followed during 6 months and compared with a matched control group (n = 174). RESULTS: Clinical recovery at the 6-month follow-up (n = 177) was generally good and no patient was found to have recurrent or progressive neurologic symptoms. However, persistent facial nerve palsy caused dysfunctional and cosmetic problems in 11% of patients. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls. Influence on daily life was reported to the same extent in patients and controls. Consequently, persistent headache and fatigue at follow-up should not be considered as attributable to NB. No prognostic factors could be identified. CONCLUSIONS: Clinical recovery was satisfactory in children being evaluated for NB although persistent symptoms from facial nerve palsy occurred. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls.
Arthritis Rheum. 2008 Dec 15;59(12):1742-9.
Role of psychiatric comorbidity in chronic Lyme disease.
Hassett AL, Radvanski DC, Buyske S, Savage SV, Gara M, Escobar JI, Sigal LH.
University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08903-0019, USA. a.hassett@umdnj.edu
OBJECTIVE: To evaluate the prevalence and role of psychiatric comorbidity and other psychological factors in patients with chronic Lyme disease (CLD). METHODS: We assessed 159 patients drawn from a cohort of 240 patients evaluated at an academic Lyme disease referral center. Patients were screened for common axis I psychiatric disorders (e.g., depressive and anxiety disorders); structured clinical interviews confirmed diagnoses. Axis II personality disorders, functional status, and traits like negative and positive affect and pain catastrophizing were also evaluated. A physician blind to psychiatric assessment results performed a medical evaluation. Two groups of CLD patients (those with post-Lyme disease syndrome and those with medically unexplained symptoms attributed to Lyme disease but without Borrelia burgdorferi infection) were compared with 2 groups of patients without CLD (patients recovered from Lyme disease and those with an identifiable medical condition explaining symptoms attributed to Lyme disease). RESULTS: After adjusting for age and sex, axis I psychiatric disorders were more common in CLD patients than in comparison patients (P = 0.02, odds ratio 2.64, 95% confidence interval 1.30-5.35), but personality disorders were not. Patients with CLD had higher negative affect, lower positive affect, and a greater tendency to catastrophize pain (P < 0.001) than comparison patients. All psychological factors except personality disorders were related to level of functioning. A predictive model based on these psychological variables was confirmed. Fibromyalgia was diagnosed in 46.8% of CLD patients. CONCLUSION: Psychiatric comorbidity and other psychological factors distinguished CLD patients from other patients commonly seen in Lyme disease referral centers, and were related to poor functional outcomes.
Arthritis Rheum.
2008 Dec;58(12):3892-901.
Persistent arthritis in Borrelia burgdorferi-infected HLA-DR4-positive CD28-negative mice post-antibiotic treatment.
Iliopoulou BP, Alroy J, Huber BT.
Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
OBJECTIVE: The immunologic events that lead to persistent joint inflammation in certain patients with Lyme arthritis post-antibiotic treatment have been elusive so far. The prevalence of this condition is highest in individuals with rheumatoid arthritis-associated HLA-DR alleles. This study was undertaken to generate a murine model with persistent arthritis post-antibiotic treatment. METHODS: We have previously shown that CD28(-/-) mice develop intermittent monarticular Lyme arthritis that is responsive to antibiotics. Since there seems to be a link in humans between persistent arthritic manifestations post-antibiotic treatment and the HLA-DR4 allele, we generated DR4+/+CD28(-/-)MHCII(-/-) mice, infected them with Borrelia burgdorferi, and subsequently treated them with antibiotics. RESULTS: Thirty-eight percent of the B burgdorferi-infected DR4+/+CD28(-/-)MHCII(-/-) mice, but none of the B burgdorferi-infected CD28(-/-)MHCII(-/-) mice, remained arthritic post-antibiotic treatment. A significant fraction (36%) of these mice, but none of the mice in which arthritis resolved, had serum antibodies to outer surface protein A of B burgdorferi. After abrogation of active B burgdorferi infection, the inflammatory reaction in mice with persistent joint inflammation was restricted to the joints, since their draining lymph nodes were no longer enlarged. Increased CD20 and interferon-gamma messenger RNA expression in the inflamed joints of these mice suggested a possible role of B cells and inflammatory cytokines in the pathogenesis of persistent arthritis post-antibiotic treatment. CONCLUSION: The establishment of this murine model allows, for the first time, the elucidation of the immunologic events that lead to persistent Lyme arthritis post-antibiotic therapy in genetically susceptible individuals.
Proc Natl Acad Sci U S A.
2008 Dec 16;105(50):19863-8. Epub 2008 Dec 5.
NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi.
Tupin E, Benhnia MR, Kinjo Y, Patsey R, Lena CJ, Haller MC, Caimano MJ, Imamura M, Wong CH, Crotty S, Radolf JD, Sellati TJ, Kronenberg M.
Divisions of Developmental Immunology and Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, CA 92037, USA.
Borrelia burgdorferi is the etiologic agent of Lyme disease, a multisystem inflammatory disorder that principally targets the skin, joints, heart, and nervous system. The role of T lymphocytes in the development of chronic inflammation resulting from B. burgdorferi infection has been controversial. We previously showed that natural killer T (NKT) cells with an invariant (i) TCR alpha chain (iNKT cells) recognize glycolipids from B. burgdorferi, but did not establish an in vivo role for iNKT cells in Lyme disease pathogenesis. Here, we evaluate the importance of iNKT cells for host defense against these pathogenic spirochetes by using Valpha14i NKT cell-deficient (Jalpha18(-/-)) BALB/c mice. On tick inoculation with B. burgdorferi, Jalpha18(-/-) mice exhibited more severe and prolonged arthritis as well as a reduced ability to clear spirochetes from infected tissues. Valpha14i NKT cell deficiency also resulted in increased production of antibodies directed against both B. burgdorferi protein antigens and borrelial diacylglycerols; the latter finding demonstrates that anti-glycolipid antibody production does not require cognate help from Valpha14i NKT cells. Valpha14i NKT cells in infected wild-type mice expressed surface activation markers and produced IFNgamma in vivo after infection, suggesting a participatory role for this unique population in cellular immunity. Our data are consistent with the hypothesis that the antigen-specific activation of Valpha14i NKT cells is important for the prevention of persistent joint inflammation and spirochete clearance, and they counter the long-standing notion that humoral rather than cellular immunity is sufficient to facilitate Lyme disease resolution.
Am J Pathol.
2008 Nov;173(5):1415-27. Epub 2008 Oct 2.
Interaction of the Lyme disease spirochete Borrelia burgdorferi with brain parenchyma elicits inflammatory mediators from glial cells as well as glial and neuronal apoptosis.
Ramesh G, Borda JT, Dufour J, Kaushal D, Ramamoorthy R, Lackner AA, Philipp MT.
Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA.
Lyme neuroborreliosis, caused by the spirochete Borrelia burgdorferi, often manifests by causing neurocognitive deficits. As a possible mechanism for Lyme neuroborreliosis, we hypothesized that B. burgdorferi induces the production of inflammatory mediators in the central nervous system with concomitant neuronal and/or glial apoptosis. To test our hypothesis, we constructed an ex vivo model that consisted of freshly collected slices from brain cortex of a rhesus macaque and allowed live B. burgdorferi to penetrate the tissue. Numerous transcripts of genes that regulate inflammation as well as oligodendrocyte and neuronal apoptosis were significantly altered as assessed by DNA microarray analysis. Transcription level increases of 7.43-fold (P = 0.005) for the cytokine tumor necrosis factor-alpha and 2.31-fold (P = 0.016) for the chemokine interleukin (IL)-8 were also detected by real-time-polymerase chain reaction array analysis. The immune mediators IL-6, IL-8, IL-1beta, COX-2, and CXCL13 were visualized in glial cells in situ by immunofluorescence staining and confocal microscopy. Concomitantly, significant proportions of both oligodendrocytes and neurons undergoing apoptosis were present in spirochete-stimulated tissues. IL-6 production by astrocytes in addition to oligodendrocyte apoptosis were also detected, albeit at lower levels, in rhesus macaques that had received in vivo intraparenchymal stereotaxic inoculations of live B. burgdorferi. These results provide proof of concept for our hypothesis that B. burgdorferi produces inflammatory mediators in the central nervous system, accompanied by glial and neuronal apoptosis.
Neurology. 2008 Mar 25;70(13):992-1003. Epub 2007 Oct 10.
Columbia University, 1051 Riverside Drive, Unit 69, New York, NY 10032, USA. baf1@columbia.edu
BACKGROUND: Optimal treatment remains uncertain for patients with cognitive impairment that persists or returns after standard IV antibiotic therapy for Lyme disease. METHODS: Patients had well-documented Lyme disease, with at least 3 weeks of prior IV antibiotics, current positive IgG Western blot, and objective memory impairment. Healthy individuals served as controls for practice effects. Patients were randomly assigned to 10 weeks of double-masked treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome was neurocognitive performance at week 12-specifically, memory. Durability of benefit was evaluated at week 24. Group differences were estimated according to longitudinal mixed-effects models. RESULTS: After screening 3368 patients and 305 volunteers, 37 patients and 20 healthy individuals enrolled. Enrolled patients had mild to moderate cognitive impairment and marked levels of fatigue, pain, and impaired physical functioning. Across six cognitive domains, a significant treatment-by-time interaction favored the antibiotic-treated group at week 12. The improvement was generalized (not specific to domain) and moderate in magnitude, but it was not sustained to week 24. On secondary outcome, patients with more severe fatigue, pain, and impaired physical functioning who received antibiotics were improved at week 12, and this was sustained to week 24 for pain and physical functioning. Adverse events from either the study medication or the PICC line were noted among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%) patients given IV placebo; these resolved without permanent injury. CONCLUSION: IV ceftriaxone therapy results in short-term cognitive improvement for patients with posttreatment Lyme encephalopathy, but relapse in cognition occurs after the antibiotic is discontinued. Treatment strategies that result in sustained cognitive improvement are needed.
Appl Neuropsychol. 2008;15(3):208-19.
Memory and executive functions in adolescents with posttreatment Lyme disease.
McAuliffe P, Brassard MR, Fallon B.
Teacher's College, Columbia University New York, New York 10027, USA. drmcauliffe@gmail.com
Although adults with late stage posttreatment Lyme disease often experience difficulties in memory, little is known about the relationship between cognition and Lyme disease in children and adolescents. Twenty-five adolescents with late stage posttreatment Lyme disease (symptoms > 6 months) and 25 participants without Lyme disease (matched on gender, IQ, age, socioeconomic status) were assessed for neuropsychological functioning, depression, school functioning, and predisease academic achievement. The Lyme group had significant deficits in cognition (short-term visual memory, short-term and delayed verbal memory, all forms of recognition memory), as well as worse attendance, grades, and subjective reports of memory problems, without differing in predisease achievement or depression. Deficits in visual memory exceeded deficits in verbal memory-a striking difference from what is reported in adults. These results reveal that adolescents with a history of treated Lyme disease are at risk for long-term problems in cognition and school functioning.
Microbes Infect. 2006;
Nov-Dec;8(14-15):2832-40. Epub 2006 Sep 22.
Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi.
Livengood JA, Gilmore RD Jr.
Centers for Disease Control and Prevention, Division of Vector-borne Infectious Diseases, 3150 Rampart Road, CSU Foothills Campus, Fort Collins, CO 80522, USA.
Human infection by Borrelia burgdorferi, the etiological agent for Lyme disease, can result in serious acute and late-term disorders including neuroborreliosis, a degenerative condition of the peripheral and central nervous systems. To examine the mechanisms involved in the cellular pathogenesis of neuroborreliosis, we investigated the ability of B. burgdorferi to attach to and/or invade a panel of human neuroglial and cortical neuronal cells. In all neural cells tested, we observed B. burgdorferi in association with the cell by confocal microscopy. Further analysis by differential immunofluorescent staining of external and internal organisms, and a gentamicin protection assay demonstrated an intracellular localization of B. burgdorferi. A non-infectious strain of B. burgdorferi was attenuated in its ability to associate with these neural cells, suggesting that a specific borrelial factor related to cellular infectivity was responsible for the association. Cytopathic effects were not observed following infection of these cell lines with B. burgdorferi, and internalized spirochetes were found to be viable. Invasion of neural cells by B. burgdorferi provides a putative mechanism for the organism to avoid the host's immune response while potentially causing functional damage to neural cells during infection of the CNS.
J Infect Dis.
2004;
May 15;189(10):1881-91. Epub 2004 Apr 26.
Borrelia-specific interferon-gamma and interleukin-4 secretion in cerebrospinal fluid and blood during Lyme borreliosis in humans: association with clinical outcome.
Widhe M, Jarefors S, Ekerfelt C, Vrethem M, Bergstrom S, Forsberg P, Ernerudh J.
Divisions of Clinical Immunology and Infectious Diseases, Department of Molecular and Clinical Medicine, Linkoping University, Linkoping, Sweden.
mona.widhe@imk.liu.se
The Borrelia-specific interferon (IFN)- gamma and interleukin (IL)-4 responses of 113 patients and control subjects were analyzed using the sensitive enzyme-linked immunospot method. Cerebrospinal fluid (CSF) and blood samples were obtained, during the course of disease, from patients with chronic or nonchronic neuroborreliosis (NB) and from control subjects without NB. Blood samples were obtained from patients with Lyme skin manifestations and from healthy blood donors. Early increased secretion of Borrelia-specific IFN- gamma (P<.05) and subsequent up-regulation of IL-4 (P<.05) were detected in the CSF cells of patients with nonchronic NB. In contrast, persistent Borrelia-specific IFN- gamma responses were observed in the CSF cells of patients with chronic NB (P<.05). In patients with erythema migrans, increased IFN- gamma (P<.001) was observed in blood samples obtained early during the course of disease, whereas increased IL-4 (P<.05) was observed after clearance. On the contrary, patients with acrodermatitis chronica atrophicans had Borrelia-specific IFN- gamma (P<.001), but not IL-4, detected in blood samples. The present data suggest that an initial IFN- gamma response, followed by up-regulation of IL-4, is associated with nonchronic manifestations, whereas a persistent IFN- gamma response may lead to chronic Lyme borreliosis.
| Top |
|
LYME & TICK-BORNE DISEASES RESEARCH CENTER
