The persistence of symptoms in Lyme disease patients following antibiotic therapy, and their causes, continue to be a matter of intense controversy. The studies presented here explore antibiotic efficacy using nonhuman primates. Rhesus macaques were infected with B. burgdorferi and a portion received aggressive antibiotic therapy 4–6 months later. Multiple methods were utilized for detection of residual organisms, including the feeding of lab-reared ticks on monkeys (xenodiagnosis), culture, immunofluorescence and PCR. Antibody responses to the B. burgdorferi-specific C6 diagnostic peptide were measured longitudinally and declined in all treated animals. B. burgdorferi antigen, DNA and RNA were detected in the tissues of treated animals. Finally, small numbers of intact spirochetes were recovered by xenodiagnosis from treated monkeys. These results demonstrate that B. burgdorferi can withstand antibiotic treatment, administered post-dissemination, in a primate host. Though B. burgdorferi is not known to possess resistance mechanisms and is susceptible to the standard antibiotics (doxycycline, ceftriaxone) in vitro, it appears to become tolerant post-dissemination in the primate host. This finding raises important questions about the pathogenicity of antibiotic-tolerant persisters and whether or not they can contribute to symptoms post-treatment.
Lyme neuroborreliosis, caused by the spirochete Borrelia burgdorferi, affects both peripheral and central nervous systems. We assessed a causal role for inflammation in Lyme neuroborreliosis pathogenesis by evaluating the induced inflammatory changes in the central nervous system, spinal nerves, and dorsal root ganglia (DRG) of rhesus macaques that were inoculated intrathecally with live B. burgdorferi and either treated with dexamethasone or meloxicam (anti-inflammatory drugs) or left untreated. ELISA of cerebrospinal fluid showed significantly elevated levels of IL-6, IL-8, chemokine ligand 2, and CXCL13 and pleocytosis in all infected animals, except dexamethasone-treated animals. Cerebrospinal fluid and central nervous system tissues of infected animals were culture positive for B. burgdorferi regardless of treatment. B. burgdorferi antigen was detected in the DRG and dorsal roots by immunofluorescence staining and confocal microscopy. Histopathology revealed leptomeningitis, vasculitis, and focal inflammation in the central nervous system; necrotizing focal myelitis in the cervical spinal cord; radiculitis; neuritis and demyelination in the spinal roots; and inflammation with neurodegeneration in the DRG that was concomitant with significant neuronal and satellite glial cell apoptosis. These changes were absent in the dexamethasone-treated animals. Electromyography revealed persistent abnormalities in F-wave chronodispersion in nerve roots of a few infected animals; which were absent in dexamethasone-treated animals. These results suggest that inflammation has a causal role in the pathogenesis of acute Lyme neuroborreliosis.
Background: Lyme neuroborreliosis (LNB) may present as meningitis, cranial neuropathy, acute radiculoneuropathy or, rarely, as encephalomyelitis. We hypothesized that glia, upon exposure to Borrelia burgdorferi, the Lyme disease agent, produce inflammatory mediators that promote the acute cellular infiltration of early LNB. This inflammatory context could potentiate glial and neuronal apoptosis.
Infections caused by Streptococcus pneumoniae are a major cause of mortality throughout the world. Protein-based pneumococcal vaccines are envisaged to replace or complement the current polysaccharide-based vaccines. In this context, detoxified pneumolysin (dPly) and pneumococcal histidine triad protein D (PhtD) are two potential candidates for incorporation into pneumococcal vaccines. In this study, the protective efficacy of a PhtD-dPly vaccine was evaluated in a rhesus macaque (Macaca mulatta) model of pneumonia. The animals were immunized twice with 10 µg of PhD and 10 µg of dPly formulated in the Adjuvant System AS02 or with AS02 alone, before they were challenged with a 19F pneumococcal strain. The survival was significantly higher in the protein-vaccinated group and seemed to be linked to the capacity to greatly reduce bacterial load within the first week post-challenge. Vaccination elicited high concentrations of anti-PhtD and anti-Ply antibodies and a link was found between survival and antibody levels. In conclusion, AS02-adjuvanted PhtD-dPly vaccine protects against S. pneumoniae-induced pneumonia. It is probable that the protection is at least partially mediated by PhtD- and Ply-specific antibodies.
C 6 , a Borrelia burgdorferi-derived peptide, is used as the antigen in the C 6 -Lyme disease diagnostic test. We assessed retrospectively whether a fourfold decrease or a decrease to a negative value in anti-C 6 antibody titer is positively correlated with a positive response to treatment in a sample of culture-confirmed patients with either early localized (single erythema migrans [EM]; n ؍ 93) or early disseminated (multiple EM; n ؍ 27) disease. All of these patients had been treated with antibiotics and were free of disease within 6 to 12 months of follow-up. Results show that a serum specimen taken at this time was either C 6 negative or had a >4-fold decrease in C 6 antibody titer with respect to a specimen taken at baseline (or during the early convalescent period if the baseline specimen was C 6 negative) for all of the multiple-EM patients (P < 0.0001) and in 89% of the single-EM patients (P < 0.0001). These results indicate that a decline in anti-C 6 antibody titer coincides with effective antimicrobial therapy in patients with early localized or early disseminated Lyme borreliosis.
Malaria transmission-blocking vaccination can effectively reduce and/or eliminate transmission of parasites from the human host to the mosquito vector. The immunity achieved by inducing an antibody response to surface antigens of male and female gametes and parasite stages in the mosquito. Our laboratory has developed DNA vaccine constructs, based on Pfs25 (a Plasmodium falciparum surface protein of 25 kDa), that induce a transmission-blocking immune response in mice (C. A. Lobo, R. Dhar, and N. Kumar, Infect. Immun. 67:1688-1693, 1999). To evaluate the safety, immunogenicity, and efficacy of the Pfs25 DNA vaccine in nonhuman primates, we immunized rhesus macaques (Macaca mulatta) with a DNA vaccine plasmid encoding Pfs25 or a Pfg27-Pfs25 hybrid or with the plasmid (empty plasmid) alone. Immunization with four doses of these DNA vaccine constructs elicited antibody titers that were high but nonetheless unable to reduce the parasite's infectivity in membrane feeding assays. Further boosting of the antibody response with recombinant Pfs25 formulated in Montanide ISA-720 increased antibody titers (30-fold) and significantly blocked transmission of P. falciparum gametocytes to Anopheles mosquitoes (ϳ90% reduction in oocyst numbers in the midgut). Our data show that a DNA prime-protein boost regimen holds promise for achieving transmissionblocking immunity in areas where malaria is endemic and could be effective in eradicating malaria in isolated areas where the level of malaria endemicity is low.Plasmodium falciparum, one of the deadliest of the malariacausing species, continues to threaten humans, especially children and pregnant women, in many parts of the world (8). The available drugs and the vector control campaigns used to date have not had a significant impact on the transmission of malaria from humans to mosquitoes. When a female Anopheles mosquito bites an infected human, the male and female gametocytes (formed during the erythrocytic phase of the malaria life cycle) are taken up in the blood meal and rapidly undergo gametogenesis and fertilization. Oocysts and eventually infective sporozoites are formed, thus completing parasite development. It has been shown that the crucial link for malaria transmission, i.e., infectivity of male and female gametocytes, can be blocked in the mosquito vector by antibodies directed against sexual-stage-specific surface antigens when they are ingested along with the parasites in the blood meal (5, 12, 18). It is believed that transmission-blocking immunity will play a significant role in reducing the emergence of vaccine-resistant strains. Such strains could be selected by vaccines targeting erythrocytic asexual forms. Likewise, spread of drug resistance could be diminished by reducing overall malaria transmission (4).P. falciparum zygote-ookinete surface protein 25 (Pfs25) is one of the most promising candidates identified so far for the development of P. falciparum transmission-blocking vaccines. Pfs25 (a 25-kDa surface protein) is expressed at the onset of gametogenesis ...
Lyme disease (Borrelia burgdorferi infection) is increasingly recognized as a significant source of morbidity worldwide. Here, we show that blood plasmablasts and CD27− memory B cells are elevated in untreated Lyme disease, with higher plasmablast levels associated with more rapid resolution of clinical symptoms. Stronger serum reactivity to surface proteins and peptides from B. burgdorferi was also associated with faster resolution of clinical symptoms. Through molecular identifier-enabled antibody heavy-chain sequencing of bulk B cells and single-cell paired-chain antibody sequencing of blood plasmablasts, we characterized immunoglobulin gene usage patterns specific to B. burgdorferi infection. Recombinantly expressed antibodies from expanded lineages bound B. burgdorferi antigens, confirming that these clones are driven by the infection. Furthermore, recombinant sequence-derived antibodies were functional, inhibiting growth of B. burgdorferi in vitro. Elevations and clonal expansion of blood plasmablasts were associated with rapid return to health, while poor plasmablast responses were associated with a longer duration of symptoms following treatment. Plasmablasts induced by B. burgdorferi infection showed preferential antibody gene segment usage, while bulk sequencing of total B cells revealed convergent CDR3 motifs specific to B. burgdorferi-infected patients. Our results show that robust plasmablast responses encoding Bb-static antibodies are associated with more rapid resolution of Lyme disease, and these antibodies could provide the basis for next-generation therapeutics for Lyme disease.
Seventy‐three patients with stable plaque psoriasis entered an investigator‐masked trial comparing once‐daily tazarotene 0.1% gel plus once‐daily mometasone furoate 0.1% cream with twice‐daily mometasone furoate 0.1% cream. The aim of the study was to determine whether tazarotene and mometasone furoate act synergistically –‐ a previous study showed that tazarotene plus mometasone furoate offered greater efficacy than tazarotene alone, and this study investigated whether tazarotene plus mometasone furoate also offered greater efficacy than mometasone furoate alone. The patients had psoriasis affecting up to 20% of their total body surface area, with at least moderate plaque elevation. Washout periods were: 2 weeks for UVB phototherapy or topical antipsoriatic therapies; 4 weeks for psoralen plus UVA (PUVA) therapy or systemic antipsoriatic drugs other than retinoids; and 8 weeks for oral retinoids. All patients gave written informed consent and the study was conducted in compliance with the ethical standards of the governing institutional review boards and the Declaration of Helsinki. Patients were treated for up to 12 weeks. If they achieved clearance by week 4, or at least 50% global improvement by week 12, they were entered into the 12‐week no‐treatment follow‐up phase. Patients were evaluated every 4 weeks in terms of percentage global improvement, plaque elevation, scaling, erythema, and pruritus. They also rated the efficacy of their own treatment (as very effective, effective, neutral, ineffective, or less effective) and the duration of improvement in their psoriasis (as much better, better, somewhat better, indifferent, or worse than that achieved with other topical medications they had used in the past). The two regimens were compared by analysis of variance, with the last recorded score for any patient who discontinued prematurely (due to lack of efficacy, adverse events, or disease flare) being carried forward to all subsequent visits.
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