< Back to Research Top Published Date 13/12/2017 Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding Journal PLoS One Citation PLoS One. 2017 Dec 13;12(12):e0189071 DOI 10.1371/journal.pone.0189071 Authors Embers ME, Hasenkampf NR, Jacobs MB, Tardo AC, Doyle-Meyers LA, Philipp MT, Hodzic E Abstract The efficacy and accepted regimen of antibiotic treatment for Lyme disease has been a point of significant contention among physicians and patients. While experimental studies in animals have offered evidence of post-treatment persistence of Borrelia burgdorferi, variations in methodology, detection methods and limitations of the models have led to some uncertainty with respect to translation of these results to human infection. With all stages of clinical Lyme disease having previously been described in nonhuman primates, this animal model was selected in order to most closely mimic human infection and response to treatment. Rhesus macaques were inoculated with B. burgdorferi by tick bite and a portion were treated with recommended doses of doxycycline for 28 days at four months post-inoculation. Signs of infection, clinical pathology, and antibody responses to a set of five antigens were monitored throughout the ~1.2 year study. Persistence of B. burgdorferi was evaluated using xenodiagnosis, bioassays in mice, multiple methods of molecular detection, immunostaining with polyclonal and monoclonal antibodies and an in vivo culture system. Our results demonstrate host-dependent signs of infection and variation in antibody responses. In addition, we observed evidence of persistent, intact, metabolically-active B. burgdorferi after antibiotic treatment of disseminated infection and showed that persistence may not be reflected by maintenance of specific antibody production by the host. URL Previous https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189071 No Review Needed? Next

< Back to Research Top Published Date 26/12/2019 Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Journal BioRxiv preprint Citation BioRxiv - citation to come DOI 10.1101/2019.12.23.887505 Authors Karhan E, Gunter CL, Ravanmehr V, Horne M, Kozhaya L, Renzullo S, Placek L, George J, Robinson PN, Vernon SD, Bateman L, Unutmaz D Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions. URL Previous https://www.biorxiv.org/content/10.1101/2019.12.23.887505v1 No Review Needed? Next

< Back to Research Top Published Date 14/01/2020 Lyme Aortitis Journal BMJ Case Reports Citation 13(1):e231957 DOI 10.1136/bcr-2019-231957. Authors Correia RR, Cruz F, Martin S, Andre ME Abstract A 72-year-old man was admitted with complaints of sudden-onset oppressive precordial pain radiating to the back for 1 hour. He had hypotension, peripheral cyanosis and cold extremities. An initial assessment was done and acute coronary syndrome was excluded. After the patient was admitted, he developed fever and increased levels of inflammatory markers. Data obtained from CT angiography and transoesophageal echocardiogram revealed diffuse parietal thickening of the arch and the descending thoracic aorta, as well as dilatation of the aortic root and the proximal ascending aorta. In addition, the test for Borrelia burgdorferi was positive, and the patient was diagnosed with Lyme vasculitis of the thoracic aorta. He was treated with doxycycline for 3 weeks. Two months later, the patient exhibited a Stanford type A aortic dissection (clinically stable), which was treated by prosthesis replacement. The patient has remained asymptomatic for 1 year after the episode, performing his routine daily activities. Keywords: cardiovascular system; infections. URL Previous https://casereports.bmj.com/content/13/1/e231957.long No Review Needed? Next

< Back to Research Top Published Date 08/04/2010 Bartonella vinsonii subsp. berkhoffii and Bartonella henselae bacteremia in a father and daughter with neurological disease Journal Parasites & Vectors Citation Parasit Vectors. 2010 Apr 8;3(1):29 DOI 10.1186/1756-3305-3-29 Authors Breitschwerdt EB, Maggi RG, Lantos PM, Woods CW, Hegarty BC, Bradley JM Abstract BACKGROUND: Bartonella vinsonii subsp. berkhoffii is an important, emerging, intravascular bacterial pathogen that has been recently isolated from immunocompetent patients with endocarditis, arthritis, neurological disease and vasoproliferative neoplasia. Vector transmission is suspected among dogs and wild canines, which are the primary reservoir hosts. This investigation was initiated to determine if pets and family members were infected with one or more Bartonella species. METHODS: PCR and enrichment blood culture in Bartonella alpha Proteobacteria growth medium (BAPGM) was used to determine infection status. Antibody titers to B. vinsonii subsp. berkhoffii genotypes I-III and B. henselae were determined using a previously described indirect fluorescent antibody test. Two patients were tested sequentially for over a year to assess the response to antibiotic treatment. RESULTS: Intravascular infection with B. vinsonii subsp. berkhoffii genotype II and Bartonella henselae (Houston 1 strain) were confirmed in a veterinarian and his daughter by enrichment blood culture, followed by PCR and DNA sequencing. Symptoms included progressive weight loss, muscle weakness, lack of coordination (the father) and headaches, muscle pain and insomnia (the daughter). B. vinsonii subsp. berkhoffii genotype II was also sequenced from a cerebrospinal fluid BAPGM enrichment culture and from a periodontal swab sample. After repeated courses of antibiotics, post-treatment blood cultures were negative, there was a decremental decrease in antibody titers to non-detectable levels and symptoms resolved in both patients. CONCLUSIONS: B. vinsonii subsp. berkhoffii and B. henselae are zoonotic pathogens that can be isolated from the blood of immunocompetent family members with arthralgias, fatigue and neurological symptoms. Therapeutic elimination of Bartonella spp. infections can be challenging, and follow-up testing is recommended. An increasing number of arthropod vectors, including biting flies, fleas, keds, lice, sandflies and ticks have been confirmed or are suspected as the primary mode of transmission of Bartonella species among animal populations and may also pose a risk to human beings. URL Previous https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859367 No Review Needed? Next

< Back to Research Top Published Date 24/08/2017 Sleeper cells: the stringent response and persistence in the Borreliella (Borrelia) burgdorferi enzootic cycle Journal Environmental Microbiology Citation Environ Microbiol. 2017 Oct;19(10):3846-3862 DOI 10.1111/1462-2920.13897 Authors Cabello FC, Godfrey HP, Bugrysheva JV, Newman SA Abstract Infections with tick-transmitted Borreliella (Borrelia) burgdorferi, the cause of Lyme disease, represent an increasingly large public health problem in North America and Europe. The ability of these spirochetes to maintain themselves for extended periods of time in their tick vectors and vertebrate reservoirs is crucial for continuance of the enzootic cycle as well as for the increasing exposure of humans to them. The stringent response mediated by the alarmone (p)ppGpp has been determined to be a master regulator in B. burgdorferi. It modulates the expression of identified and unidentified open reading frames needed to deal with and overcome the many nutritional stresses and other challenges faced by the spirochete in ticks and animal reservoirs. The metabolic and morphologic changes resulting from activation of the stringent response in B. burgdorferi may also be involved in the recently described non-genetic phenotypic phenomenon of tolerance to otherwise lethal doses of antimicrobials and to other antimicrobial activities. It may thus constitute a linchpin in multiple aspects of infections with Lyme disease borrelia, providing a link between the micro-ecological challenges of its enzootic life-cycle and long-term residence in the tissues of its animal reservoirs, with the evolutionary side effect of potential persistence in incidental human hosts. URL Previous https://onlinelibrary.wiley.com/doi/full/10.1111/1462-2920.13897 No Review Needed? Next

Testimony before House Committee on Foreign Affairs, United States Congress, 2012 Published Date 01/09/2012 ​ Authors Barthold SW ​ Lyme disease, caused by a number of closely related members of the Borrelia burgdorferi sensu lato family (B. burgdorferi sensu stricto in the United States) that are transmitted by closely related members of the Ixodes persulcatus family (I. scapularis and I. pacificus in the United States) is endemic in many parts of the world, with particularly high prevalence in the United States and Europe. Prevalence of human disease continues to rise, as does the geographic distribution of endemic areas. These events are enhanced by perturbation of the environment by humans, as well as global climate change, which favor habitation of the environment by Ixodes spp. vector ticks and suitable reservoir hosts. Interest in Lyme disease is rising globally, as Lyme disease is increasing in southern Canada, where infected ticks and reservoir hosts are extending their range from the United States, as well as an increase in prevalence throughout Europe and Asia. ​ I have been engaged in Lyme disease research since its initial discovery in coastal Connecticut in the late 1970’s/early 1980’s. At that time, I was on the faculty of the Yale School of Medicine, and collaborated with Dr. Steere and others to develop an animal model for studying mechanisms of disease and vaccine development. I have continued Lyme disease research upon joining the faculty at the University of California at Davis in 1997. I have been actively funded by NIH in Lyme disease research for over 25 years. During the course of my Lyme disease research career, I have become saddened by the negative discourse and division that exists among various factions of the Lyme disease community, including the lay community, the medical community, and the scientific community (the so-called “Lyme Wars”). In particular, debate has intensified regarding efficacy and appropriate regimens for antibiotic treatment. Central to this debate is the Infectious Disease Society of America (IDSA) position that this is a simple bacterial infection that is amenable to simple antibiotic treatment, while also recognizing that something is happening in patients after treatment, known as Post Lyme Disease Syndrome (PLDS). Lyme disease is exceedingly complex in humans, and this poses major challenges to accurate diagnosis and measuring outcome of treatment. It has been known for years that the acute signs of Lyme disease (erythema migrans, cardiac conduction abnormalities, arthritis, etc.) spontaneously regress without benefit of antibiotics, but their resolution is accelerated by treatment. There is overwhelming evidence in a variety of animal species as well as humans that B. burgdorferi persists without treatment, but the crucial question is does it survive following treatment, and if so, do surviving spirochetes cause “chronic” Lyme Disease or PLDS? These questions cannot be answered by speculative and expensive human clinical trials motivated by firmly held dogmatism. Something strange is happening with Lyme disease. Borrelia burgdorferi persistently infects a myriad of fully immunocompetent hosts as the rule, not the norm of its basic biology. When such a situation occurs, antibiotics may fail, since it is generally accepted that antibiotics eliminate the majority of bacteria, and rely upon the host to “mop up” the rest. If the bacteria are able to evade host “mopping”, then the logic of the scenario falters. It is not surprising, therefore, that experimental studies, using a broad spectrum of animal species (mice, dogs, monkeys) and a variety of antibiotics (doxycycline, amoxicillin, ceftriaxone, tigecycline) have all shown a failure to completely cure the animals of B. burgdorferi infection. What is surprising is that the surviving spirochetes can no longer be cultivated from tissues (culture is considered by some to be the gold standard for detecting viable B. burgdorferi), but their presence can be readily detected with a number of methods, including B. burgdorferi-specific DNA amplification (PCR), xenodiagnosis (feeding ticks upon the host and testing the ticks by PCR), detection of B. burgdorferi-specific RNA (indicating live spirochetes), and demonstration of intact spirochetes in tissues and xenodiagnostic ticks by labeling them with antibody against B. burgdoreri-specific targets. These surviving spirochetes are not simply “DNA debris” as some contend, but are rather persisting, but non-cultivable spirochetes. It remains to be determined if their persistence following treatment is medically significant. For example, humans are known to be persistently infected with a number of opportunistic pathogens, including viruses, bacteria, and fungi, which are held in abeyance by the immune response, without clinical symptoms. Their significance varies with individual human patients and their ability to keep them in check. Lyme disease is likely to be similar. The following report is a bit technical, but provides a summary of documented evidence of published and yet to be published experimental studies that provide compelling evidence for B. burgdorferi persistence following antibiotic treatment in animal model systems. It remains to be determined if humans are different, but the wide range of animal species studied (including non- human primates) predicts commonality from which extrapolation to humans is logical. Because of firmly entrenched opinion within the medical scientific community, evidence of persisting viable but non-cultivable spirochetes is slow to be accepted, and research proposals submitted to NIH that feature persistence following treatment are likely to receive prejudicial peer review in the contentious environment of Lyme disease*. Negative comments by peer reviewers of grant applications in the current financially austere NIH climate result in unfundable scores, if they are scored at all (triaged). I have no personal stake in this issue any more, as I am retiring within a year. In my opinion, for such important and controversial studies to go forward, NIH will need to publish a specific call for applications, known as a “Request for Applications” (RFA), that requests research on the biological significance of persisting spirochetes following antibiotic treatment. URL [PDF] Persistence of Non-Cultivable Borrelia burgdorferi Following Antibiotic Treatment : Critical Need for Further Research | Semantic Scholar HHRG-112-FA16-WState-BartholdS-20120717.pdf

< Back to Research Top Published Date 02/03/2021 The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes Journal Pathogens Citation 10(3):281 DOI 10.3390/pathogens10030281 Authors Anderson C, Brissette CA Abstract Lyme disease (LD) has become the most common vector-borne illness in the northern hemisphere. The causative agent, Borrelia burgdorferi sensu lato, is capable of establishing a persistent infection within the host. This is despite the activation of both the innate and adaptive immune responses. B. burgdorferi utilizes several immune evasion tactics ranging from the regulation of surface proteins, tick saliva, antimicrobial peptide resistance, and the disabling of the germinal center. This review aims to cover the various methods by which B. burgdorferi evades detection and destruction by the host immune response, examining both the innate and adaptive responses. By understanding the methods employed by B. burgdorferi to evade the host immune response, we gain a deeper knowledge of B. burgdorferi pathogenesis and Lyme disease, and gain insight into how to create novel, effective treatments. Keywords: Borrelia; Lyme disease; adaptive; complement; immune response; innate. URL Previous https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001052/ No Review Needed? Next

< Back to Research Top Published Date 01/02/2020 Mycotic Aneurysm of the Middle Cerebral Artery Leading to Subarachnoid Hemorrhage, as the Initial Presentation of Bartonella henselae Endocarditis Journal South Dakota Medicine Citation 73(2):68-70 DOI ​ Authors Varga Z, Gowda SN, Stys A Abstract Bartonella species was first reported as a cause of endocarditis in 1993, currently it is thought to account for 3-4 percent of all diagnosed cases. Initial symptoms of Bartonella endocarditis are non-specific like weight loss, fever and fatigue. There are very few reported cases of Bartonella endocarditis causing mycotic aneurysm. We present a case of a 60-year-old male who presented with subarachnoid hemorrhage secondary to mycotic aneurysm. Due to high suspicion of endocarditis leading to mycotic aneurysm he underwent transesophageal echocardiography which showed mitral valve vegetations. His blood cultures were negative, he was eventually diagnosed with Bartonella henselae by elevated IgG titers greater than 1:800. Due to repeated mycotic aneurysms on antibiotics, he underwent surgical mitral valve replacement along with the full course of antibiotics and has been asymptomatic since. URL Previous https://pubmed.ncbi.nlm.nih.gov/32135054/ No Review Needed? Next

Tick Bite Prevention Week 24th - 30th March 2024 As many of us head outdoors to enjoy the spring weather, here are a few reminders about how to avoid the risk of tick bites and Lyme disease: The best way to prevent Lyme disease is to avoid being bitten. Avoid exposing bare skin. Wear long sleeves and tuck trousers into socks. Light-coloured clothing may help you to see ticks more easily. Use an insect repellent which is effective against ticks during hiking or other outdoor activities. Treat your clothing with the insect repellent permethrin before you set out if you can. Keep to well-maintained paths and avoid walking in long grass. Carry a tick removal tool. Check yourself, your children and your pets regularly for ticks and brush off any that are unattached. Shower and do a thorough tick check after being outside. Don’t forget the groin, hairline, behind the ears, and places where ticks are hard to spot. ​ Our website resources can provide more information: Read more about ticks and how to manage tick bites here Learn how to recognise the signs and symptoms of Lyme disease here See our range of awareness materials - available to order or download here LRC outdoor initiatives - look out for our unique outdoor signage. Blog link : Embracing the Great Outdoors: Balancing Nature’s benefits with Tick Bite Prevention LRC tick removal cards are available to purchase here ​ FOLLOW US ON SOCIAL MEDIA THROUGHOUT TICK BITE PREVENTION WEEK:

< Back to Research Top Published Date 28/03/2019 RNA Sequencing Reveals Small and Variable Contributions of Infectious Agents to Transcriptomes of Postmortem Nervous Tissues From ALS, Alzheimer's Disease and Parkinson's Disease Subjects, and Increased Expression of Genes From Disease-Activated Microglia Journal Frontiers in Neuroscience Citation Front Neurosci. 2019 Mar 28;13:235 DOI 10.3389/fnins.2019.00235 Authors Bennett JP Jr, Keeney PM, Brohawn DG Abstract Nervous tissues from both humans with neurodegenerative diseases (NDD) and animals with genetic models of human NDD, such as rare monogenic causes of Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), show activated microglia, suggesting a potential causal role for inflammation in pathogenesis of NDD. We performed paired-end (PE) RNA sequencing (RNA seq) of total RNA's extracted from frozen sections of cervical spinal cords from ALS and CTL subjects, frontal cortical gray matter ribbons of AD and CTL subjects, and ventral midbrains of PD and CTL subjects. Trimmed PE reads were aligned against the hg38 human transcriptome using Tophat2/Bowtie2 (ALS) or HISAT2 (AD and PD) and quantitated with Cufflinks. PE reads were also aligned using Bowtie2 against genomes from representative species of Toxoplasma gondii and Trichinella sp. T6 (parasitic infectious agents), Babesia microti and Borrelia burgdorferi (tick-vector borne agents), and Treponema denticola and Porphyromonas gingivalis, agents causing chronic gingivitis. Primary aligned reads of each agent in each tissue sample were quantitated with SAMtools. We found small percentages (<0.1%) of transcriptomes aligned with B. microti, B. burgdorferi, T. denticola, and P. gingivalis genomes and larger percentages aligned with T. gondii (0.1-0.2%) and Trichinella sp. T6 (1.0-1.1%) genomes. In AD specimens, but in no others, primary aligned transcriptome percentages, although small, approached significance for being greater in AD compared to CTL samples for B. burgdorferi (p = 0.067) and P. gingivalis (p = 0.068). Genes' expressions in postmortem tissues of AD and ALS but not PD revealed significant changes among disease-associated microglial (DAM) genes. Infectious agents' transcripts can be detected in RNA seq reads of both NDD and CTL tissues and vary from agent to agent. Expressions of Stage 1 and Stage 2 DAM genes significantly changed, suggesting the presence of Stages 1 and 2 DAM in our NDD tissue samples. URL Previous https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447612 No Review Needed? Next

< Back to Research Top Published Date 15/04/2013 Bartonella henselae bacteremia in a mother and son potentially associated with tick exposure Journal Parasites & Vectors Citation Parasit Vectors. 2013 Apr 15;6:101 DOI 10.1186/1756-3305-6-101 Authors Maggi RG, Ericson M, Mascarelli PE, Bradley JM, Breitschwerdt EB Abstract BACKGROUND: Bartonella henselae is a zoonotic, alpha Proteobacterium, historically associated with cat scratch disease (CSD), but more recently associated with persistent bacteremia, fever of unknown origin, arthritic and neurological disorders, and bacillary angiomatosis, and peliosis hepatis in immunocompromised patients. A family from the Netherlands contacted our laboratory requesting to be included in a research study (NCSU-IRB#1960), designed to characterize Bartonella spp. bacteremia in people with extensive arthropod or animal exposure. All four family members had been exposed to tick bites in Zeeland, southwestern Netherlands. The mother and son were exhibiting symptoms including fatigue, headaches, memory loss, disorientation, peripheral neuropathic pain, striae (son only), and loss of coordination, whereas the father and daughter were healthy. METHODS: Each family member was tested for serological evidence of Bartonella exposure using B. vinsonii subsp. berkhoffii genotypes I-III, B. henselae and B. koehlerae indirect fluorescent antibody assays and for bacteremia using the BAPGM enrichment blood culture platform. RESULTS: The mother was seroreactive to multiple Bartonella spp. antigens and bacteremia was confirmed by PCR amplification of B. henselae DNA from blood, and from a BAPGM blood agar plate subculture isolate. The son was not seroreactive to any Bartonella sp. antigen, but B. henselae DNA was amplified from several blood and serum samples, from BAPGM enrichment blood culture, and from a cutaneous striae biopsy. The father and daughter were seronegative to all Bartonella spp. antigens, and negative for Bartonella DNA amplification. CONCLUSIONS: Historically, persistent B. henselae bacteremia was not thought to occur in immunocompetent humans. To our knowledge, this study provides preliminary evidence supporting the possibility of persistent B. henselae bacteremia in immunocompetent persons from Europe. Cat or flea contact was considered an unlikely source of transmission and the mother, a physician, reported that clinical symptoms developed following tick exposure. To our knowledge, this is the first time that a B. henselae organism has been visualized in and amplified from a striae lesion. As the tick bites occurred three years prior to documentation of B. henselae bacteremia, the mode of transmission could not be determined. URL Previous https://parasitesandvectors.biomedcentral.com/articles/10.1186/1756-3305-6-101 No Review Needed? Next

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