doi: 10.1176/appi.ajp.2021.20091347. 28 Jul 2021
July 12, 2021
Infect Immun doi:10.1128/IAI.00216-21, 28 June 2021
PLos Pathogens, 2021 Jan 11;17(1):e1009180.
doi: 10.1371/journal.ppat.1009180. eCollection 2021 Jan
Curr Issues Mol Biol. 2020 Dec 8;42:113-144. doi: 10.21775/cimb.042.113.
Front Med (Lausanne) Sep 16;7:568. doi: 10.3389/fmed.2020.00568. eCollection 2020.
Lyme borreliosis (LB) is the most common vector-borne disease in the Northern Hemisphere, and its incidence is on the rise. With 5%–20% of Lyme patients continuing to suffer from symptoms of Lyme post antibiotic treatment, it's important to understand what mechanisms are involved, how to predict which patients will develop what symptoms, and how best to treat them?
Variability in 2-tier Lyme disease test results according to the specific first-tier enzyme immunoassay (EIA) in children has not been examined rigorously. In this study, investigators paired results of clinical 2-tier Lyme disease tests to those of the C6 peptide EIA followed by supplemental immunoblotting (C6 2-tier test).
Of 1770 children undergoing emergency department evaluation for Lyme disease, 362 (20.5%) children had Lyme disease. Of those with an available tick bite history, only a minority of those with Lyme disease had a recognized tick bite (60/325; 18.5%, 95% confidence interval 14.6-23.0%). Lack of a tick bite history does not reliably exclude Lyme disease.
Conventional two-tiered testing (CTTT) for Lyme disease includes a first-tier enzyme immunoassay (EIA) followed by a supplemental immunoblot, and modified two-tiered testing (MTTT) relies on two different sequential EIAs without the inclusion of an immunoblot. MTTT has shown promising results as an alternative strategy for the diagnosis of Lyme disease in adults but has not yet been evaluated in children. We performed a cross-sectional study of children and adolescents ≤21 years of age undergoing clinical investigation for suspected Lyme disease.
Recent studies have shown that Borrelia burgdorferi can form antibiotic-tolerant persisters in the presence of microbiostatic drugs such as doxycycline. Precisely how this occurs is yet unknown. The goal of this study was to examine gene transcription by B. burgdorferi following doxycycline treatment in an effort to identify both persister-associated genes and possible targets for antimicrobial intervention.
The pathogenic spirochete Borrelia burgdorferi senses and responds to changes in the environment, including changes in nutrient availability, throughout its enzootic cycle in Ixodes ticks and vertebrate hosts. This study examined the role of DnaK suppressor protein (DksA) in the transcriptional response of B. burgdorferi to starvation.
Joint study conducted by scientists at Global Lyme Alliance (GLA) and Brown University estimates that two million people in the United States could suffer profound disability from post-treatment Lyme disease syndrome (PTLD) by the year 2020.
Borrelia burgdorferi (Bb) enters the human body via the bite of an infected Ixodes tick. Lyme disease symptoms arise from the dissemination of Bb from the initial bite site to the distal tissues such as the heart, the joints, or the nervous system. We identified a novel Bb infectivity gene, bbk13, that is important for distal tissue colonization in a mouse model of infection. Detailed characterization of the infection kinetics showed that there is a critical Bb population expansion that occurs at the skin during early infection and that bbk13 is important for this process. This study highlights the significance of early spirochete expansion in the skin towards driving downstream events that lead to distal tissue colonization. Therapeutic approaches that limit the early, localized expansion in the skin may prevent the onset of disseminated Lyme disease symptoms.
This team, based at University of Connecticut, studied genes controlled by the RpoS pathway, the regulatory system that facilitates transmission and mammalian infection by Borrelia burgdorferi. They were particularly interested in whether RpoS-controlled genes are needed for chronic infection. They were able to show, contrary to current hypotheses, that OspA was expressed on spirochetes delivered via tick, then quickly turned off via RpoS repression. OspA remains repressed until subsequent acquisition by feeding larvae. RpoS is known to be required for the early stages of infection. But it’s been hard to study RpoS during chronic infection, because mutant strains of bacteria that lack RpoS aren’t virulent. Using a creative approach, the team confirmed that expression of RpoS is required throughout infection. In support of these findings, they identified an RpoS-regulated protein that imports peptides, OppA5, that are required to maintain bacterial persistence during chronic infection. OppA5 has thus been deemed a “persistence” gene, validating the hypothesis that a specific subset of RpoS-regulated genes are essential for maintenance of chronic infection.
Dr. Alan Barbour and his team have analyzed the mitochondrial DNA from wild white-footed mice, Peromyscus leucopus. These mice are the natural host for Lyme and other tickborne bacteria, and serve as a reservoir from which ticks acquire pathogens. However, the mice themselves do not become sick despite being infected. This work focuses on mitochondria, the organelle responsible for generating energy in living cells. By sequencing and analyzing mitochondrial DNA and its transcription, Dr. Barbour’s group has provided the groundwork to determine how mice can tolerate infection, compared to lab mice and humans who do suffer symptoms. In addition, because mitochondrial DNA is inherited directly from the mother, genetic studies to understand Peromyscus subspecies geographic distribution and vectorborne disease dynamics can now be undertaken.
The Lyme PCR is a direct detection test, but has not been rigorously evaluated in children undergoing evaluation for acute Lyme disease.
In Lyme disease endemic areas, initial management of children with arthritis can be challenging because diagnostic tests take several days to return results, leading to potentially unnecessary invasive procedures. Our objective was to examine the role of the C6 peptide enzyme immunoassay (EIA) test to guide initial management.
Whether Borrelia burgdorferi, the causative agent of Lyme disease, can persist for long periods in the human body has been a controversial question. The objective of this study was to see if we could find B. burgdorferi in a Lyme disease patient after a long clinical course and after long-term antibiotic treatment.
Lymphatic vessels collect interstitial fluid that has extravasated from blood vessels and return it to the circulatory system. Another important function of the lymphatic network is to facilitate immune cell migration and antigen transport from the periphery to draining lymph nodes. This migration plays a crucial role in immune surveillance, initiation of immune responses and tolerance.
The multi-system symptoms accompanying acute and post-treatment Lyme disease syndrome pose a challenge for time-limited assessment. The General Symptom Questionnaire (GSQ-30) was developed to fill the need for a brief patient-reported measure of multi-system symptom burden. In this study we assess the psychometric properties and sensitivity to change of the GSQ-30.
According to the study, depression has been reported in 8 – 45% of patients with post-treatment Lyme disease syndrome (PTLDS), but little was known about suicidal tendencies in these patients. The extent and severity of depression and suicidality was compared between PTLDS and HIV/AIDS patients, and a non-patient control group was compared. The results conclusively demonstrate that suicidal tendencies increase among patients who are depressed and that, perhaps surprisingly, depression experienced by PTLDS and HIV/AIDS patients was statistically indistinguishable. This seminal study highlights the fact that one in five patients with PTLDS reported suicidal thoughts and the importance of screening for depression and suicidality to optimize patient care.
A mouse model of neurological Lyme disease would be helpful in understanding how patients develop symptoms and how to treat them. Until now, laboratory mice have not developed neuroborreliosis, which mimics human disease with demonstrated colonization of the central nervous system. However, a new report by Divan et al. gives hope that this may be possible. Using two different strains of B. burgdorferi and infecting mice via the skin, the researchers were able to consistently detect spirochetes in the membranes that surround the brain, called the dura and pia mater. Particularly compelling was the fact that they detected spirochetes 75 days after infection, adhering to blood vessels in the dura and pia mater, and that replicating spirochetes could be cultured from these samples. This suggests that long after acute infection, live spirochetes were still present at these sites. There were also more CD3+ T cells present in the dura of infected animals than in uninfected animals, suggesting an immune response. These findings open the door to new ways of studying neuroborreliosis in vivo. By identifying a site in the brain that is consistently colonized by spirochetes, as well as suggesting which immune pathways may be affected, further studies may reveal potential ways to alleviate the suffering of neuroborreliosis patients.
The persistence of symptoms in some Lyme disease patients treated with antibiotics has never been conclusively explained. This is known as post-treatment Lyme disease syndrome (PTLDS). It is possible that in common with animal models like mice and monkeys, human Borrelia burgdorferi infection results in residual, persistent infection even after treatment. Continued bacterial presence and/or an ongoing immune response could cause PTLDS. In an effort to identify antibiotics that might completely eradicate bacterial replication, the GLA-funded research team of Dr. Kim Lewis followed up earlier observations that beta-lactam antibiotics might be effective. The team found that vancomycin was effective against in vitro cultures of growing B. burgdorferi. However, this class of drugs is not expected to work on stationary cells, in which growth is very slow, and cell wall synthesis is expected to be minimal. Unexpectedly, when tested on stationary B. burgdorferi, they found that cell wall synthesis still occurred, and could be blocked by vancomycin. To extend their studies to an in vivo model, the group treated B. burgdorferi-infected, immunodeficient mice for five days. They found that vancomycin and ceftriaxone each completely blocked bacterial growth, compared with partial eradication by doxycycline. These studies suggest that more effective antimicrobial drugs, used early in infection, may prevent or reduce the occurrence of persisting infection. However, ceftriaxone and vancomycin are intravenously administered, and are not justifiable when most Lyme patients recover with oral doxycycline. Better identification of the subset of patients for whom doxycycline is inadequate would pave the way to studying whether vancomycin might reduce the incidence of PTLDS.
Heavy metals like iron, copper, manganese and zinc can be toxic in large amounts. But in low concentrations, they are essential micronutrients for humans as well as bacteria. As part of the defense against invasive microbes, our immune system exploits this property by starving bacteria of the metals they need to survive. One way of doing this is with calprotectin, an immune defense protein produced by neutrophils at the site of infections. Calprotectin depletes the local environment of metal nutrients, and can block Borrelia burgdorferi growth. The mechanism of how this works has now been explained in a newly published study, funded by GLA and led by Dr. Valeria Culotta.
Calprotectin was found in the dermal and epidermal layers of erythema migrans rashes of early Lyme disease patients. It is believed that epithelial keratinocytes in the skin produce calprotectin, which is more commonly associated with neutrophils, immune cells that are absent in this particular site. Surprisingly, calprotectin blocked B. burgdorferi growth not by depleting metals, as would be expected. Instead, it directly bound to the bacteria and changed their shape from spirochetes into a cyst-like form, when immersed in water. This differs from calprotectin’s mechanism of blocking another bacteria, E. coli, in which metal sequestration is essential to blocking bacterial replication. These findings suggest a unique new pathway that could be explored for a potential therapeutic that is specific to B. burgdorferi.
About 10-20% of Lyme disease patients treated with antibiotics continue to suffer debilitating symptoms, known as post-treatment Lyme disease. It is not understood whether this is due to an inappropriate immune response or continued Borrelia bacterial replication. In vitro laboratory experiments have showed that persister forms of bacteria are difficult to eliminate with antibiotics. This is because persisters are very slow-growing, and most antibiotics target actively-replicating bacteria. Limited clinical observations suggested some efficacy of dapsone, a sulfa drug, which belongs to a class of antibiotics not commonly used to treat Lyme disease. To test this drug against persister forms, Dr. Ying Zhang’s group studied sulfamethoxazole, dapsone, and sulfachlorpyridazine singly as well as in combination. By themselves, these drugs had similar efficacy as doxycycline, with 59-92% of stationary bacteria still alive after treatment. Their bacteria-killing activity was weak compared to daptomycin, which when used at the same concentrations, resulted in 26-52% of remaining cell viability. As combinations, they could not completely eradicate persister bacteria, with 74-77% bacteria remaining viable after treatment. But when they were combined with non-sulfa drugs like doxycycline, cefuroxime, ciprofloxacin, rifampin, and azithromycin, the rate of bacterial killing was higher. The most effective combinations included daptomycin. Further research will identify effective combinations that will more completely eradicate persister bacteria in vitro and in patients.
A review by Tracy and Baumgarth illustrates the complexity of Borrelia interactions with the immune system. In a masterful, thorough discussion, the authors outline current thinking of how the family of bacteria responsible for Lyme disease and other inflammatory illness persists in animals. They do so by escaping and subverting numerous immune system pathways, most notably in the principal reservoir host, the white-footed mouse. This species of mouse does not become symptomatic, and the authors explain ways that the immune response proceeds differently in the lab mouse, which does. In addition, the bacterium alters its surface proteins during various stages of infection, which makes it a moving target, but also enhances its ability to replicate and spread within the host. Finally, the authors point out that critical components of the adaptive immune response, which allow the production of highly specific and potent antibodies and immune cells, are disabled by Borrelia infection. Further study will illuminate how to target the bacteria more effectively, and to prevent persistent infection and immune dysfunction.
Lyme disease patients make antibodies that recognize Borrelia burgdorferi, the bacteria that cause illness. When the disease progresses from early to late stages, these antibodies may change. A protein on the outside of B. burgdorferi is called VlsE, and antibodies that bind to a portion of it called the membrane-proximal domain illustrate this. These specific antibodies were low in patients with early disease, and were increased in patients with symptoms typical of later illness, such as neurological symptoms.
The persistence of symptoms in Lyme patients treated with antibiotics may be due to the bacteria becoming tolerant to drugs. In lab culture, persistent Lyme bacteria grown into biofilm form were exposed to various antibiotic combinations. The authors found that double antibiotic combinations such as doxycycline and cefoperazone were not enough for biofilm eradication. The addition of either daptomycin or daunomycin was required for bacterial elimination.
The genes that are expressed in sick people differ from those who are healthy. Using advanced sequencing techniques, these researchers found that immune cells in the blood of people with Lyme disease express different genes from those of healthy controls. Genes that are linked to a strong immune response were reduced in Lyme patients compared to those with other bacterial or viral infections. People with persisting symptoms attributed to Lyme disease shared some gene expression patterns with patients suffering chronic illnesses caused by immune system dysfunction.
In lab culture, Borrelia burgdorferi, the bacterium that causes Lyme disease, can survive amoxicillin treatment by transforming into a round-body form. Such round bodies persist in a slowly-growing state and are tolerant of antibiotics. In this study, the authors tested 1581 drugs that are already approved by the FDA, for antimicrobial activity against amoxicillin-induced round-bodied B. burgdorferi. They found 23 drugs with activity against the round bodies when used singly. In addition, they identified artemisinin, a malaria drug, in combination with cefoperazone and doxycycline, as well as sulfachlorpyridazine together with daptomycin and doxycycline as potent combinations that reduced round bodies. Importantly, these combinations also had some durable inhibitory effect, because re-growth after subculture was low. These findings provide evidence that the continued search for effective drug combinations against persister bacteria is warranted.
An estimated 10-20% of Lyme disease patients who are treated with antibiotics continue to suffer persisting symptoms 6 to 12 months later. This is known as post-treatment Lyme disease syndrome, because it may affect various organs. Symptoms include chronic pain, overwhelming fatigue, and neurological or psychiatric symptoms. It is not known why this occurs in a subset of treated patients, but an aberrant immune response has long been suspected. In a new study led by Dr. John Aucott of Johns Hopkins University, elevated CCL19 was identified as associated with persistent symptoms. During acute infection, all patients diagnosed with Lyme disease (defined by physician-diagnosed erythema migrans rash) had elevated CCL19. However, by one month after diagnosis and treatment, those with serum concentrations greater than 112 pg/ml were 13 times more likely to develop post-treatment symptoms at 6 and 12 months later. Other patients who recovered, or who had symptoms without functional impairment had lower CCL19 levels after one month. CCL19 is produced by activated dendritic cells, which are sentinel cells that recruit immune cells to the site of an infection. The authors propose that sustained, elevated CCL19 is linked to continued inflammation and may account for ongoing symptoms, but point out that further studies are needed to understand the mechanistic basis and to identify other relevant immune pathways.
The human immune response to invasive microbes consists of two major arms: the innate and the adaptive response. The innate response occurs rapidly after infection, when the host tries to contain or inactivate the microbe. Two proteins involved in this process are C-reactive protein (CRP) and serum amyloid A (SAA), which are often elevated in the blood during an inflammatory response. In this study, the researchers analyzed CRP and SAA in the blood of people with varying stages of Lyme disease. They found that compared to healthy people, CRP was elevated in early Lyme disease, when patients had erythema migrans (EM) skin rashes. In contrast, CRP levels in patients with early or late neurological symptoms and arthritis were similar to healthy controls. However, patients with post-treatment Lyme disease syndrome (PTLDS) had higher CRP levels that those who recovered, suggesting ongoing inflammation in patients with long-term Lyme disease. SAA was elevated in patients with EM rashes, but was similar to healthy controls in all other patients, including those with PTLDS. These findings suggest that persisting symptoms after antibiotic therapy are associated with elevated CRP, and pave the way for further studies to understand long-term inflammatory processes in these patients.
At least 10% of patients treated with antibiotic therapy for Lyme disease continue to suffer persisting symptoms. The reason for this is unknown, but one suspect is the continued survival of persisting forms of B. burgdorferi, the bacterium responsible for Lyme disease. In the test tube, Zhang and colleagues have grown one form of persisting bacteria known as biofilms, and used it to test various combinations of antibiotics. They also compared single continuous dosing versus pulse-dosing, which consists of repeated cycles of adding and removing antibiotics. They found that pulse-dosing was not effective for all antibiotics, and in fact reduced the activity of daptomycin against persisters. The best strategy they found against biofilm-like persisters was a single dose of a combination of daptomycin, doxycycline, and cefuroxime. They also showed that bacteriocidal drugs, which kill bacteria, are better used in pulse dosing than bacteriostatic drugs, which block bacterial replication but do not directly kill them. These promising in vitro data pave the way for animal model studies. If the findings prevail, they may suggest that future human trials are warranted.
This is a review about the function of γδT cells, a specialized subset of T cells that are important in coordinating the immune response when it transitions from the innate, or immediate response, to the adaptive, more specific immune reaction. It focuses on these cells during refractory Lyme arthritis.
Persisting bacteria survive antibiotic treatment in lab culture. Here, the authors showed that antibiotics killed most of lab-grown B. burgdorferi, with a small surviving population that tolerated drug treatment. They found that mitomycin C, a cancer drug, efficiently killed persisters. They also showed how pulse-dosing, wherein four repetitive cycles that included treating bacterial cultures with ceftriaxone, followed by washing out the drug, resulted in eradication of persistent bacteria.
The persistence of symptoms in patients treated for Lyme disease remains unexplained. One possible reason could be immune system dysfunction, including antibodies that react against the patient. To study this possibility, these researchers studied whether antibodies targeting endothelial cell growth factor, a normal human protein, were associated with post-treatment Lyme disease syndrome. They found that while antibodies were observed in patients with early and later disease symptoms, they were mostly absent in patients with post-treatment Lyme syndrome.
The persistence of Borrelia burgdorferi in the form of drug-tolerant bacteria may be one reason why some Lyme disease patients may continue to suffer symptoms despite antibiotic therapy. The authors determined which drug combinations were effective in eradicating persistent microcolonies of B. burgdorferi, and identified daptomycin, doxycycline and cefoperazone together as an effective way of eliminating bacteria. Even subculturing bacteria treated with this combination to fresh media did not result in bacterial growth, suggesting durable killing.
The authors studied whether B. afzelii and B. garinii, two bacteria associated with Lyme disease in Europe, are capable of growing as biofilms in lab culture. Using chemical stains and microscopy, they showed that these two bacteria form biofilms, similar to B. burgdorferi, the North American species, when grown under specific lab culture conditions.
Patients with persisting Lyme symptoms were previously found to have higher and more frequent anti-neural antibodies compared to people who were healthy or who had recovered from Lyme disease. Patients with chronic fatigue syndrome (CFS) and persisting Lyme disease often have similar symptoms. This study found that CFS patients do not have elevated anti-neural antibodies. Thus, the common symptoms of persisting Lyme and CFS are not likely due to anti-neural antibodies
Lyme disease is caused by the bacteria called Borrelia burgdorferi. In lab cultures of B. burgdorferi that are treated with antibiotics, most are killed. However, some become persister bacteria that survive. The authors used RNA sequencing to study how the genes that are expressed may differ in persister compared to drug-free bacteria. They found that expression changes in 675 genes in persister bacteria.
The current blood test for Lyme disease has low accuracy. In this study, the authors designed and tested a new blood test that is more accurate. They used portions of proteins, called peptides, from Borrelia burgdorferi, the bacteria that cause Lyme disease. For a patient to be scored as positive, their blood had to contain antibodies that would recognize at least 2 of the 10 bacterial peptides. This test was more sensitive than the current blood test, and could be developed into a newer generation of diagnostic test for Lyme disease.
In this review, Dr. Zhang discusses the differences between B. burgdorferi persister and growing cells, and proposes a model for bacterial transition between the two states, with the balance tipped depending on the environment and stresses such as antibiotics.
The authors compared the blood of patients suffering more severe symptoms of Lyme disease against those with less. They found that the pattern of chemokines, which are chemical messengers produced by immune cells, varies between the two groups. This work may lead to better diagnostic tools and clinical treatments, and shows a biological difference between these two groups of patients.
A library of drug compounds that has already been approved by the FDA was tested for efficacy against persister forms of Borrelia burgdorferi that were grown in lab culture. They identified daptomycin, clofazimine, sulfa drugs, and cefoperazone as potential drugs worth pursuing in further studies, which may include animal models of Lyme disease.
Diagnosis of Lyme disease in late-stage patients is often erroneous. Fallon and colleagues compared Lyme disease test results from four different testing labs, using blood samples from previously diagnosed Lyme patients and healthy controls. Overall, they found variation in results, but no statistically significant difference between labs. However, there was a higher positivity rate for the C6 test, than for whole bacterial sonicate used in the diagnostic test.
The authors analyzed various methods to efficiently and accurately count live and dead Borrelia burgdorferi in lab culture. This is important for calculating the efficacy of antibiotics in the killing of bacteria. They adapted a method that stains live bacteria green, and dead ones red, allowing simple, reproducible, and high-throughput means to count bacteria.
A significant subset of patients treated for Lyme disease continue to have symptoms that persist for months or years. These may include pain, fatigue and neurocognitive problems, and collectively has been termed post-treatment Lyme disease syndrome. Whether these patients have ongoing infection is difficult to assess using current technology, and remains an open question. It is also possible that a post-infectious immune-mediated process may be responsible for continued symptoms. Here, the authors review central sensitization syndrome, in which pain and sensory processing is elevated. They discuss whether central sensitization may be related to continued symptoms in post-treatment Lyme disease.
Some patients treated for Lyme disease continue to suffer neurological symptoms. In these patients compared to healthy controls, there was increased interferon-α (IFNα) activity observed in the blood. IFNα is a cytokine, or chemical messenger, and together with the observation of elevated antibodies against B. burgdorferi and neural proteins, suggests an ongoing inflammatory response in these patients.
The authors used a new DNA identification technique to observe that Lone Star ticks in Missouri harbor DNA from both pathogenic bacteria (Ehrlichia and Borrelia) as well as from the species of squirrels on which they feed, the Eastern gray squirrel and the generic squirrel. It was not previously known that these squirrels are hosts for disease-carrying ticks.
The immune response to B. burgdorferi infection includes the production of antibodies that recognize bacterial surface proteins, one of which is called VlsE. Proteins form complex three-dimensional shapes, and only parts of them, called epitopes, are recognized by antibodies. Alaedini’s group mapped these on VlsE. The antibodies against VlsE differ in patients with later compared to earlier stages of Lyme disease.
Chronic fatigue syndrome patients and post-treatment Lyme disease patients share some similar neurological symptoms. This study showed that the protein profiles in cerebrospinal fluid from the two groups were distinctive, suggesting that they are two different diseases.
In this article, the authors used a mouse model to study B cells, which when activated, produce antibodies and release inflammatory cytokines, or chemical messengers. They found that a protein called CLIP is important in controlling B cells, and speculated that it shows a potential pathway to control chronic immune activation diseases such as Crohn’s disease and post-treatment Lyme disease.
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