Results

We demonstrate that B. garinii OspA serotype 4 (ST4) PBi resist complement-mediated killing by binding of FHL-1. To identify the primary ligands of FHL-1 four CspA orthologs from B. garinii ST4 PBi were cloned and tested for binding to human CFH and FHL-1. Orthologs BGA66 and BGA71 were found to be able to bind both complement regulators but with different intensities. In addition, all CspA orthologs were tested for binding to mammalian and avian CFH. Distinct orthologs were able to bind to CFH of different animal origins.

Conclusions

B. garinii ST4 PBi is able to evade complement killing and it can bind FHL-1 to membrane expressed proteins. Recombinant proteins BGA66 can bind FHL-1 and human CFH, while BGA71 can bind only FHL-1. All recombinant CspA orthologs from B. garinii ST4 PBi can bind CFH from different animal origins. This partly explains the wide variety of animals that can be infected by B. garinii

Excerpt:

Human ehrlichiosis and anaplasmosis are acute febrile tick-borne
diseases caused by various members of the genera Ehrlichia and
Anaplasma (Anaplasmataceae).
Human monocytotropic ehrlichiosis has become one of the most
prevalent life-threatening tick-borne disease in the United
States. Ehrlichiosis and anaplasmosis are becoming more
frequently diagnosed as the cause of human infections, as animal
reservoirs and tick vectors have increased in number and humans
have inhabited areas where reservoir and tick populations are
high.
Ehrlichia chaffeensis, the etiologic agent of human
monocytotropic ehrlichiosis (HME), is an emerging zoonosis that
causes clinical manifestations ranging from a mild febrile
illness to a fulminant disease characterized by multiorgan system
failure. Anaplasma phagocytophilum causes human granulocytotropic
anaplasmosis (HGA), previously known as human granulocytotropic
ehrlichiosis. This article reviews recent advances in the
understanding of ehrlichial diseases related to microbiology,
epidemiology, diagnosis, pathogenesis, immunity, and treatment of
the 2 prevalent tick-borne diseases found in the United States,
HME and HGA.

Excerpt:

This study was undertaken to determine which rodent species serve
as primary reservoirs for the Lyme disease spirochete Borrelia
burgdorferi in commonly occurring woodland types in inland areas
of northwestern California, and to examine whether chaparral or
grassland serve as source habitats for dispersal of B.
burgdorferi- or B. bissettii-infected rodents into adjacent
woodlands. The western gray squirrel (Sciurus griseus) was
commonly infected with B.
burgdorferi in oak woodlands, whereas examination of 30
dusky-footed woodrats (Neotoma fuscipes) and 280 Peromyscus spp.
mice from 13 widely spaced Mendocino County woodlands during 2002
and 2003 yielded only one infected woodrat and one infected deer
mouse (P. maniculatus). These data suggest that western gray
squirrels account for the majority of production by rodents of
fed Ixodes pacificus larvae infected with B. burgdorferi in the
woodlands sampled.

We previously identified ebpR, encoding a potential member of the AtxA/Mga transcriptional regulator family, and showed that it is important for transcriptional activation of the Enterococcus faecalis endocarditis and biofilm associated pilus operon, ebpABC. Although ebpR is not absolutely essential for ebpABC expression (100-fold reduction), its deletion led to phenotypes similar to those of an ebpABC mutant such as absence of pili at the cell surface and, consequently, reduced biofilm formation. A non-piliated ebpABC mutant has been shown to be attenuated in a rat model of endocarditis and in a murine urinary tract infection model, indicating an important participation of the ebpRABC locus in virulence. However, there is no report relating to the environmental conditions that affect expression of the ebpRABC locus.

 

Publication Types:
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov’t
    Research Support, U.S. Gov’t, Non-P.H.S.
    Research Support, U.S. Gov’t, P.H.S.

http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=19996447&retmode=ref&cmd=prlinks
PMID: 19996447  [PubMed – in process]

Am J Trop Med Hyg. 2009 Dec;81(6):1120-31.

Niche partitioning of Borrelia burgdorferi and Borrelia miyamotoi in the same
tick vector and mammalian reservoir species.

Barbour AG, Bunikis J, Travinsky B, Hoen AG, Diuk-Wasser MA, Fish D, Tsao JI.

Department of Microbiology and Molecular Genetics, University of California
Irvine, Irvine, California 92697-4028, USA. abarbour@uci.edu

Juvenile idiopathic arthritis (JIA) is a disease that was prominent with
increased inflammation response in immune system, appeared mostly with
peripheral arthritis and endogenous and exogenous antigens play a role
in the pathogenesis of disease. Two major reasons were thinking to be
considerably important. First of them is immunological predisposition
and the second one is environmental factors.

Infections are considered to be the most important between environmental factors but also stress and trauma are also important in the etiology of the disease. However,
the relation between JIA and infections is not clearly defined but the
relation between adult chronic arthritis and infections was
well-defined. A total of 70 patients, 26 with primer JIA, 20 with
recurrent JIA, 24 healthy control were included in this study.
Mycoplasma pneumoniae, Chlamydophila pneumoniae and C. Jejuni were
detected in 4, 1 and 1 of 10 (38.46%) patients with primer JIA,
respectively. Salmonella enteritidis, EBV, M. pneumoniae, C. jejuni and
Borrelia burgdorferi were detected in 1, 2, 2, 2, and 1 of the 8(40%)
patients with recurrent JIA, respectively. S. enteritidis were isolated
in feces culture and also identified by agglutination method. Infection
was detected in total 18 (39.13%) of patient groups. C. pneumoniae and
C. jejuni were detected in 1 and 1 of 2(8.33) healthy control groups,
respectively. Throat culture positivity was not detected in any of the
patient and healthy control groups. In conclusion, etiopathogenesis of
JIA is not clearly understood and suggested that various factors can
trigger the disease and it is the most common rheumatoid disease of
childhood. However, there are some studies focusing especially on one
infectious agent but this is the first study including such a big range
of infectious agents in the literature for the microorganisms that can
be suggested to have a role in the etiopathogenesis of JIA. We have a
conclusion in the light of our results and suggest that some
microorganisms can trigger and increase the intensity of clinical
situation according to the case. When we evaluate the primer and
recurrent JIA groups; M. pneumoniae and C. jejuni come forward and seen
common in JIA cases. We also suggest that the pre-diagnosis of
microorganisms, which can play a role as primarily or by intervening in
the etiopathogenesis of JIA and adding specific antimicrobial therapy to
the standard JIA therapy, it is possible to perform new, extended,
especially molecular based serial case studies.

PMID: 20012631 [PubMed – as supplied by publisher]

Rheumatol Int.. [Epub ahead of print]

Do infections trigger juvenile idiopathic arthritis?

Aslan M, Kasapcopur O, Yasar H, Polat E, Saribas S, Cakan H, Dirican A,
Torun MM, Ar?soy N, Kocazeybek B.

Microbiology and Clinical Microbiology Department, Cerrahpasa Medical
Faculty, Istanbul University, Kocamustafapasa, 34303, Istanbul, Turkey.

Benoit VM, Petrich A, Alugupalli KR, Marty-Roix R, Moter A, Leong JM, Boyartchuk VL.

Department of Molecular Genetics and Microbiology, and Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605; Institut für Mikrobiologie und Hygiene, Charité – Universitätsmedizin Berlin, Campus Charité Mitte, 10117 Berlin, Germany; Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107.

Host susceptibility to infection is controlled in large measure by the genetic makeup of the host. Spirochetes of the genus Borrelia include nearly 40 species of vector-borne spirochetes that are capable of infecting a wide range of mammalian hosts, causing Lyme disease and relapsing fever. Relapsing fever is associated with high-level bacteremia, as well as hematologic manifestations such as thrombocytopenia (i.e. low platelet numbers) and anemia. To facilitate studies of genetic control of susceptibility to Borrelia hermsii infection we performed a systematic analysis of the course of infection using immunocompetent and immunocompromised inbred strains of mice. Our analysis revealed that sensitivity to B. hermsii infections is genetically controlled. In addition, whereas the role of adaptive immunity to relapsing fever spirochetes is well documented, we found that innate immunity contributes significantly to reduction of bacterial burden. Similar to human infection, progression of the disease in mice was associated with thrombocytopenia and anemia. Histological and fluorescence in situ hybridization (FISH) analysis of infected tissues indicated that red blood cells were removed by tissue resident macrophages, a process that could lead to anemia. Spirochetes in the spleen and liver were often visualized associated with RBCs, lending support to the hypothesis that direct interaction of B. hermsii spirochetes with RBCs leads to clearance of bacteria from the bloodstream by tissue phagocytes.

PMID: 19995898 [PubMed – as supplied by publisher]

Methods.Separate serum sets from LD patients and control subjects were tested independently at 2 medical centers using whole‐cell enzyme immunoassays and IgM and IgG immunoblots, with recombinant VlsE added to the IgG blots. The results from both centers were combined, and a new second‐tier IgG algorithm was developed.

Results.With standard 2‐tiered IgM and IgG testing, 31% of patients with active erythema migrans (stage 1), 63% of those with acute neuroborreliosis or carditis (stage 2), and 100% of those with arthritis or late neurologic involvement (stage 3) had positive results. Using new IgG criteria, in which only the VlsE band was scored as a second‐tier test among patients with early LD (stage 1 or 2) and 5 of 11 IgG bands were required in those with stage 3 LD, 34% of patients with stage 1, 96% of those with stage 2, and 100% of those with stage 3 infection had positive responses. Both new and standard testing achieved 100% specificity.

Conclusions.Compared with standard IgM and IgG testing, the new IgG algorithm (with VlsE band) eliminates the need for IgM testing; it provides comparable or better sensitivity, and it maintains high specificity.

Received 27 May 2009; accepted 10 August 2009; electronically published 30 November 2009.

Reprints or correspondence: Dr. John A. Branda, Clinical Microbiology Laboratory, GRB 526, Massachusetts General Hospital, Boston, MA 02114 (branda.john@mgh.harvard.edu).

• Presented in part: 45th Annual Meeting of the Infectious Diseases Society of America, San Diego, CA, 4-7 October 2007; and 11th International Conference on Lyme Borreliosis and Other Tick‐Borne Diseases, Irvine, CA, 19-22 October 2008.

http://www.journals.uchicago.edu/doi/abs/10.1086/648674 Clinical Infectious Diseases 2010;50:000-000 © 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5001-00XX$15.00 DOI: 10.1086/648674 MAJOR ARTICLE

2‐Tiered Antibody Testing for Early and Late Lyme Disease Using Only an Immunoglobulin G Blot with the Addition of a VlsE Band as the Second‐Tier Test

John A. Branda,¹

Maria E. Aguero‐Rosenfeld,^3,4

Mary Jane Ferraro,^1,2

Barbara J. B. Johnson,⁵

Gary P. Wormser,⁴ and

Allen C. Steere²

Departments of ¹Pathology and ²Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Departments of ³Pathology and ⁴Medicine, Division of Infectious Diseases, New York Medical College, Valhalla, New York; ⁵Division of Vector‐Borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

Between 1994 and April 2009, IDSA issued 68 guidelines on 52 different topics (there have been 2 more since April). Most were published in Clinical Infectious Diseases. Of the 52 current guidelines, Dr. Lee’s team analyzed the 30 that followed IDSA’s standard grading system to evaluate the class of clinical recommendations and the strength of the supporting evidence underlying them.

“Our analysis revealed that more than half were based on expert opinion or not supported by properly controlled trials,” Dr. Lee announced. In an oral presentation, he reported that the 30 guidelines he analyzed contained a mean of 47 recommendations (range, 14 to 150). Recommendations ranged from class A (should always be offered) to class C (optional). The quality of evidence ranged from level I, consisting of 1 or more properly conducted RCTs, to level III, the opinion of respected authorities, based on clinical experience. Level II evidence is derived from 1 or more properly controlled trials without randomization.

The guidelines revealed a total of 589 class A recommendations. “Ideally, all should be [supported by] level I evidence,” Dr. Lee said. “However, a class A recommendation was supported by level I evidence only in 25% [of cases].” The rest were based on level II (40%) or level III (35%) evidence. Of all the guidelines evaluated, a median of 41% of recommendations were class A, but level I evidence supported them only 14% of the time.

Guidelines for common conditions were often based on fairly strong evidence. The recommendations that are most supported by level I evidence are in the guidelines for tropical medicine (41% of recommendations), intra-abdominal infection (39%), and asymptomatic bacteriuria (38%). “Influenza or Group A Streptococcus guidelines had less than 20% of level III evidence,” possibly because of the high prevalence of these diseases and the ease of designing studies, Dr. Lee reported.

He explained the lack of RCTs for some conditions, saying that certain infections occur rarely or present in heterogeneous forms, making it difficult to design a study. Furthermore, in some cases it might be unethical to conduct such a trial, and at times certain knowledge based on sound clinical judgment will never be tested in RCTs. Finally, funding to do trials might be lacking.

“Although a randomized controlled trial is referred to as level I evidence, not all RCTs are created equal,” he warned. “Some choose surrogate markers, others choose patient-centered outcomes. Well-designed nonrandomized trials may provide more information than certain randomized controlled trials, but I do think that a randomized controlled trial minimizes bias and does deserve the high levels of evidence.”

Dr. Lee summarized his presentation, saying that of the 1408 guideline recommendations he reviewed, “more than half were based on level III evidence, which is from expert opinion or not supported by properly controlled trials. Level I evidence was only 15%.” He said his study should help to point out where evidence is lacking and to suggest areas for further research.

Physicians and trainees should not just look at guidelines, but should also examine the strength of the evidence on which they are based, he advised. “When clinicians are using the guidelines, they should not assume that they are all based on well-designed studies. . . . Clinicians should remain cautious when using current guidelines as the sole source for guiding patient care.”

A second presentation supported the findings of Lee and coworkers. Abdur Khan, MD, assistant consultant at King Fahad Medical City in Riyadh, Saudi Arabia, presented his results in a poster session. Of the 65 IDSA guidelines, encompassing 6667 recommendations, issued between March 1994 and July 2009, he and his colleagues evaluated the 44, comprising 4206 recommendations, that were posted on the IDSA Web site at the end of July.

They, too, found that, overall, the strength of the recommendations did not correlate with the available evidence. Level I evidence was the basis for only 15% of the guidelines, which is in agreement with the findings that Lee and colleagues reported. Thirty percent of the evidence was level II.

“Around 55% of the guidelines had a level of evidence of III, which was based on expert opinion,” Dr. Khan toldMedscape Infectious Diseases, “but the class C recommendations [are] only 12%.” Guidelines for the treatment of fungal infections had the weakest supporting evidence; 46.5% to 89.5% of the recommendations were based on level III evidence.

Although the highest levels of evidence generally led to class A recommendations (25.9%), these strongest recommendations were most often based on lesser levels of evidence (36.3% on level II; 37.8% on level III).

Commenting on the studies’ findings, Richard Whitley, MD, professor of pediatrics, microbiology, medicine, and neurosurgery at the University of Alabama at Birmingham and president of IDSA, told Medscape Infectious Diseases that “one always has to be concerned when we don’t have randomized controlled trials that provide evidence-based medicine to write guidelines. Without a shadow of a doubt, the best evidence comes from controlled clinical trials that are adequately powered with a sample size to answer the targeted question.” But he noted that sometimes expert opinion or small uncontrolled studies have to suffice if there are not enough patients to conduct better trials.

In some situations, less than level I data can be powerful, Dr. Whitley observed. He cited the example that neuraminidase inhibitors can decrease mortality from influenza in elderly individuals. This finding was based on retrospective reviews of databases of Kaiser Permanente and other managed health care systems, he explained.

Looking forward, he said, “guidelines don’t necessarily just teach how to take care of patients. They identify areas for future investigation . . . because they tell us where the vagueness is and where we have to move forward.” This information can then be brought to the attention of the leadership of the National Institute of Allergy and Infectious Diseases so that they can fund studies and to the attention of the US Food and Drug Administration, which has funds to study targeted issues.

Dr. Whitley emphasized that “guidelines shouldn’t be just for patients in the United States. They should be for patients around the world.” As such, IDSA and the European Congress of Clinical Microbiology and Infectious Diseases will try to work on guidelines together, and IDSA will also work with Canadian colleagues “so that we can provide a level of care that’s standardized around the world,” he said. “Certainly, that’s optimistic.”

Neither of these studies received funding. Dr. Lee and Dr. Khan have disclosed no relevant financial relationships. Dr. Whitley reports being on the board of directors of Gilead Sciences and is a consultant for 3-V Biologics and Chimerix; his other consulting, review, advisory panel positions, investigator, or speaker honoraria relationships include Juvaris, Primus, Inhibitex, and JID.

Infectious Diseases Society of America (IDSA) 47th Annual Meeting: Abstract 1324. presented November 1, 2009; Abstract LB-31, presented October 31, 2009.

From Reuters Health Information http://www.medscape.com/viewarticle/703037

By Megan Rauscher

NEW YORK (Reuters Health) May 19 – Almonds have the potential to boost immune health and reduce inflammation, according to research reported Tuesday at the 109th annual meeting of the American Society for Microbiology in Philadelphia.

Almonds, study presenter Dr. Giuseppina Mandalari told Reuters Health, may have a “helpful impact on the treatment of infective and chronic diseases. Almond skins can modulate the complex cytokine network during an immunological response and positively act as novel antiviral agents.”

Dr. Mandalari, from the Institute of Food Research, Norwich, UK, and colleagues evaluated the effects of natural and blanched almond skins on the release of cytokines in peripheral blood mononuclear cells (PBMC) either infected or not infected with herpes simplex virus-2 (HSV-2).

The study was funded by the Almond Board of California.

The addition of natural almond skins to PBMC resulted in a “significant decrease in HSV-2 replication, whereas other extracts did not significantly influence the replication of the virus,” they report in a meeting abstract.

Almond skins also boosted production of several pro-inflammatory cytokines including interferon (IFN)-alpha, IFN-gamma, tumor necrosis factor (TNF)-alpha, and interleukin-12 (IL-12). Moreover, IL-10 and IL-4, representative of Th2 responses, were also detected.

“It is well known that efficient elimination of a viral infection requires a pro-inflammatory host response and the development of type 1 immunity, characterized by activation of mononuclear cells and production of pro-inflammatory cytokines, the scientists explain.

“Our data suggest that almond skins may improve the immune surveillance of PBMC towards viral infection, both by triggering the Th1 and stimulating Th2 subset. This could represent a new strategy towards the Th1/Th2 balance,” they conclude.

“If the study can be repeated in humans, it offers promise for preventing chronic inflammation and boosting immune function,” Dr. Mandalari said.