The Functional and Molecular Effects of Doxycycline Treatment on Borrelia burgdorferi Phenotype

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. Our goal 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. To do so, we performed next-generation RNA sequencing on doxycycline-treated spirochetes and treated spirochetes following regrowth, comparing them to untreated B. burgdorferi. A number of genes were perturbed and most of those which were statistically significant were down-regulated in the treated versus the untreated or treated/re-grown. Genes upregulated in the treated B. burgdorferi included a number of Erp genes and rplU, a 50S ribosomal protein. Among those genes associated with post-treatment regrowth were bba74 (Oms28), bba03, several peptide ABC transporters, ospA, ospB, ospC, dbpA and bba62. Studies are underway to determine if these same genes are perturbed in B. burgdorferi treated with doxycycline in a host environment

Human Bartonellosis: An Underappreciated Public Health Problem?

Bartonella spp. bacteria can be found around the globe and are the causative agents of multiple human diseases. The most well-known infection is called cat-scratch disease, which causes mild lymphadenopathy and fever. As our knowledge of these bacteria grows, new presentations of the disease have been recognized, with serious manifestations. Not only has more severe disease been associated with these bacteria but also Bartonella species have been discovered in a wide range of mammals, and the pathogens’ DNA can be found in multiple vectors. This review will focus on some common mammalian reservoirs as well as the suspected vectors in relation to the disease transmission and prevalence. Understanding the complex interactions between these bacteria, their vectors, and their reservoirs, as well as the breadth of infection by Bartonella around the world will help to assess the impact of Bartonellosis on public health

Evaluation of the available animal models for Bartonella infections

The diseases caused by the Bartonella genus of bacteria are clinically diverse, and can be challenging to cure. The study of bartonellosis has been hampered by the lack of a suitable animal model. Preclinical studies for novel therapeutics and a competent host for vector transmission studies are needed to fill critical knowledge gaps. The studies included here are a representation of in vivo Bartonella research and the corresponding challenges. This review examines the current state of available animal models by assessing the success of various model species and strains in Bartonella infection. With a focus on the strengths and weaknesses of current animal models, the importance of these models for improvement of human health and veterinary care is emphasized

A comparison of Bartonella henselae infection in immunocompetent and immunocompromised mice.

Bartonellosis refers to disease caused by the Bartonella genus of bacteria. The breadth of disease manifestations associated with Bartonella is currently expanding and includes regional lymphadenopathy, rheumatic, ocular, and neurological disorders. The dearth of knowledge regarding diagnosis, treatment and pathogenesis of this disease can be partially attributed to the lack of a reliable small animal model for the disease. For this study, Bartonella henselae, the most common species associated with human disease, was injected into Swiss Webster (SW) mice. When the outcome indicated that productive infection did not occur, SCID/Beige (immune compromised) mice were inoculated. While SW mice may potentially harbor an acute infection, less than 10 days in length, the SCID/Beige model provided a sustained infection lasting up to 30-days. These data indicate that SCID/Beige mice can provide a model to study Bartonella infection, therapeutics, and vector dynamics in the future

Heatmap of the tissue distribution of PCR positive tissues in SCID mice at 10-, 20-, or 30-days post-infection.

The bladders and brains of 2/3 mice and 3/3 mice were positive for infection, respectively, at 30-days post-inoculation. Other patterns remain unclear as only one mouse each was positive for the other tissues. n = 3 for each time point. Hrt = heart, LR = liver, Spl = spleen, BM = bone marrow, LyN = lymph node, ThM = thymus, ThR = thyroid, LG = lung, K = kidney, Bla = bladder, AG = adrenal glands, P = pancreas, TTJ = tiobiotarsal joint, BR = brain, Ear.</p

Pathology of SCID/Beige mice infected with <i>B</i>. <i>henselae</i>.

Pathology of SCID/Beige mice infected with B. henselae.</p

Pathology and PCR results from <i>B</i>. <i>henselae</i>-infected SW mice.

Pathology and PCR results from B. henselae-infected SW mice.</p

Histopathology of tissues from SCID/beige mice infected with <i>B</i>. <i>henselae</i>.

(A, B) Mice were necropsied 10 dpi and tissues were stained with H&E stain for histopathological analysis. (A) Liver sections were found to contain mild multifocal portal mononuclear and suppurative infiltrations; (B) Heart sections contained focally extensive, moderate mononuclear epicarditis with extensions into the myocardium. (C,D) Tissues from 20 dpi with B. henselae. (C) Liver sections contained mild multifocal portal mononuclear infiltrations with minimum extramedullary hematopoiesis; (D) Heart sections contained minimal multifocal mineralization of the blood vessels (arrows). (E,F) Tissues from mice 30 dpi with B. henselae. Livers from two different mice contained (E) mild multifocal portal mononuclear inflammation and (F) focal granuloma in the peritoneal fat with minimal portal mononuclear infiltration. All scale bars = 250μm.</p

Kidney from a mouse 30 dpi <i>Bartonella henselae</i> infection.

Arrow indicates the formation of visible mineralization. This type of mineralization is considered to be an artifact of the staining process and not a true pathology. (TIF)</p

Comparison of PCR and histological results of SCID/beige mice.

Comparison of PCR and histological results of SCID/beige mice.</p