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Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection

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      Abstract

      Lyme Disease caused by infection with Borrelia burgdorferi is an emerging infectious disease and already by far the most common vector-borne disease in the U.S. Similar to many other infections, infection with B. burgdorferi results in strong antibody response induction, which can be used clinically as a diagnostic measure of prior exposure. However, clinical studies have shown a sometimes-precipitous decline of such antibodies shortly following antibiotic treatment, revealing a potential deficit in the host’s ability to induce and/or maintain long-term protective antibodies. This is further supported by reports of frequent repeat infections with B. burgdorferi in endemic areas. The mechanisms underlying such a lack of long-term humoral immunity, however, remain unknown. We show here that B. burgdorferi infected mice show a similar rapid disappearance of Borrelia-specific antibodies after infection and subsequent antibiotic treatment. This failure was associated with development of only short-lived germinal centers, micro-anatomical locations from which long-lived immunity originates. These showed structural abnormalities and failed to induce memory B cells and long-lived plasma cells for months after the infection, rendering the mice susceptible to reinfection with the same strain of B. burgdorferi. The inability to induce long-lived immune responses was not due to the particular nature of the immunogenic antigens of B. burgdorferi, as antibodies to both T-dependent and T-independent Borrelia antigens lacked longevity and B cell memory induction. Furthermore, influenza immunization administered at the time of Borrelia infection also failed to induce robust antibody responses, dramatically reducing the protective antiviral capacity of the humoral response. Collectively, these studies show that B. burgdorferi-infection results in targeted and temporary immunosuppression of the host and bring new insight into the mechanisms underlying the failure to develop long-term immunity to this emerging disease threat.

      Author Summary

      Infections with the Lyme Disease agent, Borrelia burgdorferi, often fail to generate long-term protective immunity. We show here that this is because the immune system of the Borrelia-infected host generates only short-lived, structurally abnormal and non-functional germinal centers. These germinal centers fail to induce memory B cells and long-lived antibody-producing plasma cells, leaving the host susceptible to reinfection with Bb. This inability to induce long-term immunity was not due to the nature of Borrelia antigens, as even T-dependent antigens of Borrelia were unable to induce such responses. Moreover, influenza vaccine antigens, when applied during Borrelia-infection, failed to induce strong antibody responses and immune-protection from influenza challenge. This data illustrate the potent, if temporal, immune suppression induced by Borrelia-infection. Collectively, the data reveal a new mechanism by which B. burgdorferi subverts the adaptive immune response.

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      Most cited references 46

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      Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes.

      In little more than 30 years, Lyme disease, which is caused by the spirochaete Borrelia burgdorferi, has risen from relative obscurity to become a global public health problem and a prototype of an emerging infection. During this period, there has been an extraordinary accumulation of knowledge on the phylogenetic diversity, molecular biology, genetics and host interactions of B. burgdorferi. In this Review, we integrate this large body of information into a cohesive picture of the molecular and cellular events that transpire as Lyme disease spirochaetes transit between their arthropod and vertebrate hosts during the enzootic cycle.
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        The emergence of Lyme disease.

        Since its identification nearly 30 years ago, Lyme disease has continued to spread, and there have been increasing numbers of cases in the northeastern and north central US. The Lyme disease agent, Borrelia burgdorferi, causes infection by migration through tissues, adhesion to host cells, and evasion of immune clearance. Both innate and adaptive immune responses, especially macrophage- and antibody-mediated killing, are required for optimal control of the infection and spirochetal eradication. Ecological conditions favorable to the disease, and the challenge of prevention, predict that Lyme disease will be a continuing public health concern.
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          Extrafollicular antibody responses.

          In adaptive antibody responses, B cells are induced to grow either in follicles where they form germinal centers or in extrafollicular foci as plasmablasts. Extrafollicular growth typically occurs in the medullary cords of lymph nodes and in foci in the red pulp of the spleen. It is not a feature of secondary lymphoid tissue associated with the internal epithelia of the body. All types of naïve and memory B cells can be recruited into extrafollicular responses. These responses are associated with immunoglobulin class switching but, at the most, only low-level hypermutation.
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            Author and article information

            Affiliations
            [1 ]Center for Comparative Medicine, University of California, Davis, Davis, California, United States of America
            [2 ]Microbiology Graduate Group, University of California, Davis, Davis, California, United States of America
            [3 ]Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America
            Medical College of Wisconsin, UNITED STATES
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: RAE NB. Performed the experiments: RAE CJH KJO. Analyzed the data: RAE CJH KJO NB. Contributed reagents/materials/analysis tools: NB. Wrote the paper: RAE NB CJH.

            [¤a]

            Current Address: Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America

            [¤b]

            Current Address: Siemens AG, Sacramento, California, United States of America

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, CA USA )
            1553-7366
            1553-7374
            2 July 2015
            July 2015
            : 11
            : 7
            26136236 4489802 10.1371/journal.ppat.1004976 PPATHOGENS-D-14-02296

            This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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            Figures: 7, Tables: 0, Pages: 19
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            Funding
            This work was supported by grants from the National Institute of Health (NIH), National Institute of Allergy and Infectious Diseases grant AI073911, AI051354 and AI085568 and training grants from the NIH: T32-AI060555 and T32-AI074550. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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            Research Article
            Custom metadata
            All relevant data are within the paper and its Supporting Information files.

            Infectious disease & Microbiology

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