Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases The Short-Term and Long-Term Outcomes: Workshop Report (2011) / Chapter Skim
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6 Pathogenesis
6 Pathogenesis
Pages 97-124
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From page 97... ...
Animal models have been especially useful in shedding light on the key features of tick-borne infectious diseases. These models include naturally occurring infectious disease, such as neuroborreliosis in horses and Rocky Mountain spotted fever in dogs, and infections introduced into animals such as mice.
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From page 98... ...
. Differences in the severity and spectrum of disease among patients infected with Borrelia burgdorferi is one of the hallmarks of Lyme disease (Steere and Glickstein, 2004)
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From page 99... ...
In contrast, the bacterium produces multiple molecules that activate host responses and can lead to localized and generalized inflammatory pathogenic responses. Most of these host responses normally function to contain or clear infections and are components of the innate defense and/or inflammatory response (Liu et al., 2004; Benhnia et al., 2005; Behera et al., 2006a; Oosting et al., 2010)
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From page 100... ...
, which are normally associated with host response to viral infections, are important for the development of arthritis following B burgdorferi infection.
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. Furthermore, T lymphocytes help resolve Lyme disease carditis by production of interferon gamma and other cytokines, which in turn activate the macrophages to clear B
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From page 102... ...
burgdorferi DNA could be detected in some SCID mice that had received tissue transplants of skin from antibiotic-treated mice. Although viable spirochetes could not be cultured from the ticks, the antibiotic-treated donor mice, or the recipient mice, rare spirochete forms were visualized microscopically in specific connective tissues of some donor mice (Hodzic et al., 2008)
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From page 103... ...
With the exception of mice analyzed after one day of antibiotic treatment, no spirochetes could be visualized in ear skin or tendons of antibiotic-treated mice at any time. At the end of the experiment, however, DFA revealed green fluorescent material adjacent to the ear cartilage in all of the antibiotic-treated mice.
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From page 104... ...
DISCUSSION The discussion session focused on the pathogenesis of Lyme disease and how these studies inform us about human disease. A participant questioned if the spirochetes were able to change their morphology and "hibernate"
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From page 105... ...
ANTIGENIC VARIATION AS A MECHANISM FOR PERSISTENT BORRELIA INFECTION Steven J Norris, Ph.D., Department of Pathology & Laboratory Medicine, University of Texas Medical School at Houston Pathogens can vary in their ability to be invasive and toxic to an organism (see Figure 6-1)
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From page 106... ...
R01965 Lyme disease Borrelia is a highly motile organism. In animal models, bitmapped B
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From page 107... ...
Thus, the sequence differences in those regions provide a mechanism so that the organism can effectively evade the immune response through continuously changing the amino acid sequence of the exposed region. The invariant regions also elicit a host immune response during infection, one of which is now used to diagnose Lyme disease (see Chapter 8)
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From page 108... ...
While still preliminary, this method may provide a model to study antigenic variation in vitro. The vls antigenic variation system appears to be present in all Lyme disease Borrelia but exhibits a high degree of sequence diversity.
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From page 109... ...
First, the vls system of antigenic variation is an important mechanism allowing Lyme disease Borrelia to evade a host's immune system -- and allowing infection to persist. Second, while the vlsE gene conversion process is not well understood, it is known to involve the RuvAB Holliday junction resolvase.
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From page 110... ...
With the evolution of the host immune response, the erythema migrans will spontaneously resolve, but spirochetes persist in the same tissue, without eliciting inflammation. Thus, one of the earliest clinical signs of Lyme disease, erythema migrans, signals the onset of the immune phase of persistent infection, when spirochetes are sequestered in collagen with minimal or no inflammation.
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From page 111... ...
This occurs in immunocompetent mice, mice deficient in T cells, and SCID mice reconstituted by adoptive transfer of naïve lymphocytes. Inflammation can also be resolved with passive transfer of immune serum from persistently infected immunocompetent C3H mice into SCID mice (Barthold et al., 2006)
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From page 112... ...
For example, passively transferred immune serum administered to SCID mice will induce this state of persistence without inflammation, but if the antibody is allowed to decay, spirochetes become active again, disseminate, and reinduce inflammation. In persistently infected immunocompetent mice, biologically active antibodies (those that induce disease regression and spirochete reductions in tissues)
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From page 113... ...
She noted that while spirochetes may be more difficult to find in immunocompetent mice at 6 months of infection in comparison to earlier periods, they are always found in extracellular collagen-rich matrixes, not inside cells. Gerber noted a need to understand the phenotypic expressions of disease in humans and to identify the physiological, metabolic, and genetic determinants that affect disease expression.
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From page 114... ...
. In the mammalian hosts, including infected humans, the primary target cells of E
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From page 115... ...
The long-term goal is to develop both a vaccine and an immune-based therapy. A well-established fact is that protective immunity against several intracellular bacteria is mediated by Th1 cells that promote cell mediated immune responses (O'Garra and Murphy, 2009)
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From page 116... ...
A recent study has shown that Lyme disease patients seem to have a low number of NKT cells and low migration of those cells to joints, which was postulated to be an etiologic factor that contributes to arthritis in Lyme disease patients. One recommendation from this study was to propose enhancing the stimulation of NKT cells, and their migration to peripheral tissues, so they would suppress joint inflammation (Tupin et al., 2008)
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From page 117... ...
The next step was to show a causal association between NK cells and development of immunopathology and fatal disease. After depleting NK cells from mice, there was a significant decrease of the systemic cytokine production, mainly IL-10 and TNF-alpha, and a decreased number of apoptotic cells and necrotic foci, suggesting that NK cells directly or indirectly mediate tissue injury during fatal ehrlichiosis.
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From page 118... ...
Understanding the Host • Immune defense mechanisms and regulation at the peripheral sites of tick-borne Ehrlichia infection, such as the skin, liver, and lung; • The relative contribution of specialized Langerhans cells, hepato cytes, Kupffer cells, and endothelial cells to immune surveillance, immunity, and pathology; • Local factors influencing dendritic cell, NK, and T cell recruitment and differentiation; • The mechanisms controlling the cross-presentation of endosome/ phagosome-derived Ehrlichia antigens to CD8+T cells; and • The role of regulatory T cells in controlling immune responses to Ehrlichia. Potential Therapeutics • Molecular and cellular profiles of mild and fatal infections in pa tients with HME; • Collection of human samples, such as blood, cerebral spinal fluid, and tissues; • Development of screening tests, including biomarkers, to identify individuals at early stages of infection, and those at risk for progres sive disease; • Studies of the efficacy of highly promising interventions in animal models of disease; and
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From page 119... ...
In North America, the spotted fever group and the typhus group are of most concern. Rickettsia rickettsii cause the most severe rickettsiosis in North America, Rocky Mountain spotted fever.
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There are a number of reasons why Rocky Mountain spotted fever often becomes severe and results in a high case fatality rate. Endothelial cells normally form a barrier in the vasculature and balance the movement of fluid between the intravascular and extravascular spaces.
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This will be essential for development of a vaccine against Rocky Mountain spotted fever. • Development of better animal models including those that better re capitulate the natural mode of transmission via tick bite and include human tissue and immune systems.
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Ismail noted that in the knowledge gaps there is a need to study different parameters of the immune responses at multiple time points in humans, reservoir host (e.g., white-tailed deer) , and vector host.
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From page 123... ...
How these variants may alter the response of cells and tissues and inflammatory immune responses remain unanswered questions. Other knowledge gaps include how the bacteria's repertoire of surface proteins varies among strains, and how those variants affect disease.
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From page 124... ...
Research on Rickettsia in the spotted fever group has similarly begun to elucidate the pathogenesis of severe disease. Progress in developing animal models illustrates the possibilities.
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