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Dannenberg, Jr. Washington, D. Max Lurie. It is a publication of important historical significance to the field of tuberculosis TB. As defined in the title, the presentation is highly focused on previously described rabbit model studies of TB infection, disease, latency, and reactivation. There is a major emphasis on the host response to TB, with extensive discussion of the role of the macrophage in immunopathogenesis and host defense.

The presentation is enriched with anecdotal narrative that reflects a career-long accumulation of knowledge and experience in animal model studies.

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In this respect, this monograph may be unique in its field. The same experience in TB experimentation is used to provide reflections on unsolved problems, research directions, and ideas for development of effective TB vaccines. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account.

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Pathophysiology of Tuberculosis

The concerted action of the activated innate and adaptive immune cells successfully controls bacillary growth in rabbit lungs in the absence of significant inflammation or tissue damage. Thus, for the first time in an animal model that spontaneously establishes LTBI similar to that in human, we show that once bacillary growth is controlled, the sustained upregulation of genes associated with activation of T cells and associated networks is dispensable to maintain latency in the host. This finding contrasts with the sustained activation of T cells and inflammation markers seen in models of chronic, active pulmonary TB in both rabbit and the mouse, [ 17 , 26 ].

The blue arrow right indicates the kinetics of the host protective immune response to infection in the rabbit lungs over time, from exposure to establishment of LTBI.

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Mtb-induced upregulation of TLR-2 and TLR-4 has been observed in human studies, where elevated levels of these gene transcripts were found in the blood of TB patients, compared to controls [ 27 ]. In addition, TLRdeficient mice showed exacerbated inflammation and succumbed to Mtb infection earlier than wild-type animals [ 31 ].

Inducible nitric oxide synthase encoded by NOS2 is a key enzyme involved in the production of reactive nitrogen species RNS. Phagocytosis of Mtb by activated human and murine macrophages has been shown to induce NOS2 expression, contributing to the killing of the infecting bacilli [ 34 — 36 ]. Indeed, mice with a disrupted NOS2 gene are highly susceptible to Mtb infection, showing increased lung bacillary load compared to wild-type mice, and Mtb growth is exacerbated in infected wild-type mice treated with NOS2 inhibitors compared to untreated animals [ 36 , 37 ].

Upregulation of cathelicidin gene expression and stronger immunostaining for cathelicidin has been reported during Mtb infection of human alveolar macrophages, monocytes, neutrophils and epithelial cells, as well as in the lungs of infected mice [ 40 , 41 ]. Finally, in human and murine macrophages stimulated with cathelicidin, the extent of the LPS-mediated ROS burst was elevated [ 42 ]. These findings provide an explanation for the limited increase in the lung bacillary load during the early weeks of CDC infection.

The co-stimulatory molecules CD28 and CD69 are essential for optimal activation of T cells and establishment of adaptive immunity [ 43 , 44 ]. Thus, the efficient recognition of Mtb antigens and successful containment of the infection were likely associated with upregulation of CD28 , CD69 and other genes of the T cell activation network in the CDCinfected rabbit lungs. In addition, increased expression of FAS mRNA has been noted in association with reduced intracellular growth of mycobacteria [ 48 ]. Importantly, Mtb infection of mice defective in FAS CD95 failed to control bacterial growth during chronic disease [ 49 ].

Taken together, these findings are consistent with our results showing that efficient control of bacillary growth was associated with upregulation of early T cell activation network genes in the lungs of CDCinfected rabbits. In contrast, the limited upregulation of the B cell function network indicated that B cell activation was not prominent. These observations are supported by our previously reported functional data from CDCinfected rabbits [ 15 ].

Both the molecular and functional data demonstrate that early activation of Th1 immunity is essential for the control of Mtb infection and establishment of LTBI. Interestingly, the proportion of activated T cells and the expression of the associated gene networks subsided as the bacillary load declined in the lungs. The expression of several genes in the autophagy network was upregulated in CDCinfected rabbit lungs.

Autophagy is a conserved cellular homeostasis process that plays a crucial role in host immunity to Mtb and other intracellular pathogens [ 50 , 51 ]. Recently, autophagy has been shown to exert antibacterial and anti-inflammatory effects against Mtb infection in a mouse model of TB, as demonstrated by the exacerbation of Mtb growth and severe inflammation in the lungs of autophagy-deficient mice compared to controls [ 53 ].

Introduction

Thus, we propose that induction of autophagy is one of the mechanisms by which growth of CDC is controlled in the rabbit lungs. Genome-wide gene expression analysis is emerging as an important tool to study changes in the host immune response to infectious agents, including Mtb [ 54 , 55 ]. Identification and characterization of genes and networks corresponding to specific host immune responses can facilitate the identification of molecular signatures for diagnosis and monitoring of response to treatment [ 56 — 58 ].

Our previous reports on the Agilent rabbit microarray have relied on a partial gene annotation of rabbit genes provided by the manufacturer Agilent Technologies Inc. To achieve a more complete analysis of the rabbit transcriptome for this study, we have now updated the rabbit gene annotation by compiling additional rabbit genes, together with validated orthologous human and mouse genes, identified from the public genome databases. In addition, the Broad Institute is overseeing the future publication of the complete rabbit Oryctolagus cuniculus genome sequence. This resource will ultimately enable us to define the immunological correlates of active disease versus LTBI as well as molecular predictors of response to vaccination, drug treatment and cure of TB.

Importantly, control of bacillary growth and establishment of latency were not associated with significant activation of inflammation. Moreover, once the bacillary load is controlled, leading to establishment of LTBI, immune activation including CD4 and CD8 T cell activation and macrophage activation are dampened.

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Cavitary pulmonary tuberculosis

This contrasts with the host immune response to infection with Mtb HN, which result in a sustained and larger lung bacillary load, leading to active disease driven by chronic immune activation and extensive inflammation and tissue damage. Taken together, these studies suggest that both the kinetics and the nature of the host antimicrobial response are crucial in determining the outcome following Mtb infection. Of the 21 female New Zealand white rabbits Oryctolagus cuniculus ; Millbrook Farms, Amherst, MA used for Mtb CDC aerosol infection described in a previous report, lung tissue from 18 infected animals was used for the present study [ 15 ].

Total host lung RNA was isolated as described [ 59 ]. Random portions of lung, representing all 5 lobes were taken for RNA isolation. The homogenate was extracted with 0. Duran, Germany.

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After post-hybridization washes, the slides were scanned by an Agilent Scanner and the data was acquired using Agilent Feature Extraction software Agilent Technologies, Inc. Santa Clara, CA. The microarray data was subjected to further statistical analysis, including Lowess error calculations using Partek Genomics Suite software version 6.

Louis, MO. Each stage restricts its search space to those probes not annotated in the earlier stages. Since the current IPA knowledgebase does not include the rabbit genome, we used the functional ortholog data from human, mouse and rat genomes for the pathway analysis and network derivation. Shiga, Japan. An inert reference dye, ROX was included in all the test samples. The expression level of housekeeping GAPDH gene was used to normalize the expression levels of test genes in all samples.

The amplicon size for all the tested genes were between 90 and base pairs. Description of the target genes and primer pairs used in the qPCR experiments is listed in Additional file 8 : Table S6. Each experiment was repeated at least 3 times with cDNA from 3 animals at each experimental time point. Future Microbiol. Immunol Cell Biol. Paige C, Bishai WR: Penitentiary or penthouse condo: the tuberculous granuloma from the microbe's point of view.

Cell Microbiol.