Abstract：
:The current regimens used to treat tuberculosis are largely comprised of serendipitously discovered drugs that are combined based on clinical experience. Despite curing millions, these drug regimens are limited by the long course of therapy, the emergence of resistance, and the persistent tissue damage that remains after treatment. The last two decades have produced only a single new drug but have represented a renaissance in our understanding of the physiology of tuberculosis infection. The advent of mycobacterial genetics, sophisticated immunological methods, and imaging technologies have transformed our understanding of bacterial physiology as well as the contribution of the host response to disease outcome. Specific alterations in bacterial metabolism, heterogeneity in bacterial state, and drug penetration all limit the effectiveness of antimicrobial therapy. This review summarizes these new biological insights and discusses strategies to exploit them for the rational development of more effective therapeutics. Three general strategies are discussed. First, our emerging insight into bacterial physiology suggests new pathways that might be targeted to accelerate therapy. Second, we explore whether the concept of genetic synergy can be used to design effective combination therapies. Finally, we outline possible approaches to modulate the host response to accentuate antibiotic efficacy. These biology-driven strategies promise to produce more effective therapies.
journal_name
Immunol Revjournal_title
Immunological reviewsauthors
Baer CE,Rubin EJ,Sassetti CMdoi
10.1111/imr.12267subject
Has Abstractpub_date
2015-03-01 00:00:00pages
327-43issue
1eissn
0105-2896issn
1600-065Xjournal_volume
264pub_type
杂志文章,评审abstract：SUMMARY:Dengue viruses (DENV) are the mosquito-borne viruses of greatest global public health importance. DENV circulate as four serotypes with significant immunologic cross-reactivity that does not provide protection from secondary infection with heterologous serotypes. The strong association of severe dengue illness,...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065X.2008.00678.x
更新日期：2008-10-01 00:00:00
abstract：:The ability of T cells to respond to a wide array of foreign antigens while avoiding reactivity to self is largely determined by cellular selection of developing T cells in the thymus. While a great deal is known about the cell types and molecules involved in T-cell selection in the thymus, our understanding of the sp...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12398
更新日期：2016-05-01 00:00:00
abstract：:Cells that escape negative selection in the thymus must be inactivated or eliminated in the periphery through a series of mechanisms that include the induction of anergy, dominant suppression by regulatory T cells, and peripheral deletion of self-reactive T cells. Calcium signaling plays a central role in the inductio...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065X.2009.00817.x
更新日期：2009-09-01 00:00:00
abstract：:Mutations of the genes encoding T-cell receptor (TCR)-proximal signaling molecules, such as ZAP-70, can be causative of immunological diseases ranging from T-cell immunodeficiency to T-cell-mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap-70 gene, spontaneously de...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12841
更新日期：2020-03-01 00:00:00
abstract：:Immunity results from a complex interplay between the antigen-non-specific innate immune system and the antigen-specific adaptive immune system. The cells and molecules of the innate system employ non-clonal recognition receptors including lectins, Toll-like receptors, NOD-like receptors, and helicases. B and T lympho...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.0105-2896.2009.00884.x
更新日期：2010-03-01 00:00:00
abstract：:The mammalian gastrointestinal (GI) tract is colonized by trillions of beneficial commensal bacteria that are essential for promoting normal intestinal physiology. While the majority of commensal bacteria are found in the intestinal lumen, many species have also adapted to colonize different anatomical locations in th...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12186
更新日期：2014-07-01 00:00:00
abstract：:Viral infections may induce and sustain autoimmune processes via several and overlapping mechanisms. We outline how chronic inflammation, sustained by persisting viruses, may be "the prerequisite" for initiation and maintenance of the multistep process leading to autoimmunity. Chronic inflammation may favour priming o...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065x.1998.tb01204.x
更新日期：1998-08-01 00:00:00
abstract：:Immunologists working in the field of autoimmunity tend to concentrate all their efforts on the elucidation of possible malfunctions of the immune system, particularly pathologic changes of immune regulation. Also in the OS model various groups of investigators emphasized this approach, although it was already clear e...
journal_title：Immunological reviews
pub_type： 杂志文章
doi：10.1111/j.1600-065x.1986.tb01167.x
更新日期：1986-12-01 00:00:00
abstract：:Idiotypic networks, after being a dominating paradigm for more than a decade, have fallen out of fashion in parallel with the rapid success of molecular immunobiology. Today signs of a possible renaissance in idiotypic network studies are visible. For system biologists and also for physicists, the network idea remains...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065X.2006.00496.x
更新日期：2007-04-01 00:00:00
abstract：:Although T-cell clones bearing T-cell receptors with high affinity for self-peptide major histocompatibility complex (MHC) products are generally eliminated in the thymus (recessive tolerance), the peripheral T-cell repertoire remains strongly biased toward self-peptide MHC complexes and includes autoreactive T cells....
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.0105-2896.2005.00247.x
更新日期：2005-04-01 00:00:00
abstract：:Five of the 10 human Toll-like receptors (TLRs) (TLR3, TLR4, TLR7, TLR8, and TLR9), and four of the 12 mouse TLRs (TLR3, TLR4, TLR7, TLR9) can trigger interferon (IFN)-alpha, IFN-beta, and IFN-lambda, which are critical for antiviral immunity. Moreover, TLR3, TLR7, TLR8, and TLR9 differ from TLR4 in two particularly i...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065X.2007.00564.x
更新日期：2007-12-01 00:00:00
abstract：:Solid organ transplantation is a vital therapy for end stage diseases. Decades of research have established that components of the adaptive immune system are critical for transplant rejection, but the role of the innate immune system in organ transplantation is just emerging. Accumulating evidence indicates that the i...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12146
更新日期：2014-03-01 00:00:00
abstract：:Innate lymphoid cells (ILCs) constitute a family of effectors in innate immunity and regulators of tissue remodeling that have a cytokine and transcription factor expression pattern that parallels that of the T-helper (Th) cell family. Here, we discuss how ILCs can be categorized and summarize the current knowledge of...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12034
更新日期：2013-03-01 00:00:00
abstract：:Cell transplantation and tissue regeneration studies indicate a surprisingly broad developmental potential for lineage-committed hematopoietic stem cells (HSCs). Under these conditions HSCs transition into myocytes, neurons, hepatocytes or other types of nonhematopoietic effector cells. Equally impressive is the progr...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1034/j.1600-065x.2002.18703.x
更新日期：2002-09-01 00:00:00
abstract：:BioBreeding (BB) rats spontaneously develop an autoimmune diabetic syndrome similar to that observed in humans and NOD mice. One of the diabetes susceptibility loci maps to the lyp locus on chromosome 4. In this article we describe the consequences of the BB rat lyp mutation on T-cell homeostasis, repertoire and funct...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1034/j.1600-065x.2001.1840115.x
更新日期：2001-12-01 00:00:00
abstract：:Viruses are obligatory intracellular parasites, whose replication depends on components encoded by the virus and pathways and functions of the host cell. In addition to the pathways required for viral synthesis, viruses activate multiple mechanisms to evade immune attack, promoting viral propagation while avoiding or ...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.0105-2896.2010.00909.x
更新日期：2010-05-01 00:00:00
abstract：:The characterization of the microenvironment of human tumors led to the description of tertiary lymphoid structures (TLS) characterized by mature dendritic cells in a T-cell zone adjacent to B-cell follicle including a germinal center. TLS represent sites of lymphoid neogenesis that develop in most solid cancers. Anal...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12405
更新日期：2016-05-01 00:00:00
abstract：:Expressed predominantly on myeloid and natural killer (NK) cells, DAP12 is an adapter protein that can associate with a variety of receptors. To date, DAP12 has predominantly been characterized as an adapter protein that activates various myeloid and NK cell effector functions; however, recent findings have demonstrat...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065X.2006.00466.x
更新日期：2006-12-01 00:00:00
abstract：:The substantial importance of P-selectin glycoprotein ligand 1 (PSGL-1) in leukocyte trafficking has continued to emerge beyond its initial identification as a selectin ligand. PSGL-1 seemed to be a relatively simple molecule with an extracellular mucin domain extended as a flexible rod, teleologically consistent with...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065X.2009.00797.x
更新日期：2009-07-01 00:00:00
abstract：:Recombinant immunotoxins (RITs) are chimeric proteins designed to treat cancer. They are made up of an Fv or Fab that targets an antigen on a cancer cell fused to a 38-kDa portion of Pseudomonas exotoxin A (PE38). Because PE38 is a bacterial protein, it is highly immunogenic in patients with solid tumors that have nor...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12390
更新日期：2016-03-01 00:00:00
abstract：:Recognition of peptide presented by the major histocompatibility complex (pMHC) molecule by the T-cell receptor (TCR) determines T-cell selection, development, differentiation, fate, and function. Despite intensive studies on the structures, thermodynamic properties, kinetic rates, and affinities of TCR-pMHC interacti...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12016
更新日期：2013-01-01 00:00:00
abstract：:The expression of L3T4 and Lyt-2 cell surface molecules separates T cells into two broad, non-overlapping subsets: typical T helper cells are L3T4+ Lyt-2- whereas most T killer cells and their precursors are L3T4- Lyt-2+. This review compares highly purified populations of unprimed L3T4+ and Lyt-2+ cells for their cap...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065x.1986.tb01489.x
更新日期：1986-06-01 00:00:00
abstract：:GITR [glucocorticoid inducible tumor necrosis factor receptor (TNFR)-related protein] and 4-1BB are costimulatory TNFR family members that are expressed on regulatory and effector T cells as well as on other cells of the immune system. Here we discuss the role of GITR and 4-1BB on T cells during viral infections and i...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065X.2011.01063.x
更新日期：2011-11-01 00:00:00
abstract：:The individual role of pathogen-binding Toll-like receptors (TLRs) and antibody-binding Fc receptors (FcRs) during pathogenic infections has been studied extensively. However, combined activation of these different receptor classes has received little attention, even though they are triggered simultaneously when immun...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12333
更新日期：2015-11-01 00:00:00
abstract：:The structure and amino acid diversity of the T-cell receptor (TCR), similar in nature to that of Fab portions of antibodies, would suggest that these proteins have a nearly infinite capacity to recognize antigen. Yet all currently defined native T cells expressing an α and β chain in their TCR can only sense antigen ...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12327
更新日期：2015-09-01 00:00:00
abstract：:An intrinsic (oncogene-driven) pathway and an extrinsic (microenvironment-driven) pathway connect inflammatory reactions and cancer. M2-polarized tumor-associated macrophages and the related myeloid-derived suppressor cells are key prototypic components of smoldering inflammation driving neoplastic progression. Howeve...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065X.2008.00607.x
更新日期：2008-04-01 00:00:00
abstract：:Hematopoietic stem cell transplantation has been used for more than 50 years to combat hematologic malignancies. In addition to being the first stem cell therapy, transplantation has provided evidence for the potent anti-tumor effects of T cells. Facilitating T-cell-based immunity against malignancies requires a caref...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12142
更新日期：2014-01-01 00:00:00
abstract：:Studies of the regulation of gene expression historically focused on transcription. However, during stress and apoptosis, profound gene expression changes occur more rapidly and globally than is possible by regulating transcription. Posttranscriptional changes in mRNA processing and translation in response to diverse ...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/imr.12052
更新日期：2013-05-01 00:00:00
abstract：:Theiler's virus is a picornavirus of mouse which causes an acute encephalomyelitis followed by a persistent infection of the white matter of the spinal cord with chronic inflammation and demyelination. This late disease is studied as a model for multiple sclerosis. Inbred strains of mice differ in their susceptibility...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065x.1997.tb01014.x
更新日期：1997-10-01 00:00:00
abstract：:Genes encoding several serum complement components and the gene(s) for steroid 21-hydroxylase (21-OH) have been located in the class III region of the major histocompatibility complex (MHC). All these genes are highly polymorphic in man, and these polymorphisms have been used to draw conclusions about the structure an...
journal_title：Immunological reviews
pub_type： 杂志文章,评审
doi：10.1111/j.1600-065x.1985.tb01148.x
更新日期：1985-10-01 00:00:00
