Plant Viral Clearance in the Vacuole

Although molecular evidence for viral clearance through autophagy is lacking in plants, there are numerous reports indicating the possibility that viruses might be transported to the vacuole for degradation. The tobacco ringspot virus in Nicotiana tabacum and southern bean mosaic virus in cowpea cells accumulate in high numbers in the vacuole (Fig. 2, Region 1 and Fig. 5a) (Roberts et al. 1970 Weintraub and Ragetli 1970). Double-membrane vesicles filled with electron-dense material, presumably...

Something Old Something New Plant Innate Immunity and Autophagy

Hayward, Jeffrey Tsao, and S.P. Dinesh-Kumar 2 Autophagy in Plant Development and 3 Autophagy and Plant Innate 4 Does Autophagy Limit Death Signals A Model to Explain Regulation of HR-PCD 292 5 Autophagy During the Basal Immune 6 Plant RNA Viruses and the 6.1 Physiological Consequences of Viruses in the 6.2 Virus-Induced Transport of Chloroplast into the Vacuole Chlorophagy or Executed Innocent 7 Plant Viral Clearance in the Abstract Autophagy performs a variety of...

Spacious Listeria Containing Phagosomes

It has long been believed that intracellular L. monocytogenes either undergo phagocytosis and are killed by the phagosome-lysosomal pathway or escape into cytosol and rapidly replicate in this compartment (Pamer 2004 Gouin et al. 2005 Seveau et al. 2007). However, during persistent L. monocytogenes infection of severe combined immunodeficiency (SCID) mice, the majority of bacteria are localized within large vacuolar compartments in macrophages in the liver (Bhardwaj et al. 1998 Birmingham et...

Lifestyle of Intracellular S typhimurium in Mammalian Cells

In vitro studies have shown that S. typhimurium invasion of epithelial cells is a force feeding process, in contrast to the receptor-mediated endocytosis processes normally exploited by other pathogenic bacteria (Brumell et al. 1999). During invasion, S. typhimurium uses a syringe-needle structure, called a type three secretion system (T3SS), and injects a set of virulence proteins into the host cell cytosol. These bacterial proteins (referred to as effectors) rearrange the host cytoskeleton to...

Molecular Mechanism of Autophagy 21 Induction and Regulation of Autophagy

Insufficient autophagy can be deleterious (Komatsu et al. 2007a Kuma et al. 2004), but excessive levels may also be harmful. Accordingly, autophagy is a tightly regulated process in all eukaryotes. The induction and regulation of autophagy have been studied extensively in yeast, mammalian cells and Drosophila. Several signaling pathways, as summarized in the following, are involved in the control of autophagy. TORC1. The protein target of rapamycin, Tor, plays a major regulatory role in...

Macroautophagy in Epithelial Cells

In epithelial cells that have diminished phagocytic capacity, macroautophagy may be even more important to the loading of MHC class II molecules due to its delivery of proteins to MHC class II loading compartments, and may play major roles in both immune surveillance of inflamed tissues and central and peripheral tolerance in the thymus and secondary lymphoid organs. 4.6.1 Possible Roles of Autophagy in Central Tolerance The thymus is involved in the education of the T cell compartment. In this...

Autophagy Evasion as a Common Virulence Mechanism

Autophagy is emerging as a common target for viral evasion, as recent reports suggest that cytomegalovirus (CMV a member of a third subfamily of herpesviruses, the P-herpesviruses) and human immunodeficiency virus (HIV), a retrovirus, also antagonize host autophagy. CMV causes infectious mononucleosis in healthy individuals, but may lead to severe disease in neonates and immunocompromised patients (Gandhi and Khanna 2004). Chaumorcel and colleagues found that CMV significantly decreases levels...

Staphylococcus aureus

The Gram-positive bacterium Staphylococcus aureus is a facultative anaerobic cocci responsible for a variety of serious infections. Among the different clinical syndromes caused by S. aureus, endocarditis, pneumonia, septic arthritis, and skin and soft tissue infections are the most frequent. This pathogen expresses several factors that combat the first lines of defense against infection exerted by macrophages and neutrophils. For example, S. aureus is resistant to defensins, probably because...

References

Agrawal L, Lu X, Jin Q, Alkhatib G (2006) Anti-HIV therapy current and future directions.Curr Pharm Des 12 2031-55 Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA (1996) CC-CKR5 a RANTES, MIP-1a, MIP-1b receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272 1955-1958 Ameisen JC, Capron A (1991) Cell dysfunction and depletion in AIDS the programmed cell death hypotheses. Immunol Today 12 102-105 Barre-Sinoussi F, Chermann J-C, Rey F, Nugeyre M-T,...

Immunity Related GTPases IRGs Regulate Autophagy in Antimicrobial Defense and Inflammation

The work on M. tuberculosis led to the initial connection between IRGs and autophagy in murine cells (Gutierrez et al. 2004), and has been recently expanded to the control of M. tuberculosis in human cells (Singh et al. 2006). IFN-g is a major correlate of immunity against tuberculosis, but the exact nature of IFN-g antimycobacterial action remained an elusive issue, as neither reactive oxygen nor reactive nitrogen intermediates could explain its potent antimycobacterial action (MacMicking et...

Convergence of Autophagy and Phagocytosis

Striking similarities exist between phagosome and autophagosome formation and maturation. After all, phagocytosis and autophagy are both processes of ingestion, where the cargo or pathogen resides in extracellular or cytosolic spaces, respectively. It is tempting to speculate on the nature of the relationship between autophagy and phagocytosis and the degree to which these two processes are intertwined. Below, we will describe studies that demonstrated that TLR signals induce (1) autophagy to...

Porphyromonas gingivalis

Porphyromonas gingivalis, a Gram-negative bacterial pathogen and natural component of the oral mucosal microbiome, is the causative agent of periodontal disease (i.e., gingivitis), which can lead to periodontal bone loss (Fiehn et al. 1992). This pathogen has also been involved in cardiovascular disease, pulmonary infections and atherosclerosis. Gingival epithelial cells are among the first host cells colonized by P. gingivalis. P. gingivalis invades and replicates in human endothelial cells,...

How Autophagy Can Be Manipulated

Understanding how autophagy can be manipulated is important for potential therapeutic applications of autophagy. In this section we will focus on drugs that act at different stages of autophagy (Rubinsztein et al. 2007). Of course, autophagy can be manipulated by genetic approaches. Atg-knockout mice and Atg knockdown by RNA interference-based methods are of fundamental importance in identifying the function of autophagy in various physiological and pathophysiological situations (Levine and...

Autophagy in B Lymphocytes

Although fewer studies have investigated autophagy in B cells, the available data demonstrates an important role for autophagy in this second lymphocyte lineage. As in T cells, deletion of the essential autophagy gene Atg5 leads to selective survival defects in B cells in mouse models. However, the stages impacted in T and B cells differ. While thymocyte development appears normal in Atg5 ' fetal liver hematopoietic chimeric mice, the development of B cells is altered in the bone marrow of...

Regulation of the Maturation Events

The maturation of autophagosomes depends on molecules that allow the autophago-somes to fuse with the vesicular compartments of the vacuolar system (endosomes, lysosomes). The late stage of autophagy is also dependent on molecules that regulate the acidification of the autophagic compartments and molecules that are involved in recycling of degraded material from the lysosomal compartment. SNAREs (soluble NSF attachment protein receptors) are basic elements required for intracellular membrane...

Conclusion and Future Perspectives

Macrophages and Paneth cells, both of which are critical for mucosal immunity in the intestine, are two of the newest cell types in which autophagy genes have been associated with unique cell type-specific roles (Fig. 3). Other chapters in this volume discuss the essential roles of the autophagy pathway in the biology of additional cell types implicated in intestinal inflammation, including lymphocytes and Fig. 3 Mutation of autophagy genes leads to striking abnormalities in key cell types...

Atg9 and Its Cycling Systems

One of the intriguing questions concerning autophagy is the source of the lipid that is used for autophagosome formation and the mechanism used for lipid movement to the site of autophagosome assembly. Atg9 is an integral membrane protein and is thought to be a membrane carrier during the assembly process (He et al. 2006 Noda et al. 2000). Unlike most other Atg proteins, which primarily display single punctate localization at the PAS, Atg9 localizes to multiple punctate structures, including...

Autophagy is an Effector of Th1Th2 Polarization

It is now known that autophagy is regulated by immunologically relevant cytokines and ligands (Andrade et al. 2006 Arico et al. 2001 Djavaheri-Mergny et al. 2006 Gutierrez et al. 2004 Harris et al. 2007 Inbal et al. 2002 Li et al. 2006 Paludan et al. 2005 Petiot et al. 2000 Pyo et al. 2005 Schlottmann et al. 2008). This knowledge has its early roots in nonimmunological studies where cytokines were used simply as convenient agonists or antagonists to induce or repress autophagy (Arico et al....

Autophagy of Shigella flexneri and Other Intracellular Bacteria

Extracellular Bacteria Immune Response

Besides S. typhimurium, L. monocytogenes, M. tuberculosis (introduced in this chapter and discussed in detail in the chapter by Deretic et al. in this volume) and Group A Streptococcus (introduced in the chapter by Yoshimori and Amano in this volume), other bacteria have also been reported to be targets of autophagy, including Rickettsia conorii and S. flexneri. Little is known about the autophagy of Rickettsia. Only one report has shown that in vitro incubation of these bacteria with guinea...

Autophagy is an Effector of Pattern Recognition Receptor Signaling

The autophagy-M. tuberculosis system has also helped to connect immunologically relevant autophagy with innate immunity receptor signaling. The innate immunity receptors and downstream effectors are responsible for early detection and initial elimination of invading microbes plus the modulation of adaptive immunity that subsequently develops (Ishii et al. 2008 Medzhitov 2007). The innate immunity receptors (Fig. 3), collectively referred to as PRRs, encompass three major classes TLRs, retinoic...

Autophagy Induction in T Lymphocytes

Autophagy is a well-conserved catabolic process in eukaryotic cells with diverse functional roles both outside and within the immune system (Klionsky and Emr 2000 Levine and Kroemer 2008 Mizushima et al. 2002 Schmid and Munz 2007). Defined by the de novo formation of specialized double-membrane vesicles within the cytoplasm of cells, an explosion of research examining the molecular and cellular regulation of autophagy has followed the recent discovery of a network of genes required for...

Differences from Canonical Autophagy

The characterization of the host cell response to intracellular GAS described above strongly indicates that the autophagic machinery, which is conserved from yeast to human and is ubiquitous among most cell types, acts as an innate immune system against the bacteria (Fig. 3). However, autophagy against GAS differs in several respects from basal or starvation-induced autophagy (Table 1).Usually, autophagy is suppressed to a basal level in cells under nutrient-rich conditions. GAS infection...

Response and Increased Expression of the Proinflammatory Cytokine IL1fi in Macrophages

Similar to studies with certain Nod2 mutant mice (see above), challenging fetal liver chimeric mice with DSS shows that Atg16L1 expression in hematopoietic cells is necessary for the normal response to intestinal injury. Compared to controls, Atg16L1 KO chimeric mice have increased mortality and weight loss in response to DSS, indicative of an exaggerated inflammatory response (Saitoh et al. 2008). Indeed, these mice have severe ulceration and infiltration of lymphocytes in the colon. This...

Reference

Abrahams MA, Tylkowski CM (1985) Brucella osteomyelitis of a closed femur fracture. Clin Orthop Relat Res 194-196 Almeida RA, Matthews KR, Cifrian E, Guidry AJ, Oliver SP (1996) Staphylococcus aureus invasion of bovine mammary epithelial cells. J Dairy Sci 79 1021-1026 Amano A, Nakagawa I, Yoshimori T (2006) Autophagy in innate immunity against intracellular bacteria. J Biochem 140 161-166 Amer AO, Swanson MS (2005) Autophagy is an immediate macrophage response to Legionella pneumophila. Cell...

Bacterial Autophagy in Inflammatory Bowel Disease

Inflammatory bowel disease is a chronic disorder caused by abnormal inflammation in the intestinal tract. Ulcerative colitis and Crohn's disease (CD) are the two major forms of inflammatory bowel disease (Podolsky 2002 Mizoguchi and Mizoguchi 2008). Ulcerative colitis is most often restricted to the colon, while CD involves patchy inflammation throughout the gastrointestinal tract (Xavier and Podolsky 2007). The pathogenesis of these disorders is now believed to involve multiple factors,...

Autophagy Contributes to Homeostatic T Cell Survival In Vivo

To investigate the role of autophagy in T cells in vivo, two mouse genetic model systems have been employed. Since mice lacking the essential autophagy genes Atg5 or Atg7 die within the first 24-48 h of birth (Komatsu et al. 2005 Kuma et al. 2004), the role of autophagy in T cells has been studied using Atg5 ' fetal liver chimeric mice as well as Atg7f f Lck-Cre mice with a conditional deletion early in thymocyte development (Pua et al. 2007 Pua et al. 2009). In both mice, there are subtle but...

Virulence Factors of L monocytogenes

Crohn Risk Factors

Expression of most of the key virulence factors of L. monocytogenes is controlled by the PrfA transcriptional activator (Dussurget et al. 2004 Scortti et al. 2007). PrfA regulates the expression of at least nine genes (inlA, inlB, inlC, plcA, plcB, hly, mpl, actA, and hpt) that contribute to virulence (Dussurget et al. 2004 Scortti et al. 2007). The adhesins internalin A (InlA) and InlB recognize host cell membrane receptors and mediate bacterial entry (Hamon et al. 2006 Ireton 2007). InlA...

Blog Samonella Cerda

Abubakar I, Myhill D, Aliyu SH, Hunter PR (2008) Detection of Mycobacterium avium subspecies paratuberculosis from patients with Crohn's disease using nucleic acid-based techniques a systematic review and meta-analysis. Inflamm Bowel Dis 14 401-410 Alpuche-Aranda CM, Racoosin EL, Swanson JA, Miller SI (1994) Salmonella stimulate macrophage macropinocytosis and persist within spacious phagosomes. J Exp Med 179 601-608 Alvarez-Dominguez C, Roberts R, Stahl PD (1997) Internalized Listeria...

Two Mouse Models to Examine Atg16L1 Function In Vivo

The human genetic data and our expanding understanding of the roles of ATG16L1 and IRGM1 support a model in which autophagy contributes to Crohn's disease susceptibility, but also leave open critical questions, including what intestinal or immune cell-types have altered function when either ATG16L1 or IRGM1 are altered, and what functional abnormalities are present in such cells. Given the strong associations between bacteria and intestinal inflammation, are the effects of autophagy genes in...

Clinical Aspects of Inflammatory Bowel Disease in Humans

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease. Both are associated with high morbidity and their pathogenesis has been the subject of many excellent review articles (Xavier and Podolsky 2007 Cho 2008 Ferguson et al. 2007 Pineton de et al. 2008 Neuman 2007). The incidence of Crohn's disease has risen in several regions of the globe, suggesting a strong environmental contribution to disease in addition to an undisputed heritable component (Xavier and...

Cytokines in T Cell Homeostasis

Cytokines are small secreted proteins that act on cellular targets to promote diverse biological responses, including survival, differentiation, proliferation, and migration. A group of cytokines sharing the common gc chain receptor subunit including inter-leukin-2 (IL-2), IL-7, and IL-15 support T cell survival and play important roles in regulating T cell homeostasis (Boise et al. 1995 He and Malek 1998 Rathmell et al. 2001 Vella et al. 1997). Many T cell subsets, including double negative...

Mice with Reduced Atg16L1 Expression Reproduce Aspects of Crohns Disease Pathology and Reveal a Cellular Target for the

While the Atg16L1 KO model is ideal for studying the role of Atg16L1 in hemat-opoietic lineages, perinatal lethality of these mice does not allow examination of the role of Atg16L1 in the small intestine in adult mice. The newly developed Atg16L1HM mice are therefore a unique tool since, instead of relying on a lineage-specific deletion of the gene, there is a systemic reduction of the protein (Cadwell et al. 2008a). As it is unlikely that Atg16L1 function is completely abolished in humans...

Identification of ATG16L1 and IRGM1 as Crohns Disease Susceptibility Genes

The genetic loci for both ATG16L1 and IRGM1 were linked to Crohn's disease by genome-wide association studies in which genetic variations between Crohn's disease patients and controls were analyzed using gene chips containing 10,000 known single nucleotide polymorphisms (SNPs) across the human genome (The Wellcome Trust Case Control Consortium 2007 Rioux et al. 2007 Hampe et al. 2007 Parkes et al. 2007 McCarroll et al. 2008 Barrett et al. 2008). For ATG16L1, the genetic linkage is stronger for...

Autophagy in Staphylococcus aureus Infection

A substantial increase in resistance to antimicrobial agents among bacterial pathogens has been found, particularly in Gram-positive bacteria this compromises traditional therapies (Finch 2006). Staphylococcus aureus, one of the most ubiquitous Gram-positive pathogens, is a major cause of infections in both hospitals and care centers, and has exhibited significant resistance to methicillin (methicillin-resistant S. aureus, MRSA) (Kollef and Micek 2006). MRSA is generally considered to be a...

The Cvt Pathway and Other Selective Types of Autophagy

Atg9 Vesicle

Although autophagy is generally considered to be a nonselective pathway for the degradation of bulk cytoplasmic components, recent findings indicate that there are many types of selective autophagy in both yeast and higher eukaryotes. In yeast, even bulk autophagy can be selective cytosolic acetaldehyde dehydrogenase, Ald6, is preferentially sequestered into autophagosomes relative to other cytosolic proteins (Onodera and Ohsumi 2004). Several organelles are selectively degraded through...

Virus Induced Transport of Chloroplast into the Vacuole Chlorophagy or Executed Innocent Bystander

Arabidopsis Vesicles

The majority of the literature dedicated to autophagy has focused on the ability of autophagosomes to sequester cytoplasmic material. Most references point to protein turnover and increases in free pools of amino acids as evidence that one of the primary functions of autophagosomes is to provide nutrients during suboptimal conditions. Several excellent reviews have outlined the uptake of the mitochondria (mitophagy) (Mijaljica et al. 2007) and peroxisome (pexophagy) (Dunn et al. 2005) however,...

De Novo Vesicle Formation

Unlike most other intracellular trafficking processes, autophagy undergoes de novo formation of double-membrane vesicles. This is a de novo process in that the sequestering vesicles do not bud from a pre-existing organelle. Instead, these vesicles are thought to form through the expansion of a membrane core of unknown origin, termed the phagophore (Mizushima et al. 2001 Noda et al. 2002 Seglen et al. 1990). Figure 8 shows a hypothetical model for de novo vesicle formation. The proposed site for...

The Role of Atg16L1 in Autophagy

ATG16L1 (or Atg16-like 1) is one of two mammalian homologs of the yeast autophagy gene Atg16. The Atg16 protein was first identified in S. cerevisiae as a binding partner of the Atg5-Atg12 conjugate (Mizushima et al., 1999). The binding of Atg16 to Atg5-Atg12 is essential for autophagy (Matsushita et al. 2007). Atg16 has an N-terminal Atg5 binding domain and a coiled-coil domain that mediates homomultimerization. Atg16 forms a large and essential multimeric complex with the Atg5-Atg12 conjugate...