virus-infected cells. The exhaustion does not limit itself to T cells, B cells are also exhausted during HIV-infection (Moir, Ho et al. 2008, Moir and Fauci 2014). The phenomenon of exhaustion is not restricted to HIVinfection; in fact, it is manifested in all chronic viral infections, as well as in cancer (Kahan, Wherry et al. 2015). It has been demonstrated that γ chain-using cytokines (IL-2, IL-4, IL-15 and IL-21, etc.) play an important roleinthe expression of these IC in immune cells. Furthermore, activation of GSK-3β has been shown to play an important roleinthe induction of PD-1 in T cells. It has been demonstrated that blocking these checkpoints using small molecule inhibitors or molecule-specific monoclonal antibodies (so-called immune checkpoint inhibitors or ICI) can restore anti-cancer immunity and cause the regression of several types of cancers (Mahoney, Freeman et al. 2015). The only caveat is that long-term usage of these ICI can cause autoimmune phenomenon such as colitis. It would be better to decrease the expression of these IC using anti-inflammatory drugs or biological substances that reduce cell activation. As IL-37 exerts anti-inflammatory effects and inhibits cell activation (Abulkhir, Samarani et al. 2017), we sought to determine the effects ofthe cytokine on these IC. For this purpose, we cultured PBMCs from HIV- infected individuals in culture medium and inthe presence and absence of human recombinant IL-3. After 24 hours, we determined the expression of PD-1 on CD4+ and CD8+ T cells. The treatment ofthe cells with the cytokine significantly reduced their expression of PD-1.
Address: INSERM, Unite U955, Universite Paris 12, Faculte de Medecine, AP-HP, Groupe Henri-Mondor Albert-Chenevier, Immunologie clinique, Creteil, F-94010 France
HIV-1 infection is characterized by chronic and general- ized immune activation which, in combination with the progressive depletion of CD4 T cells, profoundly perturbs antigen-specific CD8 T cell responses. The population of CD4+CD25 high FoxP3+ regulatory T cells (Treg) sup-
Rapidly evolving DAA-based anti-HCV therapies now enable more than 90% of SVR rate with all-oral regimens even inthe cases hard to cure before . In patients previously treated with older, IFN-based regimens, SVR was significantly associated with reduced but not eliminated future risk of HCC development over a decade . Inthe retrospective studies, several clinical characteristics such as more advanced liver fibrosis, older age, and male sex among others have been suggested as predisposing factors for post-SVR HCC (Table 1). However, estimation of HCC risk in patients newly achieving an SVR is still infeasible and the mechanisms of carcinogenesis are totally unknown. Given the annual incidence of post-SVR HCC, which is likely below the threshold that rationalizes regular HCC surveillance, HCC risk biomarkers or indices will play a critical role to perform cost- effective and practically feasible HCC surveillance by triaging the patients according to the predicted HCC risk . Also, such biomarkers may provide clues to targets of HCC chemopreventive interventions. It is still unanswered question whether HCC risk after DAA- based or other types of anti-HCV therapies such as viral entry inhibition  is comparable to that of IFN-based therapies. Modulation of cellular signaling pathways such as IFN, EGF, mTOR, and retinoid X receptor- α pathways and drugs for metabolic disorder, some of which have been already clinically evaluated, may serve as alternative options of HCC chemoprevention for broader etiologies, including post-SVR HCC [50–56]. Experimental systems that allow mechanistic assessments ofthe carcinogenic drivers will be critical in identifying and developing rational molecular-targeted HCC chemoprevention therapies. Acknowledgments
In this review, we present the main large-scale experimental studies that have been performed intheHIV/AIDS field. These “omics” studies are based on several technologies including genotyping, RNA interference, and transcriptome or epigenome analysis. Due to the direct connection with disease evolution, there has been a large focus on genotyping cohorts of well-characterized patients through genome-wide association studies (GWASs), but there have also been several in vitro studies such as small interfering RNA (siRNA) interference or transcriptome analyses ofHIV-1–infected cells. After describing the major results obtained with these omics technologies—including some with a high relevance for HIV-1 treatment—we discuss the next steps that the community needs to embrace in order to derive new actionable therapeutic or diagnostic targets. Only integrative approaches that combine all big data results and consider their complex interactions will allow us to capture the global picture ofHIV molecular pathogenesis. This novel challenge will require large collaborative efforts and represents a huge open field for innovative bioinformatics approaches.
substitutions, some of which have been suggested as being related to viral neuro-invasiveness . The effective roleof such candidate mutations inthe development of both viral infectivity and virulence remains to be determined. At present, up to nine lineages have been proposed to classify WNV strains . Lineage 1 is subdivided into clades 1a and 1b (or Kunjin virus) and 1 c , and is the most widespread inthe USA (NY99 strain), Africa (KN3829), Europe and the Middle East . Virulence is highly variable among WNV lineages. For instance, lineage 3 (Rabensburg virus) has never been isolated from humans and did not experimentally infect mammalian or avian cell cultures, the house sparrow (Passer domesticus) (HOSPs) or specific-pathogen-free (SPF) chicken eggs . On the contrary, WNV lineages 1 and 2 have been responsible for major outbreaks in animals and humans [35, 36]. Viral strains from the same lineage (and clade) can also express variation in pathogenicity. For instance, despite the high genetic relatedness between strains KN3829 and NY99 (a total of 11 amino acid differences between the strains) , the latter exhibits a strikingly different avian virulence phenotype, eliciting significantly higher viremia and mortality inthe American crow (Corvus brachyrhyncos; AMCR) [22, 37]. A mutation inthe NS3 gene resulting in a T249P amino acid substitution was involved in increased pathogenicity in AMCR , and this mutation was proposed as a key determinant of WNV pathogenicity. Furthermore, the NS3- 249 residue was shown to be under strong positive selective pressure because birds can drive adaptive evolution in WNV . However, the mere presence of Pro at NS3-249 was neither sufficient nor necessary to enhance the virulence of WNV strains in theHOSP [39, 40], red-legged partridge  and SPF chicken . Variation in virulence for avian species in regard to this mutation remains unexplained. Nonetheless, one study showed that WNV virulence in AMCR is corre- lated with increased ATP hydrolysis due to direct interaction between the NS3-249 residue and unknown host factors . Helicase activity, however, did not differ between NS3 proteins with proline or threonine at position 249, and thus could not explain thein vivo effects in AMCR . Other studies showed that the NS3-249 residue modulates replication in avian leukocytes [22, 44] and hence could affect the host immune response in a temperature-dependent manner and under the control of NS proteins .
• Persistent infectionof human thymic epithelial cells by Coxsackievirus B4. F. Brilot et al. J Virol (2002) 76:5260-5265.
• Coxsackievirus B4 infectionof human fetal thymus cells.
F. Brilot, V. Geenen, D. Hober & C. Stoddart, J Virol (2004) 78:9854-9861.
which were isolated from blood that was immediately treated with PFA to fix platelets and hence prevent their activation, did not express IL-18. These data suggest that quiescent platelets do not contain pre-formed IL-18 but they rather synthesize it de novo upon activation. To confirm it, we pre-treated platelets with cycloheximide, a known inhibitor of protein synthesis [37, 38], before their activation with thrombin. As expected, IL-18 was markedly decreased inthe lysates ofthe cycloheximide pre-treated platelets. These data provide direct evidence that IL-18 is synthesized de novo in these anucleate cellular elements upon activation and they do not contain or express it when in quiescence. However, it was not the case with IL-18BP. Unlike IL-18, PFA-treated platelets expressed IL-18BP. Furthermore, cycloheximide pre-treatment had no effect on the expression of this IL-18 antagonist. In line with these results, freshly isolated platelet-poor-plasma (PPP) had little IL-18 but was rich in IL-18BP. These data suggest that quiescent platelets release pre-formed IL-18BP but not IL-18. Consequently, PPP contains IL- 18BP but not IL-18. The differential production and release of these two soluble mediators result from the presence∕absence of some poorly understood motifs in their transcripts that may be required for their non-random incorporation into platelets . Furthermore, IL-18 mRNA is has no signal sequences and is translated on free ribosomes inthe cytosol as a leaderless polypeptide . Such proteins are secreted independent of ER and a Golgi via a non- conventional mode of secretion . This differential regulation ensures that IL-18BP is present inthe circulation of an individual, as it is present in pre-formed form in platelets and its release does not require platelet activation, whereas IL-18 is only synthesized de novo and released from platelets upon activation. Since IL-18BP inactivates IL-18 via its high affinity binding to the latter [16, 40], its continuous presence inthe circulation may serve as a buffer against highly pro-inflammatory systemic effects of IL-18 inthe circulation, should platelets synthesize and release it into circulation upon activation. Here we add yet another pro-inflammatory cytokine, IL-18, as well as its antagonist, IL-18BP, to the growing list of soluble mediators produced/released by human platelets.
1.2.2 Structure of an HIV-1 virion
HIV is a retrovirus of about 100 nm in diameter. The structure of a typical mature HIV virion is shown in Figure 13. The viral envelope is a lipid bilayer derived from the cell membrane during viral budding. The viral envelope proteins are studded inthe envelope. Each envelope protein comprises a surface unit (SU) or glycoprotein (gp)-120, and a transmembrane part TM), gp-41. The SU is attached non-covalently to the TM. The gp120/41 complex is found as trimmers on the surface ofthe virion. Beneath the envelope lies the viral matrix comprising ofthe matrix (MA) protein, p17. The viral capsid comprises the capsid protein, p24. The viral nucleocapsid contains two copies ofthe single stranded viral RNA, viral reverse transcriptase (RT), integrase (IN), and protease (PR). In addition to the major structural proteins, group- specific antigen (gag), polymerase (pol), and envelope (env), theHIV-1 genome encodes two regulatory proteins, Regulator of expression of viral proteins (Rev) and Transactivator (Tat); and four accessory proteins, which include the Viral infectivity factor (Vif), Negative factor (Nef), Viral protein R (Vpr), and Viral protein U (Vpu). The proteins play a diverse rolein ensuring theinfectionof non-dividing host cells, efficient replication, the budding of virions, and evasion from the host’s antiviral immune factors (Li et al 2005). The non-immune cellular factors such as the apolipoprotein B mRNA editing enzyme/catalytic polypeptide-like (APOBEC)-3G, SAM- and HD domain-containing protein (SAMHD)-1, and tetherin, inhibit HIV replication by different mechanisms. The virus has developed strategies to overcome and to evade the host’s antiviral activities (Malim & Bieniasz, 2012)
markedly different husbandry conditions between these two institutions. Taconic Farms rederives their mice into a germ-free state and then colonizes them with altered Schaedler Flora (ASF; a group of 8 known commensal bacterial species) and then maintains them under specific-pathogen free (SPF) conditions . Mice from the Jackson Laboratory are not rederived into a germ-free state, but instead are maintained under SPF conditions. A similar finding was demonstrated when mice from Taconic Farms were found to be less susceptible to infection with Giardia lamblia in comparison to mice from the Jackson Laboratory . Subsequent prospective studies involving fecal gavage and co- housing of strains proved that these differences in enteric disease susceptibility were attributable to differences inthe gastrointestinal microbiota . More recent studiesin both humans and mice clearly demonstrate that the intestinal microbiome alters proclivity to a variety of metabolic diseases including obesity and diabetes [12–14]. Further, since we have demonstrated a roleofthe immune system in gallstone pathogenesis, microbes may exert an influence by modulating the immune response .
Inflammation is a protective response ofthe body to ensure removal of detrimental stimuli, as well as a healing process for repairing damaged tissue (239). Germline- encoded pattern recognition receptors (PRR) are responsible for sensing the presence of microorganisms by recognizing structures conserved among microbial species, which are called pathogen-associated molecular patterns (PAMPs). Different classes of PRR families have been identified, such as transmembrane and endosomal proteins: the Toll-Like Receptors (TLRs), as well as cytoplasmic proteins such as the Retinoic acid- inducible gene (RIG)-I-like receptors (RLRs) and NOD-like receptors (NLRs). These PRRs are expressed in macrophages, neutrophiles and dendritic cells but also in various nonprofessional immune cells. The sensing of PAMPs by PRRs upregulates the transcription of genes involved in inflammatory responses. These genes encode pro- inflammatory cytokines, type I IFNs, chemokines and antimicrobial proteins, proteins involved inthe modulation of PRR signaling, and many uncharacterized proteins (240). Focusing on interferons, these are a family of cytokines which act early inthe innate immune response and are very well known for inducing an antiviral activity in infected cells. In addition to this antiviral activity, they play a rolein regulating the immune response (12). Among the three distinct interferon families, the type I IFN (IFN-I) family is a multi-gene cytokine family, being IFNα and IFNβ (IFNα/β) the best-defined and most broadly expressed ones. IFN-I have numerous additional functions not only during the viral, but also in bacterial infections. The outcome of its response during infectious diseases is highly context-dependent. Different conditions induced during specific infections modulate when and where IFN-I signals are delivered, as well as the signalling pathways that are triggered downstream ofthe type I IFN receptor (IFNAR) (19). Recents in vivo studies with extracellular bacteria have shown contradictory results, since in some cases type I interferon have played a protective role, but in other cases therole was detrimental (44-52, 255). In relation with the source of IFN-I, particularly IFN-β, previous studies have compared theroleof antigen presenting cells, such as DCs and Mθ, after theinfection with different streptococci (83, 85).
Several studies previously demonstrated interactions between S. suis and different cell types. Murine dendritic cells (DCs) and macrophages (MΦ) were widely used and shown to be a good model for the study of bacterial internalization, interactions between S. suis and immune receptors, and cytokine-induced pathways. Moreover, DCs and MΦ are phagocytic cells, residents in filter organs such as liver and spleen, and probably some ofthe cell types involved inthe high IL-1 production observed in vivo. In our study, we observed a modest production of IL-1 after stimulation of DCs with strain P1/7. By contrast, very high levels of IL-1α and IL-1β were induced by strain SC84. These results, in accordance with the virulence degree ofthe strain, suggested that extra virulence factors are probably involved in an enhanced cell activation. Surprisingly, however, DCs stimulated with the intermediate virulence strain 89- 1591 produced higher levels than P1/7 (see Annex II – Fig. 2 and 3) further indicating that cell activation leading to IL-1 production differs between strains. Interestingly, overall production of IL-1 by MΦ was somewhat delayed when compared to DCs following infection with strains P1/7 and SC84. This characteristic was already described for other extracellular pathogens including GBS, GAS, and S. pneumoniae (192, 218, 227), and might be due to a lower capacity of these cells to process the cytokine into the mature form.
A3A is the only member ofthe APOBEC3 family specifically expressed in primary blood cells of myeloid origins
A few reports have indicated that among circulating white blood cells, A3A was highly expressed in monocytes [42–44]. To determine more widely the pattern of expression of A3A and ofthe different members ofthe APOBEC3 family, quantitative RT- PCR was performed on quiescent or PHA-stimulated primary blood cells (PBLs, depleted of monocytes), monocytes, macro- phages and dendritic cells (DCs) differentiated upon incubation of monocytes for 4 to 5 days with M-CSF and GM-CSF/IL4, respectively (Figure 1). Our analysis reveals that A3A is overexpressed by at least 100 fold in differentiated macrophages over PBLs, irrespectively of their activation status. This difference increases further in DCs and is the greatest in monocytes in which A3A is expressed over 5 logs more than in stimulated PBLs. The expression ofthe remaining APOBEC3 members did not display such cell type specific variations, with the exception of A3D/E that seems expressed at least 10 fold more in PBLs than inthe myeloid cells tested. On the contrary, A3B and to a lower extent A3H are less expressed in non-stimulated monocytes than in stimulated PBLs, although their expression increased during differentiation into either macrophages or DCs. Overall, myeloid cells express consistent levels of all APOBEC3 members, but A3A is the only one whose expression is restricted to them. These results are in line with previous reports and extend them inthe absolute quantifi- cation ofthe copy number ofthe different APOBEC3 members during the differentiation of circulating monocytes into macro- phages and DCs. Of note, IFNa treatment increased the expression levels of A3A at both the mRNA and protein level, Author Summary
ER stress induces the cytosolic kinase and RNase activities of IRE1α. This leads to the nonconventional splicing of X-box binding protein 1 (XBP1) mRNA, RNA degradation via IRE1 α- dependent RNA decay (RIDD), and JNK phosphorylation. XBP1 spliced (XBP1s) is a transcription factor that promotes tran- scription of genes encoding proteins involved in entry into the ER, folding, glycosylation, ERAD, lipid biogenesis, and vesicular trafficking ( Huh et al., 2010 ). RIDD activity has been described as either adaptive or terminal ( Maurel et al., 2014 ). It has been shown to degrade ER-associated mRNA to facilitate ER homeo- stasis (adaptive) or mRNA encoding prosurvival proteins, thereby contributing to ER stress–induced cell death (terminal). SARS-CoV infection failed to induce XBP1 splicing, RIDD, or JNK phosphorylation ( DeDiego et al., 2014 ; Versteeg et al., 2007 ), suggesting that the IRE1 branch ofthe UPR remains inactive during SARS-CoV infection. However, CoV-2 nsp6 protein binds Sigma receptor 1. This ER-resident integral membrane protein, together with SR2 (TMEM97), which interacts with CoV-2 orf9c, modulates calcium fluxes ( Table 1 ) and controls IRE1 activation ( Mori et al., 2013 ; Rosen et al., 2019 ). Thus, CoV-2 may affect IRE1 activity through its interaction with Sigma receptor 1. Last, ER stress induces ATF6 cleavage and its ER-to-Golgi transloca- tion and finally an ATF6 transcriptional program, whose main target genes consist of ER chaperones (i.e., GRP78/BiP or GRP94) and ERAD components ( Shoulders et al., 2013 ). Thus, activation ofthe ATF6 branch enhances the ER protein–folding capacity and homeostatic balance ( Adachi et al., 2008 ). Overexpression ofthe SARS-CoV S protein leads to the activation of both GRP78 and GRP94 promoters ( Siu et al., 2014 ), suggesting ATF6 acti- vation. Notably, the small amounts of BiP found on the cell surface have been proposed to help CoV entry and have been suggested as a target to impede SARS-CoV-2 infection ( Ha et al., 2020 ). ATF6 cleavage and nuclear translocation ofthe released cytosolic fragment were observed following SARS-CoV orf8ab transfection. In addition, orf8ab has also been shown to localize to the ER and to interact with the luminal domain of ATF6 ( Sung et al., 2009 ). These observations are consistent with the fact that many proteins that interact with CoV-2 orf8 are encoded by ATF6 target genes. Moreover, the cytosolic ATF6 fragment has been shown to be phosphorylated and activated by p38 MAPK ( Luo and Lee, 2002 ), one ofthe most active kinases upon SARS- CoV-2 infection ( Bouhaddou et al., 2020 ), supporting a role for ATF6 in CoV-2 infection. Collectively, these studies indicate the importance of evaluating the precise impact of CoV-2 proteins on the activation of ER stress receptors and induction ofthe UPR.
Daly AF, Tichomirowa MA, Petrossians P, Heliövaara E, Jaffrain-Rea ML, Barlier A, Naves LA, Ebeling T, Karhu A, Raappana A, Cazabat L, De Menis E, Montañana CF, Raverot G, Weil RJ, Sane T, Maiter D, Neggers S, Yaneva M, Tabarin A, Verrua E, Eloranta E, Murat A, Vierimaa O, Salmela PI, Emy P, Toledo RA, Sabaté MI, Villa C, Popelier M, Salvatori R, Jennings J, Longás AF, Labarta Aizpún JI, Georgitsi M, Paschke R, Ronchi C, Valimaki M, Saloranta C, De Herder W, Cozzi R, Guitelman M, Magri F, Lagonigro MS, Halaby G, Corman V, Hagelstein MT, Vanbellinghen JF, Barra GB, Gimenez-Roqueplo AP, Cameron FJ, Borson-Chazot F, Holdaway I, Toledo SP, Stalla GK, Spada A, Zacharieva S, Bertherat J, Brue T, Bours V, Chanson P, Aaltonen LA, Beckers A (2010) Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab 95:E373–E383 De Oliveira SK, Smolenski A (2009) Phosphodiesterases
Canada, J1H 5N4
Phages are bacterial parasites that are present in virtually all ecosystems and have a massive effect on the life cycle of bacterial cells. Despite the importance of bacteriophages in bacterial biology, their function inthe biology of Clostridium difficile has not been extensively studied. C. difficile is an important bacterial pathogen that causes severe intestinal infections in humans and animals. With this work, we seek to understand theroleof two closely related surface layer proteins, CwpV and SlpA in C. difficile bacteriophage infection. The function of SlpA is still not completely understood. A possible rolein bacteriophage infection has been suggested, although experimental evidence is lacking. C. difficile is prone to infection by bacteriophages, and the bacterial receptors used by these bacteriophages are unknown. CwpV is the largest protein ofthe C. difficile Cwp family. The variable region of CwpV is located toward the C-terminal end, and it is composed of a serine-glycine enriched flexible linker which is followed by repetitive sequences, whose sequence and number change depending on the C. difficile strain. The N-terminal domain possesses the cell-wall anchoring activity. Like SlpA, the CwpV protein undergoes maturation into two subunits that are re- associated in a non-covalent manner that forms a heterodimeric complex. Based on previous data from our lab on CwpV, the first objective of this study involved the use ofthe heterologous host Lactococcus lactis to transfer the antiphage functionality of CwpV against a new bacteriophage. We observed that the expression of CwpV conferred antiphage protection against bacteriophage p2 in L. lactis NZ9000 (EOP= 4.4x10 -2 ). Additionally, bacterial survival assays showed a reduced susceptibility to p2 bacteriophage infectionin L. lactis expressing CwpV (around 60 %). Also, the adsorption of
improve disease activity score, and it may have a therapeutic potential ( 53 ).
As previously discussed, the epithelial barrier must be functional and not allow the entry of pathogens to the inner layers. If the tight junctions are altered, the permeability ofthe barrier could increase and, along with this, there will be a greater paracellular flow of microorganisms, promoting theinfectionofthe lamina propria with pathogenic and/or opportunistic bacteria ( 54 ). It has been described that both TNF-α and IFN-γ can modify these junction structures, and it is known that IBD patients have an elevated production of TNF-α, which could be mediating the increased permeability due to the loss of tight junctions structure ( 54 ). However, it is not well understood if this dysfunction is a consequence of increased inflammation during an active disease or if it is the cause of IBD development, because some susceptible patients without symptoms or those in remission also show altered intestinal permeability ( 55 ). In normal conditions, the intestine is the major antibody producer tissue ofthe body, and the intestinal mucous membrane contains more than 80% ofthe activated B cells ( 56 ). IBD patients have a dysfunction inthe B cell response, which involves an abnormal mucosal secretion of IgG antibodies against commensal bacteria instead ofthe physiological secretion of IgA (Figure 1B) ( 57 , 58 ). This overproduction causes an exacerbated pro-inflammatory response and injury inthe epithelium, which is not observed in healthy individuals and may be relevant inthe development ofthe disease ( 59 ). Further, IBD patients also present antibodies to self-antigens or cross-reactivity against several bacterial and fun- gal antigens, which often precedes the onset ofthe disease ( 60 ). For example, CD patients have antibodies against Saccharomyces
Hypothetical host-pathogen two dimensional array inspired by data from Benghezal et al. [*10]. The ability of host mutants to resist (green) or to be killed (red) by different bacterial strains and bacterial mutants is indicated. Gene names are arbitrary with hrg and pvf for Host Resistance Gene and Pathogen Virulence Factor, respectively. Based on this matrix, it can be speculated that hrg-1 encoded protein is specifically involved in a mechanism necessary for host resistance to bacterial virulence factors encoded by pvfB and pvfC. The hrg-3-pvfD interaction would correspond to the case described by Liehl and colleagues [**18] with hrg-3 and pvfD being the Drosophila Imd and Pseudomonas aprA genes, respectively. Finally, HRG-2 and HRG-4 can be host proteins necessary for bacterial invasion by pathogen C and pathogen B and C, respectively, corresponding to the observations described inthe reports by Philips et al. and Agaisse et al. [*12, *13].
The formation ofthe autophagosome is a highly regulated process depending on a molecular machin- ery[ 33 ], of which a large part has been identified thanks to mutant screening assays inthe yeast Saccharomyces cerevisiae[ 37 ]. AuTophaGy-related (ATG) proteins coordinate this process, which is initiated by the for- mation of a double-membrane cytosol-sequestering vesicle, termed the phagophore that can engulf either random portions ofthe cytosol or specific proteins and organelles ( Figure 2(a )). This is regulated by upstream kinases such as the Target Of Rapamycin (TOR) com- plex, acting as a repressor[ 38 ], and the class III phos- phatidylinositol 3-kinase (PtdIns3K) complex, which is a positive regulator[ 39 ]. The phagophore then matures into a fully closed autophagosome that will subse- quently fuse with lysosomes to give a hybrid organelle called autolysosome, in which digestion and recycling ofthe sequestered material will take place ( Figure 2(a )). One central protein inthe process is a ubiquitin-like regulator of autophagosome biogenesis called microtu- bule-associated protein 1 Light Chain 3 (LC3)[ 40 ]. LC3 association to the autophagosomal membrane is tightly regulated by a core ubiquitin-like conjugation machin- ery that consists of proteins ATG3, 4, 5, 7, 10, 12 and 16L1 ( Figure 2(a )). Briefly, the C-terminus of LC3-I (the cytosolic form ofthe protein) is cleaved by the ATG4 protease to expose a glycine residue. This residue is then covalently linked to the membrane-embedded lipid phosphatidylethanolamine, though the action of a
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Dermatophytoses are common zoonotic skin diseases whose immunology remains largely unknown, which could explain the failure of most vaccination assays against them. Despite their confinement in keratinized structures ofthe skin and its annexes, dermatophytes can induce a specific immune response that can lead to total or partial protection against reinfection. It is commonly accepted that the protective immune response is of Th1 type but the involvement ofthe Th17 pathway has so far not been evaluated, although its role is increasingly recognized as being instrumental inthe evolution of many other fungal and microbial infections. The aim of this study was to evaluate the potential involvement ofthe Th17 pathway inthe immune response against dermatophytes using a new mouse model ofinfection.