Himanshu Kumar - Academia.edu (original) (raw)
Papers by Himanshu Kumar
The purpose of this study was to characterize changes in gene expression in the brain of a season... more The purpose of this study was to characterize changes in gene expression in the brain of a seasonal hibernator, the goldenmantled ground squirrel, Spermophilus lateralis, during the hibernation season. Very little information is available on molecular changes that correlate with hibernation state, and what has been done focused mainly on seasonal changes in peripheral tissues. We produced over 4000 reverse transcription-PCR products from euthermic and hibernating brain and compared them using differential display. Twenty-nine of the most promising were examined by Northern analysis. Although some small differences were observed across hibernation states, none of the 29 had significant changes. However, a more direct approach, investigating expression of putative hibernationresponsive genes by Northern analysis, revealed an increase in expression of transcription factors c-fos, junB, and c-Jun, but not junD, commencing during late torpor and peaking during the arousal phase of individual hibernation bouts. In contrast, prostaglandin D2 synthase declined during late torpor and arousal but returned to a high level on return to euthermia. Other genes that have putative roles in mammalian sleep or specific brain functions, including somatostatin, enkephalin, growth-associated protein 43, glutamate acid decarboxylases 65/67, histidine decarboxylase, and a sleep-related transcript SD464 did not change significantly during individual hibernation bouts. We also observed no decline in total RNA or total mRNA during torpor; such a decline had been previously hypothesized. Therefore, it appears that the dramatic changes in body temperature and other physiological variables that accompany hibernation involve only modest reprogramming of gene expression or steady-state mRNA levels.
Critical Reviews in Microbiology, 2003
Tuberculosis, a bacterial disease prevalent since ancient times, continues to cause the most deat... more Tuberculosis, a bacterial disease prevalent since ancient times, continues to cause the most deaths globally compared with all other diseases. The causative agent Mycobacterium tuberculosis is responsible for different types of tuberculosis in humans; however, pulmonary tuberculosis is the most common and causes the most deaths. Mycobacterium tuberculosis is an intracellular pathogenic bacterium, which has developed sophisticated mechanisms to survive inside host mononuclear phagocytes and thus evade the host immune system. This is attributed primarily to an inadequate immune response toward infecting bacteria, which results in temporary growth inhibition rather than death and subsequently allows the bacteria to multiply immensely, leading to full-blown disease in an individual. This disease has become a challenge due to poor diagnosis, a low-efficiency tuberculosis vaccine (Mycobacterium bovis Bacillus Calmette-Guerin [BCG]), a long-term antibacterial chemotherapy regimen (approximately 6 months), and an emergence of multiple drug resistant strains of Mycobacterium tuberculosis especially in people with human immune deficiency virus (HIV) infection, for whom researchers worldwide must develop effective short-term chemotherapy and an effective vaccine. In this review different aspects of vaccines in tuberculosis are discussed, and these include the traditional BCG vaccine, the modern auxotrophic vaccine, the subunit or acellular vaccine; and a DNA vaccine. We discuss also the potential of mycobacterial lipids as a vaccine or as an adjuvant in the future. Since complete genome information of Mycobacterium tuberculosis H37Rv and bioinformatics tools are available, it is possible to develop new strategies for a better and effective tuberculosis vaccine, which can replace the traditional BCG vaccine.
European Journal of Human Genetics, 2006
Single nucleotide polymorphisms (SNPs) in the regulatory region shared by PARK2 and PACRG have be... more Single nucleotide polymorphisms (SNPs) in the regulatory region shared by PARK2 and PACRG have been identified as major risk factors for leprosy susceptibility in two ethnically distinct populations. We investigated the association of six SNPs present in this regulatory region with leprosy susceptibility in an Indian population. Genotyping was performed by direct PCR sequencing in 286 leprosy patients and 350 healthy controls. Our results showed that T allele of SNPs PARK2_e01 (À2599) and 28 kb target_2_1 was significantly associated with susceptibility to leprosy per se (P ¼ 0.03 and 0.03, respectively). The T allele of SNPs PARK2_e01 (À2599) showed a significant recessive effect (P ¼ 0.04) in susceptibility to leprosy in Indian population as against the dominant effect of haplotype T-C of the major risk SNPs PARK2_e01 (À2599) and rs1040079 in Brazilian and Vietnamese population. However, after bonferroni corrections, these significant differences disappeared. Haplotype analysis also showed a lack of significant association of any haplotype with cases or controls. The noninvolvement of major risk SNPs in the regulatory region of PARK2 and PACRG locus with leprosy susceptibility in Indian population highlights the differential effect of these SNPs in regulating genetic susceptibility to leprosy in different populations.
Fungal -glucan, such as curdlan, triggers antifungal innate immune responses as well as shaping ... more Fungal -glucan, such as curdlan, triggers antifungal innate immune responses as well as shaping adaptive immune responses. In this study, we identified a key pathway that couples curdlan to immune responses. Curdlan promoted the production of the proinflammatory cytokine IL-1 by dendritic cells and macrophages through the NLRP3 inflammasome. Stimulation with Candida albicans and Saccharomyces cerevisiae also triggered the NLRP3 inflammasome-mediated IL-1 production. In vivo, NLRP3 was required for efficient Ag-specific Ab production when curdlan was used as an adjuvant, whereas it was dispensable for the induction of Th1 and Th17 cell differentiation. Furthermore, stimulation of purified B cells with curdlan-induced CD69 upregulation and IgM production while stimulation with other NLRP3 inflammasome activators, such as silica and aluminum salt, did not. Notably, this induction required NLRP3 but was independent of Toll-like receptor and IL-1 receptor family signaling, suggesting the presence of NLRP3-dependent and IL-1 receptor family independent mechanisms in B cells responsible for Ab responses. Collectively, these findings reveal a critical role for the NLRP3 inflammasome in the regulation of antifungal innate immune responses as well as B cell activation.
Journal of Virology, 2008
Journal of Experimental Medicine, 2008
. Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, au... more . Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, autoantibodymediated uptake of endogenous nucleic acids is thought to play a role. 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) induces a lupus-like disease in mice characterized by immune complex nephritis with autoantibodies to DNA and ribonucleoproteins. We recently reported that TMPD also causes increased ISG expression and that the development of the lupus is completely dependent on IFN-I signaling (Nacionales, D). We show that TMPD elicits IFN-I production, monocyte recruitment, and autoantibody production exclusively through a Tolllike receptor (TLR) 7 -and myeloid differentiation factor 88 (MyD88) -dependent pathway. In vitro studies revealed that TMPD augments the effect of TLR7 ligands but does not directly activate TLR7 itself. The effects of TMPD were amplifi ed by the Y-linked autoimmune acceleration cluster, which carries a duplication of the TLR7 gene. In contrast, deficiency of Fc ␥ receptors (Fc ␥ Rs) did not affect the production of IFN-I. Collectively, the data demonstrate that TMPD-stimulated IFN-I production requires TLR7/MyD88 signaling and is independent of autoantibody-mediated uptake of ribonucleoproteins by Fc ␥ Rs.
Journal of Experimental Medicine, 2007
Immunity
The innate immune system detects pathogen- and host-derived double-stranded DNA exposed to the cy... more The innate immune system detects pathogen- and host-derived double-stranded DNA exposed to the cytosol and induces type I interferon (IFN) and other cytokines. Here, we identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNA-mediated type I interferon induction. TRIM56 overexpression enhanced IFN-β promoter activation after double-stranded DNA stimulation whereas TRIM56 knockdown abrogated it. TRIM56 interacted with STING and targeted it for lysine 63-linked ubiquitination. This modification induced STING dimerization, which was a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent induction of IFN-β. Taken together, these results indicate that TRIM56 is an interferon-inducible E3 ubiquitin ligase that modulates STING to confer double-stranded DNA-mediated innate immune responses.
Cell Host & Microbe, 2011
Secondary bacterial infection is a common sequela to viral infection and is associated with incre... more Secondary bacterial infection is a common sequela to viral infection and is associated with increased lethality and morbidity. However, the underlying mechanisms remain poorly understood. We show that the TLR3/MDA5 agonist poly I:C or viral infection dramatically augments signaling via the NLRs Nod1 and Nod2 and enhances the production of proinflammatory cytokines. Enhanced Nod1 and Nod2 signaling by poly I:C required the TLR3/ MDA5 adaptors TRIF and IPS-1, and was mediated by type I IFNs. Mechanistically, poly I:C or IFN-β induced the expression of Nod1, Nod2, and the Nod-signaling adaptor RIP2. Systemic administration of poly I:C or IFN-β, or infection with murine norovirus-1, promoted inflammation and lethality in mice superinfected with E. coli, which was independent of bacterial burden, but attenuated in the absence of Nod1/Nod2 or RIP2. Thus, crosstalk between type I IFNs and Nod1/ Nod2 signaling promotes bacterial recognition, but induces harmful effects in the virally infected host.
Biochemical and Biophysical Research Communications, 2009
The innate immune system is an evolutionally conserved host defense mechanism against pathogens.
Immunity, 2007
Type I interferons (IFNs) are critical for antiviral responses. Here we generated a knockin mouse... more Type I interferons (IFNs) are critical for antiviral responses. Here we generated a knockin mouse in which green fluorescence protein (GFP) was expressed under the control of the Ifna6 promoter. Virus-induced expression of GFP recapitulated various IFN-a subtypes. Systemic infection of the mice with Newcastle disease virus (NDV) increased GFP + plasmacytoid dendritic cells (pDCs) via the Toll-like receptor system, and GFP + conventional dendritic cells (cDCs) and macrophages via the RIG-I-like helicase system. By contrast, lung infection with NDV led to IFN-a production in alveolar macrophages (AMs) and cDCs, but not in pDCs. Specific depletion of AMs caused a marked defect in the initial viral elimination in the lung. pDCs produced IFN-a in the absence of AM-mediated viral recognition, suggesting that pDCs function when the first defense line is broken. Thus, AMs act as a type I IFN producer that is important for the initial responses to viral infection in the lung.
Journal of Biological Chemistry, 2006
Vibrio parahaemolyticus, causative agent of human gastrointestinal diseases, possesses several vi... more Vibrio parahaemolyticus, causative agent of human gastrointestinal diseases, possesses several virulent machineries including thermostable direct hemolysin and type III secretion systems (TTSS1 and -2). In this report, we establish that TTSS1-dependent secretion and translocation of a V. parahaemolyticus effector protein VP1686 into the cytosol induces DNA fragmentation in macrophages. We performed yeast two-hybrid screening to identify the molecules involved in VP1686-mediated cell death pathways and showed that nuclear factor RelA p65/NF-B physically interacts with VP1686. To understand the impact of this interaction on the NF-B DNA binding activities in infected macrophages, we analyzed a series of deletion mutants for the TTSS and its secreted proteins. Induction of DNA binding activity of NF-B was significantly suppressed, and increased macrophage apoptosis has been associated with V. parahaemolyticus strain, which contains both VP1686 and TTSS1. Macrophages lacking Toll-like receptor adaptor molecules MyD88 (myeloid differentiation primary response protein 88) or TRIF (TIR domain-containing adapter-inducing interferon ) showed similar sensitivity to VP1686. As a consequence of NF-B suppression, microarray analysis has revealed that VP1686 translocation alerted the expression of many genes that have known functions in cellular responses to apoptosis, cell growth, and transcriptional regulation. Our results suggest an important role for Vibrio effector protein VP1686 that activate a conserved apoptotic pathway in macrophages through suppression of NF-B activation independent of Toll-like receptor signaling.
Nature Immunology, 2005
Type I interferons are central mediators for antiviral responses. Using high-throughput functiona... more Type I interferons are central mediators for antiviral responses. Using high-throughput functional screening of interferon inducers, we have identified here a molecule we call interferon-b promoter stimulator 1 (IPS-1). Overexpression of IPS-1 induced type I interferon and interferon-inducible genes through activation of IRF3, IRF7 and NF-jB transcription factors. TBK1 and IKKi protein kinases were required for the IPS-1-mediated interferon induction. IPS-1 contained an N-terminal CARD-like structure that mediated interaction with the CARD of RIG-I and Mda5, which are cytoplasmic RNA helicases that sense viral infection. 'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection. Thus, IPS-1 is an adaptor involved in RIG-I-and Mda5-mediated antiviral immune responses.
Journal of Experimental Medicine, 2007
Biochemical Journal, 2009
Immunity against microbial pathogens primarily depends on the recognition of pathogen components ... more Immunity against microbial pathogens primarily depends on the recognition of pathogen components by innate receptors expressed on immune and non-immune cells. Innate receptors are evolutionarily conserved germ-line-encoded proteins and include TLRs (Toll-like receptors), RLRs [RIG-I (retinoic acid-inducible gene-I)-like receptors] and NLRs (Nod-like receptors). These receptors recognize pathogens or pathogen-derived products in different cellular compartments, such as the plasma membrane, the endosomes or the cytoplasm, and induce the expression of cytokines, chemokines and co-stimulatory molecules to eliminate pathogens and instruct pathogen-specific adaptive immune responses. In the present review, we will discuss the recent progress in the study of pathogen recognition by TLRs, RLRs and NLRs and their signalling pathways.
The purpose of this study was to characterize changes in gene expression in the brain of a season... more The purpose of this study was to characterize changes in gene expression in the brain of a seasonal hibernator, the goldenmantled ground squirrel, Spermophilus lateralis, during the hibernation season. Very little information is available on molecular changes that correlate with hibernation state, and what has been done focused mainly on seasonal changes in peripheral tissues. We produced over 4000 reverse transcription-PCR products from euthermic and hibernating brain and compared them using differential display. Twenty-nine of the most promising were examined by Northern analysis. Although some small differences were observed across hibernation states, none of the 29 had significant changes. However, a more direct approach, investigating expression of putative hibernationresponsive genes by Northern analysis, revealed an increase in expression of transcription factors c-fos, junB, and c-Jun, but not junD, commencing during late torpor and peaking during the arousal phase of individual hibernation bouts. In contrast, prostaglandin D2 synthase declined during late torpor and arousal but returned to a high level on return to euthermia. Other genes that have putative roles in mammalian sleep or specific brain functions, including somatostatin, enkephalin, growth-associated protein 43, glutamate acid decarboxylases 65/67, histidine decarboxylase, and a sleep-related transcript SD464 did not change significantly during individual hibernation bouts. We also observed no decline in total RNA or total mRNA during torpor; such a decline had been previously hypothesized. Therefore, it appears that the dramatic changes in body temperature and other physiological variables that accompany hibernation involve only modest reprogramming of gene expression or steady-state mRNA levels.
Critical Reviews in Microbiology, 2003
Tuberculosis, a bacterial disease prevalent since ancient times, continues to cause the most deat... more Tuberculosis, a bacterial disease prevalent since ancient times, continues to cause the most deaths globally compared with all other diseases. The causative agent Mycobacterium tuberculosis is responsible for different types of tuberculosis in humans; however, pulmonary tuberculosis is the most common and causes the most deaths. Mycobacterium tuberculosis is an intracellular pathogenic bacterium, which has developed sophisticated mechanisms to survive inside host mononuclear phagocytes and thus evade the host immune system. This is attributed primarily to an inadequate immune response toward infecting bacteria, which results in temporary growth inhibition rather than death and subsequently allows the bacteria to multiply immensely, leading to full-blown disease in an individual. This disease has become a challenge due to poor diagnosis, a low-efficiency tuberculosis vaccine (Mycobacterium bovis Bacillus Calmette-Guerin [BCG]), a long-term antibacterial chemotherapy regimen (approximately 6 months), and an emergence of multiple drug resistant strains of Mycobacterium tuberculosis especially in people with human immune deficiency virus (HIV) infection, for whom researchers worldwide must develop effective short-term chemotherapy and an effective vaccine. In this review different aspects of vaccines in tuberculosis are discussed, and these include the traditional BCG vaccine, the modern auxotrophic vaccine, the subunit or acellular vaccine; and a DNA vaccine. We discuss also the potential of mycobacterial lipids as a vaccine or as an adjuvant in the future. Since complete genome information of Mycobacterium tuberculosis H37Rv and bioinformatics tools are available, it is possible to develop new strategies for a better and effective tuberculosis vaccine, which can replace the traditional BCG vaccine.
European Journal of Human Genetics, 2006
Single nucleotide polymorphisms (SNPs) in the regulatory region shared by PARK2 and PACRG have be... more Single nucleotide polymorphisms (SNPs) in the regulatory region shared by PARK2 and PACRG have been identified as major risk factors for leprosy susceptibility in two ethnically distinct populations. We investigated the association of six SNPs present in this regulatory region with leprosy susceptibility in an Indian population. Genotyping was performed by direct PCR sequencing in 286 leprosy patients and 350 healthy controls. Our results showed that T allele of SNPs PARK2_e01 (À2599) and 28 kb target_2_1 was significantly associated with susceptibility to leprosy per se (P ¼ 0.03 and 0.03, respectively). The T allele of SNPs PARK2_e01 (À2599) showed a significant recessive effect (P ¼ 0.04) in susceptibility to leprosy in Indian population as against the dominant effect of haplotype T-C of the major risk SNPs PARK2_e01 (À2599) and rs1040079 in Brazilian and Vietnamese population. However, after bonferroni corrections, these significant differences disappeared. Haplotype analysis also showed a lack of significant association of any haplotype with cases or controls. The noninvolvement of major risk SNPs in the regulatory region of PARK2 and PACRG locus with leprosy susceptibility in Indian population highlights the differential effect of these SNPs in regulating genetic susceptibility to leprosy in different populations.
Fungal -glucan, such as curdlan, triggers antifungal innate immune responses as well as shaping ... more Fungal -glucan, such as curdlan, triggers antifungal innate immune responses as well as shaping adaptive immune responses. In this study, we identified a key pathway that couples curdlan to immune responses. Curdlan promoted the production of the proinflammatory cytokine IL-1 by dendritic cells and macrophages through the NLRP3 inflammasome. Stimulation with Candida albicans and Saccharomyces cerevisiae also triggered the NLRP3 inflammasome-mediated IL-1 production. In vivo, NLRP3 was required for efficient Ag-specific Ab production when curdlan was used as an adjuvant, whereas it was dispensable for the induction of Th1 and Th17 cell differentiation. Furthermore, stimulation of purified B cells with curdlan-induced CD69 upregulation and IgM production while stimulation with other NLRP3 inflammasome activators, such as silica and aluminum salt, did not. Notably, this induction required NLRP3 but was independent of Toll-like receptor and IL-1 receptor family signaling, suggesting the presence of NLRP3-dependent and IL-1 receptor family independent mechanisms in B cells responsible for Ab responses. Collectively, these findings reveal a critical role for the NLRP3 inflammasome in the regulation of antifungal innate immune responses as well as B cell activation.
Journal of Virology, 2008
Journal of Experimental Medicine, 2008
. Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, au... more . Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, autoantibodymediated uptake of endogenous nucleic acids is thought to play a role. 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) induces a lupus-like disease in mice characterized by immune complex nephritis with autoantibodies to DNA and ribonucleoproteins. We recently reported that TMPD also causes increased ISG expression and that the development of the lupus is completely dependent on IFN-I signaling (Nacionales, D). We show that TMPD elicits IFN-I production, monocyte recruitment, and autoantibody production exclusively through a Tolllike receptor (TLR) 7 -and myeloid differentiation factor 88 (MyD88) -dependent pathway. In vitro studies revealed that TMPD augments the effect of TLR7 ligands but does not directly activate TLR7 itself. The effects of TMPD were amplifi ed by the Y-linked autoimmune acceleration cluster, which carries a duplication of the TLR7 gene. In contrast, deficiency of Fc ␥ receptors (Fc ␥ Rs) did not affect the production of IFN-I. Collectively, the data demonstrate that TMPD-stimulated IFN-I production requires TLR7/MyD88 signaling and is independent of autoantibody-mediated uptake of ribonucleoproteins by Fc ␥ Rs.
Journal of Experimental Medicine, 2007
Immunity
The innate immune system detects pathogen- and host-derived double-stranded DNA exposed to the cy... more The innate immune system detects pathogen- and host-derived double-stranded DNA exposed to the cytosol and induces type I interferon (IFN) and other cytokines. Here, we identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNA-mediated type I interferon induction. TRIM56 overexpression enhanced IFN-β promoter activation after double-stranded DNA stimulation whereas TRIM56 knockdown abrogated it. TRIM56 interacted with STING and targeted it for lysine 63-linked ubiquitination. This modification induced STING dimerization, which was a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent induction of IFN-β. Taken together, these results indicate that TRIM56 is an interferon-inducible E3 ubiquitin ligase that modulates STING to confer double-stranded DNA-mediated innate immune responses.
Cell Host & Microbe, 2011
Secondary bacterial infection is a common sequela to viral infection and is associated with incre... more Secondary bacterial infection is a common sequela to viral infection and is associated with increased lethality and morbidity. However, the underlying mechanisms remain poorly understood. We show that the TLR3/MDA5 agonist poly I:C or viral infection dramatically augments signaling via the NLRs Nod1 and Nod2 and enhances the production of proinflammatory cytokines. Enhanced Nod1 and Nod2 signaling by poly I:C required the TLR3/ MDA5 adaptors TRIF and IPS-1, and was mediated by type I IFNs. Mechanistically, poly I:C or IFN-β induced the expression of Nod1, Nod2, and the Nod-signaling adaptor RIP2. Systemic administration of poly I:C or IFN-β, or infection with murine norovirus-1, promoted inflammation and lethality in mice superinfected with E. coli, which was independent of bacterial burden, but attenuated in the absence of Nod1/Nod2 or RIP2. Thus, crosstalk between type I IFNs and Nod1/ Nod2 signaling promotes bacterial recognition, but induces harmful effects in the virally infected host.
Biochemical and Biophysical Research Communications, 2009
The innate immune system is an evolutionally conserved host defense mechanism against pathogens.
Immunity, 2007
Type I interferons (IFNs) are critical for antiviral responses. Here we generated a knockin mouse... more Type I interferons (IFNs) are critical for antiviral responses. Here we generated a knockin mouse in which green fluorescence protein (GFP) was expressed under the control of the Ifna6 promoter. Virus-induced expression of GFP recapitulated various IFN-a subtypes. Systemic infection of the mice with Newcastle disease virus (NDV) increased GFP + plasmacytoid dendritic cells (pDCs) via the Toll-like receptor system, and GFP + conventional dendritic cells (cDCs) and macrophages via the RIG-I-like helicase system. By contrast, lung infection with NDV led to IFN-a production in alveolar macrophages (AMs) and cDCs, but not in pDCs. Specific depletion of AMs caused a marked defect in the initial viral elimination in the lung. pDCs produced IFN-a in the absence of AM-mediated viral recognition, suggesting that pDCs function when the first defense line is broken. Thus, AMs act as a type I IFN producer that is important for the initial responses to viral infection in the lung.
Journal of Biological Chemistry, 2006
Vibrio parahaemolyticus, causative agent of human gastrointestinal diseases, possesses several vi... more Vibrio parahaemolyticus, causative agent of human gastrointestinal diseases, possesses several virulent machineries including thermostable direct hemolysin and type III secretion systems (TTSS1 and -2). In this report, we establish that TTSS1-dependent secretion and translocation of a V. parahaemolyticus effector protein VP1686 into the cytosol induces DNA fragmentation in macrophages. We performed yeast two-hybrid screening to identify the molecules involved in VP1686-mediated cell death pathways and showed that nuclear factor RelA p65/NF-B physically interacts with VP1686. To understand the impact of this interaction on the NF-B DNA binding activities in infected macrophages, we analyzed a series of deletion mutants for the TTSS and its secreted proteins. Induction of DNA binding activity of NF-B was significantly suppressed, and increased macrophage apoptosis has been associated with V. parahaemolyticus strain, which contains both VP1686 and TTSS1. Macrophages lacking Toll-like receptor adaptor molecules MyD88 (myeloid differentiation primary response protein 88) or TRIF (TIR domain-containing adapter-inducing interferon ) showed similar sensitivity to VP1686. As a consequence of NF-B suppression, microarray analysis has revealed that VP1686 translocation alerted the expression of many genes that have known functions in cellular responses to apoptosis, cell growth, and transcriptional regulation. Our results suggest an important role for Vibrio effector protein VP1686 that activate a conserved apoptotic pathway in macrophages through suppression of NF-B activation independent of Toll-like receptor signaling.
Nature Immunology, 2005
Type I interferons are central mediators for antiviral responses. Using high-throughput functiona... more Type I interferons are central mediators for antiviral responses. Using high-throughput functional screening of interferon inducers, we have identified here a molecule we call interferon-b promoter stimulator 1 (IPS-1). Overexpression of IPS-1 induced type I interferon and interferon-inducible genes through activation of IRF3, IRF7 and NF-jB transcription factors. TBK1 and IKKi protein kinases were required for the IPS-1-mediated interferon induction. IPS-1 contained an N-terminal CARD-like structure that mediated interaction with the CARD of RIG-I and Mda5, which are cytoplasmic RNA helicases that sense viral infection. 'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection. Thus, IPS-1 is an adaptor involved in RIG-I-and Mda5-mediated antiviral immune responses.
Journal of Experimental Medicine, 2007
Biochemical Journal, 2009
Immunity against microbial pathogens primarily depends on the recognition of pathogen components ... more Immunity against microbial pathogens primarily depends on the recognition of pathogen components by innate receptors expressed on immune and non-immune cells. Innate receptors are evolutionarily conserved germ-line-encoded proteins and include TLRs (Toll-like receptors), RLRs [RIG-I (retinoic acid-inducible gene-I)-like receptors] and NLRs (Nod-like receptors). These receptors recognize pathogens or pathogen-derived products in different cellular compartments, such as the plasma membrane, the endosomes or the cytoplasm, and induce the expression of cytokines, chemokines and co-stimulatory molecules to eliminate pathogens and instruct pathogen-specific adaptive immune responses. In the present review, we will discuss the recent progress in the study of pathogen recognition by TLRs, RLRs and NLRs and their signalling pathways.