Koichi S Kobayashi

Koichi S Kobayashi
Harvard Medical School | HMS · Department of Microbiology and Immunobiology

About

77
Publications
13,277
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6,375
Citations
Citations since 2016
10 Research Items
2690 Citations
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400

Publications

Publications (77)
Preprint
Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative...
Article
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The tumor microenvironment (TME) is characterized by the activation of immune checkpoints, which limit the ability of immune cells to attack the growing cancer. To overcome immune suppression in the clinic, antigen-expressing viruses and bacteria have been developed to induce antitumor immunity. However, the safety and targeting specificity are the...
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The MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. Here we show that the MHC class I pathway is targeted by SARS-CoV-2. Analysis of the gene expression profile from COVID-19 patients as well as SARS-CoV-2 infected epithelial cell lines reveals that the induction of the MHC class I pathway is inhibited...
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Checkpoint blockade-mediated immunotherapy is emerging as an effective treatment modality for multiple cancer types. However, cancer cells frequently evade the immune system, compromising the effectiveness of immunotherapy. It is crucial to develop screening methods to identify the patients who would most benefit from these therapies because of the...
Article
The presentation of antigenic peptides by major histocompatibility complex (MHC) class I and class II molecules are crucial for activation of the adaptive immune system. The nucleotide‐binding domain and leucine‐rich repeat receptor family member, CIITA and NLRC5 functions as the major transcriptional activator of MHC class II and class I gene expr...
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Major histocompatibility complex (MHC) class I and class II molecules play critical roles in the activation of the adaptive immune system by presenting antigens to CD8+ and CD4+ T cells, respectively. Although it has been well known that CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein,...
Article
Cryptococcus neoformans (Cn) is a deadly fungal pathogen whose intracellular lifestyle is important for virulence. Host mechanisms controlling fungal phagocytosis and replication remain obscure. Here, we perform a global phosphoproteomic analysis of the host response to Cryptococcus infection. Our analysis reveals numerous and diverse host proteins...
Article
Cancer cells need to escape immune surveillance for successful tumor growth. Loss of MHC class I has been described as a major immune evasion strategy in many cancers. MHC class I transactivator (CITA), NLRC5 [nucleotide-binding domain and leucine-rich repeats containing (NLR) family, caspase activation and recruitment domain (CARD) domain containi...
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The human intestinal tract harbors large bacterial community consisting of commensal, symbiotic, and pathogenic strains, which are constantly interacting with the intestinal immune system. This interaction elicits a non-pathological basal level of immune responses and contributes to shaping both the intestinal immune system and bacterial community....
Article
Significance Tumor antigen presentation to CD8 ⁺ T cells by MHC class I molecules is crucial for immune responses against cancers, whereas the loss of MHC class I is a common immune evasion strategy used by cancers. However, the molecular mechanisms leading to MHC class I deficiency have remained poorly defined. We demonstrate here that MHC class I...
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Helicobacter pylori (H. pylori) infects the gastric mucosa and persists for the life of the host. Bacterial persistence may be due to the induction of regulatory T cells (Tregs) whichmay have protective effects against other diseases such as asthma. It has been shown that H. pylori modulates the T cell response through dendritic cell reprogramming...
Data
WT and IRAK-M deficient BMDCs have similar T cell differentiation capabilities in the presence of H. pylori stimulation. BMDCs isolated from WT and IRAK-M−/− mice were plated and pulsed with either media or H. pylori SS1 lysate for 2 hours before CD4+ T cells isolated from SS1 infected C56BL/6 animals were added to the wells for 72 hours. Cells wer...
Data
GM-CSF BMDCs and Flt3L BMDCs share similar cytokine profiles when IRAK-M is deficient. Supernatant from WT and IRAK-M−/− BMDCs generated by the two different methods stimulated with either live H. pylori SS1 (MOI 10) or SS1 and 26695 antigen lysate were collected at 24 h and used to determine TNFα and IL-10 levels by ELISA. Data reflects two indepe...
Article
Background: Microbial sensing by Toll-like receptors (TLR) and its negative regulation have an important role in the pathogenesis of inflammation-related cancer. In this study, we investigated the role of negative regulation of Toll-like receptors signaling and gut microbiota in the development of colitis-associated cancer in mouse model. Methods...
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The human intestine harbors a diverse microbial community consisting of a large number of bacteria and other micro-organisms that have co-evolved with the host intestinal immune system. During this process, microbiota and the host immune system shape one another by various mechanisms to achieve a successful symbiotic relationship. An increasing amo...
Article
The expression of MHC class I molecules is crucial for the initiation and regulation of adaptive immune responses against pathogens. NOD-, LRR- and CARD-containing 5 (NLRC5) was recently identified as a specific transactivator of MHC class I genes (CITA). NLRC5 and the master regulator for MHC class II genes, class II transactivator (CIITA), intera...
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The innate immune system serves as the first line of defense by detecting microbes and initiating inflammatory responses. Although both TLR and NLR proteins are important for this process, their excessive activation is hazardous to hosts; thus, tight regulation is required. Endotoxin tolerance is refractoriness to repeated LPS stimulation and serve...
Article
The Gram-negative obligate intracellular bacterium Anaplasma phagocytophilum is the causative agent of human granulocytic anaplasmosis (HGA), an emerging tick-borne infectious disease occurring worldwide. HGA is generally self-limiting; however, the underlying mechanisms, particularly the innate immune pathways that mediate the immune clearance of...
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MHC class I and class II are crucial for the adaptive immune system. Although regulation of MHC class II expression by CIITA has long been recognized, the mechanism of MHC class I transactivation has been largely unknown until the recent discovery of NLRC5/class I transactivator. In this study, we show using Nlrc5-deficient mice that NLRC5 is requi...
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Orientia tsutsugamushi, a causative agent of scrub typhus, is an obligate intracellular bacterium, which escapes from the endo/phagosome and replicates in the host cytoplasm. O. tsutsugamushi infection induces production of pro-inflammatory mediators including interleukin-1β (IL-1β), which is secreted mainly from macrophages upon cytosolic stimuli...
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Tight regulation of MHC class I gene expression is critical for CD8 T cell activation and host adaptive-immune responses. The promoters of MHC class I genes contain a well-conserved core module, the W/S-X-Y motif, which assembles a nucleoprotein complex termed MHC enhanceosome. A member of the nucleotide-binding domain, leucine-rich repeat (NLR) pr...
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Genetic variants of nucleotide-binding oligomerization domain 2 (NOD2) lead to aberrant microbial recognition and can cause chronic inflammatory diseases in patients with Crohn's disease (CD). We utilized gene-specific siRNA mediated knockdown and expression of guanine nucleotide exchange factor H1 (GEF-H1) in wildtype, Rip2-, and Nod2-deficient ma...
Article
Major histocompatibility complex (MHC) class I and class II are crucial for the function of the human adaptive immune system. A member of the NLR (nucleotide-binding domain, leucine-rich repeat) protein family, NLRC5, has recently been identified as a transcriptional regulator of MHC class I and related genes. While a 'master regulator' of MHC clas...
Article
Full-text available
The decision between survival and death in cells exposed to TNF relies on a highly regulated equilibrium between proapoptotic and antiapoptotic factors. The TNF-activated antiapoptotic response depends on several transcription factors, including NF-κB and its RelA/p65 subunit, that are activated through phosphorylation-mediated degradation of IκB i...
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Major histocompatibility complex (MHC) class I and class II are crucial for the function of the human adaptive immune system. An NLR protein, CIITA (MHC class II transactivator), is a master regulator of MHC class II gene expression as well as of some of the genes involved in MHC class II antigen presentation. It has recently been discovered that a...
Article
Nod2 belongs to the nucleotide-binding domain leucine-rich repeat family of proteins and senses bacterial cell wall components to initiate innate immune responses against various pathogens. Recently, it has been reported that T-cell-intrinsic expression of Nod2 promotes host defense against Toxoplasma gondii infection by inducing type 1 immunity. H...
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Muramyl dipeptide (MDP) is a synthetic immunoreactive peptide consisting of N-acetyl muramic acid attached to a short amino acid chain of L-Ala-D-isoGln. It was first identified in bacterial cell wall peptidoglycan as an active component in Freund's complete adjuvant. In the cell, MDP is detected by NOD2, a cytoplasmic receptor belonging to the hum...
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The human intestine harbors a large number of bacteria that are constantly interacting with the intestinal immune system, eliciting non-pathological basal level immune responses. Increasing evidence points to dysbiosis of microbiota in the intestine as an underlying factor in inflammatory bowel disease susceptibility. Loss-of-function mutations in...
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The internalization of Borrelia burgdorferi, the causative agent of Lyme disease, by phagocytes is essential for an effective activation of the immune response to this pathogen. The intracellular, cytosolic receptor Nod2 has been shown to play varying roles in either enhancing or attenuating inflammation in response to different infectious agents....
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Toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat (NLR) proteins are two major forms of innate immune receptors that trigger inflammatory responses by various biological mechanisms such as cytokine production, recruitment of inflammatory cells, or activation of adaptive immunity. Although the innate immune system is desi...
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A healthy intestinal tract is characterized by controlled homeostasis due to the balanced interaction between commensal bacteria and the host mucosal immune system. Human and animal model studies have supported the hypothesis that breakdown of this homeostasis may underlie the pathogenesis of inflammatory bowel diseases. However, it is not well und...
Article
Ulcerative colitis is associated with increased colon permeability resulting in bacterial translocation into the lamina propria. We investigate the importance of the Toll-like receptor (TLR) regulating protein IL-1 receptor-associated kinase M (IRAK-M) using the erosive dextran sulfate sodium (DSS)-induced model of colitis. IRAK-M-competent and -in...
Article
The intracellular bacterium Legionella pneumophila induces a severe form of pneumonia called Legionnaires diseases, which is characterized by a strong neutrophil (NE) infiltrate to the lungs of infected individuals. Although the participation of pattern recognition receptors, such as Toll-like receptors, was recently demonstrated, there is no infor...
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Mutations in the NOD2 gene are strong genetic risk factors for ileal Crohn's disease. However, the mechanism by which these mutations predispose to intestinal inflammation remains a subject of controversy. We report that Nod2-deficient mice inoculated with Helicobacter hepaticus, an opportunistic pathogenic bacterium, developed granulomatous inflam...
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MHC class I plays a critical role in the immune defense against viruses and tumors by presenting antigens to CD8 T cells. An NLR protein, class II transactivator (CIITA), is a key regulator of MHC class II gene expression that associates and cooperates with transcription factors in the MHC class II promoter. Although CIITA also transactivates MHC c...
Data
IL-1β production by Asc-, Nalp3-, or Ipaf-deficient macrophages infected with E. muris. Bone marrow-derived macrophages from both wild-type and Asc-, Nalp3- or Ipaf-deficient mice were treated with LPS (10 ng/ml) for 16 hours and then infected with E. muris in vitro for the indicated time period or stimulated with 2.5 mM ATP for 3 hours. IL-1β secr...
Data
Histopathology of infected MyD88-deficient mice. Wild-type and MyD88-deficient mice were infected with E. muris by i.p. for 10 days. Infected spleens were H&E-stained and photographed. Scale bar, 0.1 mm. Data are representative of at least three independent experiments. (8.27 MB TIF)
Data
DCs but not macrophages produce IL-12 p40 efficiently during E. muris infection. Bone marrow-derived DCs and macrophages were infected with E. muris for the indicated time period. (A) Infected cells (5 days postinfection) were stained by Diff-Quick and Hoechst 33342 staining. Scale bar, 10 µm. (B) Bacterial loads in infected cells were quantified b...
Data
MyD88-dependent E. muris recognition in macrophages. Bone marrow-derived macrophages from wild-type and MyD88-deficient mice were infected with E. muris in vitro for the indicated time period. (A) Cytokine production from infected cells was assessed by ELISA. LPS (10 ng/ml) stimulation was used as a control. (B) Infected cells (5 days postinfection...
Data
Rip2-independent E. muris recognition in DCs. Bone marrow-derived DCs from wild-type and Rip2-deficient mice were infected with E. muris for the indicated time period. (A) Cytokine production from infected cells was assessed by ELISA. LPS (10 ng/ml) stimulation was used as a control. (B) Infected cells (5 days post infection) were stained by Diff-Q...
Data
TLR2/3/4/5/7/9/11 do not play major roles in E. muris recognition. Bone marrow-derived DCs from wild-type, TLR2/4/5/11-deficient (A), or TLR3/7/9-deficient (B) mice were infected with E. muris for the indicated time period, and IL-12 p40 production from infected cells was assessed by ELISA. LPS (10 ng/ml), CpG (1 µM), R-848 (1 µM) and Pam3CSK4 (1 µ...
Data
Similar CD4/CD8 T cell ratio between wild-type and MyD88-deficient mice during E. muris infection. Wild-type and MyD88-deficient mice were infected with E. muris for 10 days. Total splenocytes were analyzed by flow cytometry for surface expression of CD4 and CD8. Numbers in quadrants indicate the percentages of CD8+ and CD4+ cells among total splen...
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The ehrlichiae are small gram-negative obligate intracellular bacteria in the family Anaplasmataceae. Ehrlichial infection in an accidental host may result in fatal diseases such as human monocytotropic ehrlichiosis, an emerging, tick-borne disease. Although the role of adaptive immune responses in the protection against ehrlichiosis has been well...
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NOD2 (nucleotide-binding oligomerization domain containing 2) is an important cytosolic pattern recognition receptor that activates NF-kappaB and other immune effector pathways such as autophagy and antigen presentation. Despite its intracellular localization, NOD2 participates in sensing of extracellular microbes such as Staphylococcus aureus. NOD...
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Multiple pattern recognition systems have been shown to initiate innate immune responses to microbial pathogens. The degree to which these detection systems cooperate with each other to provide host protection is unknown. Here, we investigated the importance of several immune surveillance pathways in protecting mice against lethal infection by the...
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An effective innate immune recognition of the intracellular protozoan parasite Trypanosoma cruzi is critical for host resistance against Chagas disease, a severe and chronic illness that affects millions of people in Latin America. In this study, we evaluated the participation of nucleotide-binding oligomerization domain (Nod)-like receptor protein...
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Full-text available
Mutations in the Nod2 gene are among the strongest genetic risk factors in the pathogenesis of ileal Crohn's disease, but the exact contributions of Nod2 to intestinal mucosal homeostasis are not understood. Here we show that Nod2 plays an essential role in controlling commensal bacterial flora in the intestine. Analysis of intestinal bacteria from...
Article
Full-text available
Cytolytic CD8(+) T cells (CTLs) kill virally infected cells, tumor cells, or other potentially autoreactive T cells in a calcium-dependent manner. To date, the molecular mechanism that leads to calcium intake during CTL differentiation and function has remained unresolved. We demonstrate that desmoyokin (AHNAK1) is expressed in mature CTLs, but not...
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Despite their ability to cause septic shock and myocardial dysfunction, components of Gram-negative bacterial cell walls, like lipopolysaccharide, have been shown in numerous studies to induce myocardial protection during ischaemia-reperfusion injury. Muramyl dipeptide (MDP) is another such component recognized by an intracellular receptor, nucleot...
Article
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NOD2/CARD15 mediates innate immune responses to mycobacterial infection. However, its role in the regulation of adaptive immunity has remained unknown. In this study, we examined host defense, T cell responses, and tissue pathology in two models of pulmonary mycobacterial infection, using wild-type and Nod2-deficient mice. During the early phase of...
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The immune system must discriminate between pathogenic and nonpathogenic microbes in order to initiate an appropriate response. Toll-like receptors (TLRs) detect microbial components common to both pathogenic and nonpathogenic bacteria, whereas Nod-like receptors (NLRs) sense microbial components introduced into the host cytosol by the specialized...
Data
Quantitation of IκBα degradation in Myd88−/− and Myd88−/−Rip2−/− macrophages infected with WT or ΔdotA L. pneumophila. (2.29 MB TIF)
Data
The L. pneumophila Dot/Icm system translocates three Ser/Thr protein kinases that are dispensable for p38 MAPK activation. (2.36 MB TIF)
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Genes that exhibit two-fold or greater Dot/Icm-dependent transcriptional changes in both Myd88−/−Trif−/− and Myd88−/−Rip2−/− macrophages and are shared by the ISD response in Myd88−/−Trif−/− macrophages. (0.05 MB XLS)
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Genes that exhibit two-fold or greater Dot/Icm-dependent transcriptional changes in Myd88−/−Trif−/− macrophages but not in Myd88−/−Rip2−/− macrophages. (0.07 MB XLS)
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Genes that exhibit two-fold or greater Dot/Icm-dependent transcriptional changes in both Myd88−/−Trif−/− and Myd88−/−Rip2−/− macrophages and are unique from the ISD response in Myd88−/−Trif−/− macrophages. (0.08 MB XLS)
Data
p38 and SAPK/JNK MAPK signaling contribute to Dot/Icm-dependent gene transcription in the absence of MyD88 and RIP2. (1.83 MB TIF)
Data