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Bali Pulendran

Publications and source records attributed to Bali Pulendran.

At least 19 recordsLinked to original sources
PubMed2025

High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.

CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcriptomic, proteomic, and clinical data. The high-affinity CD16AV176 allele was associated with a significantly reduced risk of ICU admission, mechanical ventilation, and severe disease trajectories. Lower anti-SARS-CoV-2 IgG titers were correlated to CD16AV176; however, there was no difference in viral load across CD16A genotypes. Proteomic analysis revealed that participants homozygous for CD16AV176 had lower levels of inflammatory mediators. These findings suggest that CD16AV176 enhances early NK cell-mediated immune responses, limiting severe respiratory complications in COVID-19. This study identifies a protective genetic factor against severe COVID-19, informing future host-directed therapeutic strategies.

Humans↗
PubMed2025

Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection.

At this stage in the COVID-19 pandemic, most infections are "breakthrough" infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.

Immunity, Innate↗
PubMed2006

ERK1-/- mice exhibit Th1 cell polarization and increased susceptibility to experimental autoimmune encephalomyelitis.

Activation of MAPK ERK1/2 has been shown to play an important role in Th1/Th2 polarization and in regulating cytokine production from APCs. The ERK family consists of two members ERK1 and ERK2, which share approximately 84% identity at the amino acid level and can compensate for each other for most functions. Despite these features, ERK1 and ERK2 do serve different functions, but there is very little information on the contribution of individual forms of ERK on innate and adaptive immune responses. In this study, we describe that ERK1(-/-) mice display a bias toward Th1 type immune response. Consistent with this observation, dendritic cells from ERK1(-/-) mice show enhanced IL-12p70 and reduced IL-10 secretion in response to TLR stimulation. Furthermore, serum from ERK1(-/-) mice had 100-fold higher total IgG2b and 10-fold higher total IgG2a and IgG1 Ab isotype titers, and enhanced levels of Ag-specific IgG2b Ab titers, compared with wild-type mice. Consistent with this enhanced Th1 bias, ERK1(-/-) mice showed enhanced susceptibility to myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) and developed EAE earlier, and with increased severity, compared with wild-type mice. Importantly, there was a profound skewing toward Th1 responses in ERK1(-/-) mice, with higher IFN-gamma production and lower IL-5 production in MOG35-55-primed T cells, as well as an augmentation in the MOG-specific IgG2a and IgG2b Th1 Ab isotypes. Finally, increased infiltrating cells and myelin destruction was observed in the spinal cord of ERK1(-/-) mice. Taken together, our data suggest that deficiency of ERK1 biases the immune response toward Th1 resulting in increased susceptibility to EAE.

Animals↗
PubMed2006

Ebola virus-like particles produced in insect cells exhibit dendritic cell stimulating activity and induce neutralizing antibodies.

Recombinant baculoviruses (rBV) expressing Ebola virus VP40 (rBV-VP40) or GP (rBV-GP) proteins were generated. Infection of Sf9 insect cells by rBV-VP40 led to assembly and budding of filamentous particles from the cell surface as shown by electron microscopy. Ebola virus-like particles (VLPs) were produced by coinfection of Sf9 cells with rBV-VP40 and rBV-GP, and incorporation of Ebola GP into VLPs was demonstrated by SDS-PAGE and Western blot analysis. Recombinant baculovirus infection of insect cells yielded high levels of VLPs, which were shown to stimulate cytokine secretion from human dendritic cells similar to VLPs produced in mammalian cells. The immunogenicity of Ebola VLPs produced in insect cells was evaluated by immunization of mice. Analysis of antibody responses showed that most of the GP-specific antibodies were of the IgG2a subtype, while no significant level of IgG1 subtype antibodies specific for GP was induced, indicating the induction of a Th1-biased immune response. Furthermore, sera from Ebola VLP immunized mice were able to block infection by Ebola GP pseudotyped HIV virus in a single round infection assay, indicating that a neutralizing antibody against the Ebola GP protein was induced. These results show that production of Ebola VLPs in insect cells using recombinant baculoviruses represents a promising approach for vaccine development against Ebola virus infection.

Animals↗
PubMed2006

Translating innate immunity into immunological memory: implications for vaccine development.

Vaccination is the most effective means of preventing infectious diseases. Despite the success of many vaccines, there is presently little knowledge of the immunological mechanisms that mediate their efficacy. Such information will be critical in the design of future vaccines against old and new infectious diseases. Recent advances in immunology are beginning to provide an intellectual framework with which to address fundamental questions about how the innate immune system shapes adaptive immunity. In this review, we summarize current knowledge about how the innate immune system modulates the quantity and quality of long-term T and B cell memory and protective immune responses to pathogens. In addition, we point out unanswered questions and identify critical challenges, the solution of which, we believe, will greatly facilitate the rational design of novel vaccines against a multitude of emerging infections.

Adjuvants, Immunologic↗
PubMed2006

Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity.

The live attenuated yellow fever vaccine 17D (YF-17D) is one of the most effective vaccines available, with a 65-yr history of use in >400 million people globally. Despite this efficacy, there is presently no information about the immunological mechanisms by which YF-17D acts. Here, we present data that suggest that YF-17D activates multiple Toll-like receptors (TLRs) on dendritic cells (DCs) to elicit a broad spectrum of innate and adaptive immune responses. Specifically, YF-17D activates multiple DC subsets via TLRs 2, 7, 8, and 9 to elicit the proinflammatory cytokines interleukin (IL)-12p40, IL-6, and interferon-alpha. Interestingly, the resulting adaptive immune responses are characterized by a mixed T helper cell (Th)1/Th2 cytokine profile and antigen-specific CD8+ T cells. Furthermore, distinct TLRs appear to differentially control the Th1/Th2 balance; thus, whilst MyD88-deficient mice show a profound impairment of Th1 cytokines, TLR2-deficient mice show greatly enhanced Th1 and Tc1 responses to YF-17D. Together, these data enhance our understanding of the molecular mechanism of action of YF-17D, and highlight the potential of vaccination strategies that use combinations of different TLR ligands to stimulate polyvalent immune responses.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Dendritic cells at the host-pathogen interface.

How DCs integrate information from pathogens, tissues, and innate leukocytes for the induction of immune responses was presented at the second International Conference on Dendritic Cells at the Host-Pathogen Interface.

Animals↗
PubMed2006

Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance.

Emerging evidence suggests critical roles for APCs in suppressing immune responses. Here, we show that zymosan, a stimulus for TLR2 and dectin-1, regulates cytokine secretion in DCs and macrophages to induce immunological tolerance. First, zymosan induces DCs to secrete abundant IL-10 but little IL-6 and IL-12(p70). Induction of IL-10 is dependent on TLR2- and dectin-1-mediated activation of ERK MAPK via a mechanism independent of the activation protein 1 (AP-1) transcription factor c-Fos. Such DCs stimulate antigen-specific CD4+ T cells poorly due to IL-10 and the lack of IL-6. Second, zymosan induces F4-80+ macrophages in the splenic red pulp to secrete TGF-beta. Consistent with these effects on APCs, injection of zymosan plus OVA into mice results in OVA-specific T cells that secrete little or no Th1 or Th2 cytokines, but secrete robust levels of IL-10, and are unresponsive to challenge with OVA plus adjuvant. Finally, coinjection of zymosan with OVA plus LPS suppresses the response to OVA via a mechanism dependent on IL-10, TGF-beta, and lack of IL-6. Together, our data demonstrate that zymosan stimulates IL-10+ IL-12(p70)- IL-6low regulatory DCs and TGF-beta+ macrophages to induce immunological tolerance. These data suggest several targets for pharmacological modulation of immune responses in various clinical settings.

Animals↗
PubMed2005

Hexa-acylation and KDO(2)-glycosylation determine the specific immunostimulatory activity of Neisseria meningitidis lipid A for human monocyte derived dendritic cells.

To better understand immune modulation by endotoxin and facilitate the development of novel vaccine adjuvants, the structural requirements of Neisseria meningitidis lipopoly(oligo)saccharide (LOS) for activation of human monocyte derived dendritic cell (MDDC) was determined. Highly purified LOS from wild type and genetically-defined mutants of N. meningitidis serogroup B were used. Unglycosylated or penta-acylated meningococcal KDO(2)-lipid A failed to induce human MDDC maturation and activation. However, both wild type meningococcal LOS and KDO(2)-lipid A, significantly up-regulated CD80, CD83 and CD86 and released significantly higher amounts of IL-12p70, IL-6, IL-10, TNFalpha, MCP-1, IP-10 and RANTES. Further, DCs stimulated with wild type or KDO(2)-lipid A but not meningococcal lipid A or penta-acylated KDO(2)-lipid A stimulated naïve allogeneic CD4+ T cells to secrete enhanced levels of IFN-gamma, relative to T cells primed with immature DCs. In contrast to Escherichia coli LPS, IL-5 production was enhanced or maintained in CD4+ T-cells stimulated with MDDC exposed to wild-type meningococcal LOS and KDO(2)-lipid A. These data suggest that KDO linked to a fully acylated meningococcal lipid A is required for meningococcal endotoxin's immunostimulatory activity of human MDDC via TLR4/MD-2 and that different endotoxin structures influence Th responses mediated by MDDC.

Acylation↗
PubMed2005

Variegation of the immune response with dendritic cells and pathogen recognition receptors.

One of the most fundamental questions in biology is: "How do cells differentiate in the right place, at the right time, into the right kinds?" Understanding the phenomenon of cell differentiation in its spatial and temporal framework is a prelude to understanding the development and physiology of all multicellular systems, including the immune system. Insights over the past 2300 years, since Aristotle, suggest that biological differentiation is guided by the interplay between genetic programs and specific environmental signals. This is exemplified by the mammalian immune response to pathogens, where qualitatively different types can emerge. Although it is appreciated that this type immunity is critical for optimal defense against different pathogens, the early "decision-making mechanisms" are largely obscure. Recent developments in innate immunity and genomics, especially in the biology of dendritic cells (DCs) and pathogen recognition receptors, have stimulated intense research in understanding the mechanisms guiding the differentiation of Th1, Th2, and T regulatory responses. In this study, I summarize recent findings which suggest that activation of DCs via distinct pathogen recognition receptors stimulate different gene expression programs and signaling networks in DCs that guide the variegation of immune responses.

Adaptor Proteins, Signal Transducing↗
PubMed2004

A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells.

The adaptive immune system can generate distinct classes of responses, but the mechanisms that determine this are poorly understood. In this study, we demonstrate that different Toll-like receptor (TLR) ligands induce distinct dendritic cell (DC) activation and immune responses in vivo. Thus, Escherichia coli LPS (TLR-4 stimulus), activates DCs to produce abundant IL-12(p70), but little IL-10, and stimulates Th1 and Tc1 responses. In contrast, Pam-3-cys (TLR-2 stimulus) elicits less IL-12(p70), but abundant IL-10, and favors Th2 and T cytotoxic 2 (Tc2) responses. These distinct responses likely occur via differences in extracellular signal-regulated kinase signaling in DCs. Thus, Pam-3-cys induces enhanced extracellular signal-regulated kinase signaling, compared with LPS, resulting in suppressed IL-12(p70) and enhanced IL-10 production, as well as enhanced induction of the transcription factor, c-Fos. Interestingly, DCs from c-fos(-/-) mice produce more IL-12(p70), but less IL-10, compared with control DCs. Therefore, different TLR ligands induce distinct cytokines and signaling in DCs, and differentially bias Th responses in vivo.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Immune activation: death, danger and dendritic cells.

Dendritic cells are critical for host immunity, and sense microbes with pathogen recognition receptors. New evidence indicates that these cells also sense uric acid crystals in dead cells, suggesting that the immune system is conscious not only of pathogens, but also of death and danger.

Cell Death↗
PubMed2004

Dendritic cells generated in the presence of GM-CSF plus IL-15 prime potent CD8+ Tc1 responses in vivo.

Dendritic cells (DC) comprise a system of professional antigen-presenting cells, which induce the stimulation of very rare antigen-specific naive T cells. DC progenitors can be stimulated to differentiate into immature DC by various growth factors, including GM-CSF and IL-4. Here we show that IL-15, in combination with GM-CSF, is a growth factor for murine DC. Murine bone marrow cells, depleted of T cells, B cells, I-A+ cells and Gr-1+ granulocytes, and cultured in the presence of GM-CSF plus IL-15 (IL-15 DC), yielded DC expressing high levels of CD11c and MHC class II molecules, as well as CD11b. These cells expressed significant levels of CD40, CD80 and CD86, and could stimulate allogeneic CD4+ T cells efficiently. Interestingly, IL-15 DC were far superior to DC generated with GM-CSF plus IL-4 in stimulating allogeneic CD8+ T cells in vitro. Consistent with this, IL-15 DC induced much more potent antigen-specific CD8+ T cell responses with high levels of Th1 cytokines in vivo, compared to DC generated with GM-CSF plus IL-4, or with GM-CSF plus TGF-beta, or with GM-CSF alone. Together, these data suggest that IL-15 promotes the development of DC, which induce potent Th1 and Tc1 responses in vivo. This suggests potential roles for these IL-15 DC cells in the immunotherapy of tumors and infectious diseases.

Animals↗
PubMed2004

Modulating vaccine responses with dendritic cells and Toll-like receptors.

The immune system is ignorant or even unresponsive to most foreign proteins that are injected in a soluble, deaggregated form, but when injected together with an immune-stimulating agent (i.e. an adjuvant, such as CpG-rich DNA), these foreign proteins can generate robust immunity and long-lived memory to the antigen. In fact, the nature of the adjuvant is what determines the particular type of immune response that follows, which may be biased towards cytotoxic T-cell responses, antibody responses, particular classes of T-helper responses, or antibody isotypes. Clearly, the ability of a vaccine to skew the response toward a particular type is of paramount importance, because different pathogens require distinct types of protective immunities. Therefore, the quest to manipulate the immune system to generate optimally effective immunity against different pathogens can justifiably be considered the 'grand challenge' of modern immunology. Central to this issue is a rare but widely distributed network of cells known as dendritic cells (DCs). DCs, which have been called 'Nature's adjuvants,' express pathogen recognition receptors, such as the Toll-like receptors (TLRs) and C-type lectins, which enable them to sense and respond to microbes or vaccines. Research in the last decade has demonstrated a fundamental role for DCs in initiating and controlling the quality and strength of the immune response. As such, DCs and TLRs represent attractive immune modulatory targets for vaccinologists. The present review provides a summary of emerging themes in the biology DCs and TLRs, with a particular focus on relevance for vaccine development.

Adjuvants, Immunologic↗
PubMed2004

Modulating TH1/TH2 responses with microbes, dendritic cells, and pathogen recognition receptors.

The adaptive immune system has evolved different types of immune responses, each one effective against a given class of pathogen. For example, Th1 and Th2 responses represent two qualitatively different types of immune responses that are preferentially effective against intracellular microbes and helminths, respectively. Since the original description of Th1 and Th2 T-cell clones (1), we have learned much about the cytokines that influence the type of Th response. Thus, interleukin-4 (IL-4) is known to induce IL-4 production in T cells; conversely IL-12 and interferon-gamma (IFN-gamma) are known to induce IFN-gamma production by T cells. However, the original sources of these cytokines in vivo are less clear. Recent developments from several labs point to a potential role for dendritic cells (DCs) in orchestrating this decision making process. Here, we present our current view of DC development, and then review the evidence for two opposing concepts: (1) that distinct subsets of DCs are predetermined to differentially bias the T-helper response; and (2) that microbes and the local microenvironment are potent modulators of DC function. Thus, nature appears to have evolved different mechanisms to regulate immune responses via DCs.

Animals↗