Publications by authors named "Kevin W Hoffman"

15 Publications

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Aberrant type 1 immunity drives susceptibility to mucosal fungal infections.

Science 2021 01;371(6526)

Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA.

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.
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http://dx.doi.org/10.1126/science.aay5731DOI Listing
January 2021

Hippocampal metabolite concentrations in schizophrenia vary in association with rare gene variants in the TRIO gene.

Schizophr Res 2020 10 9;224:167-169. Epub 2020 Nov 9.

Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University, NY, NY, USA; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany.

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http://dx.doi.org/10.1016/j.schres.2020.11.001DOI Listing
October 2020

Considering the Microbiome in Stress-Related and Neurodevelopmental Trajectories to Schizophrenia.

Front Psychiatry 2020 3;11:629. Epub 2020 Jul 3.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Early life adversity and prenatal stress are consistently associated with an increased risk for schizophrenia, although the exact pathogenic mechanisms linking the exposures with the disease remain elusive. Our previous view of the HPA stress axis as an elegant but simple negative feedback loop, orchestrating adaptation to stressors among the hypothalamus, pituitary, and adrenal glands, needs to be updated. Research in the last two decades shows that important bidirectional signaling between the HPA axis and intestinal mucosa modulates brain function and neurochemistry, including effects on glucocorticoid hormones and brain-derived neurotrophic factor (BDNF). The intestinal microbiome in earliest life, which is seeded by the vaginal microbiome during delivery, programs the development of the HPA axis in a critical developmental window, determining stress sensitivity and HPA function as well as immune system development. The crosstalk between the HPA and the Microbiome Gut Brain Axis (MGBA) is particularly high in the hippocampus, the most consistently disrupted neural region in persons with schizophrenia. Animal models suggest that the MGBA remains influential on behavior and physiology across developmental stages, including the perinatal window, early childhood, adolescence, and young adulthood. Understanding the role of the microbiome on critical risk related stressors may enhance or transform of understanding of the origins of schizophrenia and offer new approaches to increase resilience against stress effects for preventing and treating schizophrenia.
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http://dx.doi.org/10.3389/fpsyt.2020.00629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350783PMC
July 2020

Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance.

Sci Transl Med 2019 06;11(495)

Fungal Pathogenesis Section, LCIM, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.
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http://dx.doi.org/10.1126/scitranslmed.aav5597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647037PMC
June 2019

Sex differences in cytokine production following West Nile virus infection: Implications for symptom manifestation.

Pathog Dis 2019 03;77(2)

Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, NY 10029, USA.

West Nile virus (WNV) infection outcomes vary among individuals, with most infections resulting in asymptomatic or mild flu-like symptoms. We previously reported an association between early cytokine production and symptom outcome following WNV infection in US blood donors. In this meta-analysis, we found that WNV-infected females reported more symptoms than WNV-infected males, despite similar initial viremia and type I interferon responses. As the infection progressed, males exhibited a protracted cytokine response-marked by sustained CCL2 (MCP-1), CCL11 (eotaxin-1), CXCL10 (IP-10) and IL-15-that was absent in females. Our results suggest that sex differences may be a factor in sustaining WNV immunity.
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http://dx.doi.org/10.1093/femspd/ftz016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465207PMC
March 2019

Dengue Virus Immunity Increases Zika Virus-Induced Damage during Pregnancy.

Immunity 2019 03 5;50(3):751-762.e5. Epub 2019 Feb 5.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Zika virus (ZIKV) has recently been associated with birth defects and pregnancy loss after maternal infection. Because dengue virus (DENV) and ZIKV co-circulate, understanding the role of antibody-dependent enhancement in the context of pregnancy is critical. Here, we showed that the presence of DENV-specific antibodies in ZIKV-infected pregnant mice significantly increased placental damage, fetal growth restriction, and fetal resorption. This was associated with enhanced viral replication in the placenta that coincided with an increased frequency of infected trophoblasts. ZIKV-infected human placental tissues also showed increased replication in the presence of DENV antibodies, which was reversed by FcγR blocking antibodies. Furthermore, ZIKV-mediated fetal pathogenesis was enhanced in mice in the presence of a DENV-reactive monoclonal antibody, but not in the presence of the LALA variant, indicating a dependence on FcγR engagement. Our data suggest a possible mechanism for the recent increase in severe pregnancy outcomes after ZIKV infection in DENV-endemic areas.
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http://dx.doi.org/10.1016/j.immuni.2019.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947917PMC
March 2019

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model.

J Virol 2019 01 10;93(1). Epub 2018 Dec 10.

Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. An human tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1β) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation. Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.
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http://dx.doi.org/10.1128/JVI.01186-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288349PMC
January 2019

The homozygous CX3CR1-M280 mutation impairs human monocyte survival.

JCI Insight 2018 02 8;3(3). Epub 2018 Feb 8.

Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID) , and.

Several reports have demonstrated that mouse Cx3cr1 signaling promotes monocyte/macrophage survival. In agreement, we previously found that, in a mouse model of systemic candidiasis, genetic deficiency of Cx3cr1 resulted in increased mortality and impaired tissue fungal clearance associated with decreased macrophage survival. We translated this finding by showing that the dysfunctional CX3CR1 variant CX3CR1-M280 was associated with increased risk and worse outcome of human systemic candidiasis. However, the impact of this mutation on human monocyte/macrophage survival is poorly understood. Herein, we hypothesized that CX3CR1-M280 impairs human monocyte survival. We identified WT (CX3CR1-WT/WT), CX3CR1-WT/M280 heterozygous, and CX3CR1-M280/M280 homozygous healthy donors of European descent, and we show that CX3CL1 rescues serum starvation-induced cell death in CX3CR1-WT/WT and CX3CR1-WT/M280 but not in CX3CR1-M280/M280 monocytes. CX3CL1-induced survival of CX3CR1-WT/WT monocytes is mediated via AKT and ERK activation, which are both impaired in CX3CR1-M280/M280 monocytes, associated with decreased blood monocyte counts in CX3CR1-M280/M280 donors at steady state. Instead, CX3CR1-M280/M280 does not affect monocyte CX3CR1 surface expression or innate immune effector functions. Together, we show that homozygocity of the M280 polymorphism in CX3CR1 is a potentially novel population-based genetic factor that influences human monocyte signaling.
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http://dx.doi.org/10.1172/jci.insight.95417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821174PMC
February 2018

Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice.

Nat Commun 2017 10 10;8(1):846. Epub 2017 Oct 10.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

The aim of candidate universal influenza vaccines is to provide broad protection against influenza A and B viruses. Studies have demonstrated that broadly reactive antibodies require Fc-Fc gamma receptor interactions for optimal protection; however, the innate effector cells responsible for mediating this protection remain largely unknown. Here, we examine the roles of alveolar macrophages, natural killer cells, and neutrophils in antibody-mediated protection. We demonstrate that alveolar macrophages play a dominant role in conferring protection provided by both broadly neutralizing and non-neutralizing antibodies in mice. Our data also reveal the potential mechanisms by which alveolar macrophages mediate protection in vivo, namely antibody-induced inflammation and antibody-dependent cellular phagocytosis. This study highlights the importance of innate effector cells in establishing a broad-spectrum antiviral state, as well as providing a better understanding of how multiple arms of the immune system cooperate to achieve an optimal antiviral response following influenza virus infection or immunization.Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.
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http://dx.doi.org/10.1038/s41467-017-00928-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635038PMC
October 2017

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis.

J Virol 2017 05 28;91(10). Epub 2017 Apr 28.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain. In this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.
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http://dx.doi.org/10.1128/JVI.02409-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411599PMC
May 2017

Batf3-dependent CD103(+) dendritic cell accumulation is dispensable for mucosal and systemic antifungal host defense.

Virulence 2016 10 18;7(7):826-35. Epub 2016 May 18.

a Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda , MD , USA.

Dendritic cells (DCs) are critical for defense against a variety of pathogens and the formation of adaptive immune responses. The transcription factor Batf3 is critical for the development of CD103(+)CD11b(-) DCs, which promote IL-12-dependent protective immunity during viral and parasitic infections, dampen Th2 immunity during helminthic infection, and exert detrimental effects during bacterial infection. Whether CD103(+) DCs modulate immunity during systemic or mucosal fungal disease remains unknown. Herein, we report that Batf3 is critical for accumulation of CD103(+) DCs in the kidney and tongue at steady state, for their expansion during systemic and oropharyngeal candidiasis, and for tissue-specific production of IL-12 in kidney but not tongue during systemic and oropharyngeal candidiasis, respectively. Importantly, deficiency of CD103(+) DCs does not impair survival or fungal clearance during systemic or oropharyngeal candidiasis, indicating that Batf3-dependent CD103(+) DC accumulation mediates pathogen- and tissue-specific immune effects.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029292PMC
http://dx.doi.org/10.1080/21505594.2016.1186324DOI Listing
October 2016

Differences in Early Cytokine Production Are Associated With Development of a Greater Number of Symptoms Following West Nile Virus Infection.

J Infect Dis 2016 08 3;214(4):634-43. Epub 2016 May 3.

Department of Microbiology.

Background: West Nile virus (WNV) is an emerging cause of meningitis and encephalitis in the United States. Although severe neuroinvasive disease and death can occur in rare instances, the majority of infected individuals remain asymptomatic or present with a range of clinical manifestations associated with West Nile fever.

Methods: To better understand the interindividual variability associated with the majority of WNV infections, we evaluated the association of cytokine/chemokine production and outcome of infection among 115 WNV-positive US blood donors identified in 2008-2011. All subjects self-reported symptoms as having occurred during the 2 weeks following blood donation, using a standardized questionnaire.

Results: We discovered that, prior to seroconversion, an early potent, largely type I interferon-mediated response correlated with development of a greater number of symptoms in WNV-infected individuals. Interestingly, individuals who developed fewer symptoms had not only a more modest type I interferon response initially, but also a protracted cytokine response after seroconversion, marked by the production of monocyte and T-cell-associated chemokines.

Conclusions: Collectively, our data suggest that, although an early type I interferon response appears to be crucial to control WNV infection, successful immunity may require a modest early response that is maintained during the course of infection.
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http://dx.doi.org/10.1093/infdis/jiw179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957436PMC
August 2016

Differential Roles of Chemokines CCL2 and CCL7 in Monocytosis and Leukocyte Migration during West Nile Virus Infection.

J Immunol 2015 Nov 23;195(9):4306-18. Epub 2015 Sep 23.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

West Nile virus (WNV) is a re-emerging pathogen and the leading cause of epidemic encephalitis in the United States. Inflammatory monocytes are a critical component of the cellular infiltrate found in the CNS during WNV encephalitis, although the molecular cues involved in their migration are not fully understood. In mice, we previously showed that WNV infection induces a CCR2-dependent monocytosis that precedes monocyte migration into the CNS. Currently, the relative contribution of the CCR2 ligands, chemokines CCL2 and CCL7, in directing monocyte mobilization and leukocyte migration into the CNS is unclear. In this study, we demonstrate that, although both CCL2 and CCL7 are required for efficient monocytosis and monocyte accumulation in the CNS, only CCL7 deficiency resulted in increased viral burden in the brain and enhanced mortality. The enhanced susceptibility in the absence of CCL7 was associated with the delayed migration of neutrophils and CD8(+) T cells into the CNS compared with WT or Ccl2(-/-) mice. To determine whether CCL7 reconstitution could therapeutically alter the survival outcome of WNV infection, we administered exogenous CCL7 i.v. to WNV-infected Ccl7(-/-) mice and observed a significant increase in monocytes and neutrophils, but not CD8(+) T cells, within the CNS, as well as an enhancement in survival compared with Ccl7(-/-) mice treated with a linear CCL7 control peptide. Our experiments suggest that CCL7 is an important protective signal involved in leukocyte trafficking during WNV infection, and it may have therapeutic potential for the treatment of acute viral infections of the CNS.
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http://dx.doi.org/10.4049/jimmunol.1500352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610864PMC
November 2015

Dynamic asymmetry and the role of the conserved active-site thiol in rabbit muscle creatine kinase.

Biochemistry 2015 Jan 6;54(1):83-95. Epub 2014 Nov 6.

Department of Chemistry, Haverford College , 370 Lancaster Avenue, Haverford, Pennsylvania 19041, United States.

Symmetric and asymmetric crystal structures of the apo and transition state analogue forms, respectively, of the dimeric rabbit muscle creatine kinase have invoked an "induced fit" explanation for asymmetry between the two subunits and their active sites. However, previously reported thiol reactivity studies at the dual active-site cysteine 283 residues suggest a more latent asymmetry between the two subunits. The role of that highly conserved active-site cysteine has also not been clearly determined. In this work, the S-H vibrations of Cys283 were observed in the unmodified MM isoform enzyme via Raman scattering, and then one and both Cys283 residues in the same dimeric enzyme were modified to covalently attach a cyano group that reports on the active-site environment via its infrared CN stretching absorption band while maintaining the catalytic activity of the enzyme. Unmodified and Cys283-modified enzymes were investigated in the apo and transition state analogue forms of the enzyme. The narrow and invariant S-H vibrational bands report a homogeneous environment for the unmodified active-site cysteines, indicating that their thiols are hydrogen bonded to the same H-bond acceptor in the presence and absence of the substrate. The S-H peak persists at all physiologically relevant pH's, indicating that Cys283 is protonated at all pH's relevant to enzymatic activity. Molecular dynamics simulations identify the S-H hydrogen bond acceptor as a single, long-resident water molecule and suggest that the role of the conserved yet catalytically unnecessary thiol may be to dynamically rigidify that part of the active site through specific H-bonding to water. The asymmetric and broad CN stretching bands from the CN-modified Cys283 suggest an asymmetric structure in the apo form of the enzyme in which there is a dynamic exchange between spectral subpopulations associated with water-exposed and water-excluded probe environments. Molecular dynamics simulations indicate a homogeneous orientation of the SCN probe group in the active site and thus rule out a local conformational explanation at the residue level for the multipopulation CN stretching bands. The homogeneous simulated SCN orientation suggests strongly that a more global asymmetry between the two subunits is the cause of the CN probe's broad and asymmetric infrared line shape. Together, these spectral observations localized at the active-site cysteines indicate an intrinsic, dynamic asymmetry between the two subunits that exists already in the apo form of the dimeric creatine kinase enzyme, rather than being induced by the substrate. Biochemical and methodological consequences of these conclusions are considered.
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http://dx.doi.org/10.1021/bi5008063DOI Listing
January 2015

A new Raman spectroscopic probe of both the protonation state and noncovalent interactions of histidine residues.

J Phys Chem A 2013 Jul 21;117(29):5987-96. Epub 2013 Mar 21.

Department of Chemistry, Haverford College, 370 Lancaster Avenue, Haverford, Pennsylvania 19041-1392, USA.

The amino acid histidine (His) has a number of unique roles that can dictate function in proteins, and these roles are typically conferred through noncovalent interactions that depend on the protonation state of His's 4-substituted imidazole ring. His's protonation state can vary near physiological pH, and a probe of His's variable protonation state and its resulting noncovalent interactions that has both high time resolution and no sample limitations could find wide use in determining the role of particular His residues in proteins. Here we use a classic deuterium exchange reaction to replace the C2-H hydrogen atom of the His imidazole ring with deuterium, leading to a unique aromatic C2-D stretching vibration whose frequency is sensitive to environmental changes across the entire imidazole ring. Using nonresonant Raman spectroscopy, we demonstrate using model compounds that the frequency of this C2-D vibration shifts by 35 cm(-1) upon changes in the His protonation state. The C2-D band is a very weak infrared absorber, so this vibration is not expected to be useful in infrared transmission experiments for proteins. Solvent-dependent Raman experiments indicate that the C2-D band of the neutral imidazole ring is sensitive to H-bonding interaction with donors and acceptors of varying strengths, suggesting that the C2-D frequency can be used to identify H-bonding partners of specific His residues. Raman spectra at varying concentrations of Cu(2+) also show the C2-D band's sensitivity to metal coordination, with differences due to changes in the coordination environment. The strong Raman signal of this band and the sampling flexibility of Raman spectroscopy suggest that this vibration could be very useful in documenting the local role of His residues in many His-containing proteins and protein assemblies.
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http://dx.doi.org/10.1021/jp311815kDOI Listing
July 2013