Robert L Modlin

Publications (105)1035.82 Total impact

• Article: Type I Interferon Suppresses Type II Interferon-Triggered Human Anti-Mycobacterial Responses.

  Rosane M B Teles, Thomas G Graeber, Stephan R Krutzik, Dennis Montoya, Mirjam Schenk, Delphine J Lee, Evangelia Komisopoulou, Kindra Kelly-Scumpia, Rene Chun, Shankar S Iyer, Euzenir N Sarno, Thomas H Rea, Martin Hewison, John S Adams, Stephen J Popper, David A Relman, Steffen Stenger, Barry R Bloom, Genhong Cheng, Robert L Modlin
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  ABSTRACT: Type I interferons (IFN-α and IFN-β) are important for protection against many viral infections, whereas type II interferon (IFN-γ) is essential for host defense against some bacterial and parasitic pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-β and IFN-γ gene expression programs. IFN-γ and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro. In contrast, IFN-β and its downstream genes, including interleukin 10 (IL-10), were induced in monocytes by M. leprae in vitro, and preferentially expressed in disseminated and progressive lepromatous lesions. The IFN-γ-induced macrophage vitamin D-dependent antimicrobial peptide response was inhibited by IFN-β and by IL-10, suggesting that the differential production of IFNs contributes to protection versus pathogenesis in some human bacterial infections.
  Science 02/2013; · 31.20 Impact Factor
• Source

  Available from: Sorel Fitz-Gibbon

  Article: Propionibacterium Acnes Strain Populations in the Human Skin Microbiome Associated with Acne.

  Sorel Fitz-Gibbon, Shuta Tomida, Bor-Han Chiu, Lin Nguyen, Christine Du, Minghsun Liu, David Elashoff, Marie C Erfe, Anya Loncaric, Jenny Kim, Robert L Modlin, Jeff F Miller, Erica Sodergren, Noah Craft, George M Weinstock, Huiying Li
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  ABSTRACT: The human skin microbiome plays important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that while the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may play roles in determining virulence properties of P. acnes strains and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain level analysis of the human microbiome to define the role of commensals in health and disease.Journal of Investigative Dermatology accepted article preview online, 21 January 2013; doi:10.1038/jid.2013.21.
  Journal of Investigative Dermatology 01/2013; · 6.31 Impact Factor
• Article: CD40L and IFN-γ induce an antimicrobial response against M. tuberculosis in human monocytes.

  Georgiana M Klug-Micu, Steffen Stenger, Andrea Sommer, Philip T Liu, Stephan R Krutzik, Robert L Modlin, Mario Fabri
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  ABSTRACT: The ability of T cells to activate antimicrobial pathways in infected macrophages is essential to host defense against many intracellular pathogens. Here, we compared the ability of two T cell-mediated mechanisms to trigger antimicrobial responses against Mycobacterium tuberculosis in humans, CD40 activation and the release of IFN-γ. Given that IFN-γ activates a vitamin D-dependent antimicrobial response, we focused on induction of the key components of this pathway. We show that activation of human monocytes via CD40L and IFN-γ, alone, and in combination, induces the CYP27b1-hydroxylase, responsible for the conversion of 25-hydroxyvitamin D (25D) to the bioactive 1,25-dihydroxyvitamin D (1,25D), and the vitamin D receptor (VDR). The activation of the vitamin D pathway by CD40L and/or IFN-γ results in upregulated expression of the antimicrobial peptides, cathelicidin and DEFB4, as well as induction of autophagy. Finally, activation of monocytes via CD40L and/or IFN-γ results in an antimicrobial activity against intracellular M. tuberculosis. Our data suggest that at least two parallel T cell-mediated mechanisms, CD40L and IFN-γ, activate the vitamin D-dependent antimicrobial pathway and trigger antimicrobial activity against intracellular M. tuberculosis, thereby contributing to human host defense against intracellular infection. © 2013 The Authors. Immunology © 2013 Blackwell Publishing Ltd.
  Immunology 01/2013; · 3.32 Impact Factor
• Article: Galectin-3 regulates the innate immune response of human monocytes.

  Andrew W Chung, Peter A Sieling, Mirjam Schenk, Rosane M B Teles, Stephan R Krutzik, Daniel K Hsu, Fu-Tong Liu, Euzenir N Sarno, Steffen Stenger, Robert L Modlin, Delphine J Lee
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  ABSTRACT: Galectin-3 is a β-galactoside binding lectin widely expressed on epithelial and hematopoietic cells and its expression is frequently associated with a poor prognosis in cancer. Since it has not been well-studied in human infectious disease, we examined galectin-3 expression in mycobacterial infection by studying leprosy, an intracellular infection caused by Mycobacterium leprae. Galectin-3 was highly expressed on macrophages in lesions of patients with the clinically progressive lepromatous form of leprosy; in contrast, galectin-3 was almost undetectable in self-limited tuberculoid lesions. We investigated the potential function of galectin-3 in cell-mediated immunity using peripheral blood monocytes. Galectin-3 enhanced monocyte IL-10 production to a TLR2/1 ligand, while IL-12p40 secretion was unaffected. Furthermore, galectin-3 diminished monocyte to DC differentiation and T cell antigen presentation. These data demonstrate an association of galectin-3 with unfavorable host response in leprosy and a potential mechanism for impaired host defense in humans.
  The Journal of Infectious Diseases 12/2012; · 6.41 Impact Factor
• Article: Antimicrobial and Anti-Inflammatory Activity of Chitosan-Alginate Nanoparticles: A Targeted Therapy for Cutaneous Pathogens.

  Adam J Friedman, Jenny Phan, David O Schairer, Jackson Champer, Min Qin, Aslan Pirouz, Karin Blecher-Paz, Ami Oren, Phil T Liu, Robert L Modlin, Jenny Kim
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  ABSTRACT: Advances in nanotechnology have demonstrated potential application of nanoparticles (NPs) for effective and targeted drug delivery. Here we investigated the antimicrobial and immunological properties and the feasibility of using NPs to deliver antimicrobial agents to treat a cutaneous pathogen. NPs synthesized with chitosan and alginate demonstrated a direct antimicrobial activity in vitro against Propionibacterium acnes, the bacterium linked to the pathogenesis of acne. By electron microscopy (EM) imaging, chitosan-alginate NPs were found to induce the disruption of the P. acnes cell membrane, providing a mechanism for the bactericidal effect. The chitosan-alginate NPs also exhibited anti-inflammatory properties as they inhibited P. acnes-induced inflammatory cytokine production in human monocytes and keratinocytes. Furthermore, benzoyl peroxide (BP), a commonly used antiacne drug, was effectively encapsulated in the chitosan-alginate NPs and demonstrated superior antimicrobial activity against P. acnes compared with BP alone while demonstrating less toxicity to eukaryotic cells. Together, these data suggest the potential utility of topical delivery of chitosan-alginate NP-encapsulated drug therapy for the treatment of dermatologic conditions with infectious and inflammatory components.Journal of Investigative Dermatology advance online publication, 29 November 2012; doi:10.1038/jid.2012.399.
  Journal of Investigative Dermatology 11/2012; · 6.31 Impact Factor
• Article: The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response.

  Kislay Parvatiyar, Zhiqiang Zhang, Rosane M Teles, Songying Ouyang, Yan Jiang, Shankar S Iyer, Shivam A Zaver, Mirjam Schenk, Shang Zeng, Wenwan Zhong, Zhi-Jie Liu, Robert L Modlin, Yong-Jun Liu, Genhong Cheng
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  ABSTRACT: The induction of type I interferons by the bacterial secondary messengers cyclic di-GMP (c-di-GMP) or cyclic di-AMP (c-di-AMP) is dependent on a signaling axis that involves the adaptor STING, the kinase TBK1 and the transcription factor IRF3. Here we identified the heliase DDX41 as a pattern-recognition receptor (PRR) that sensed both c-di-GMP and c-di-AMP. DDX41 specifically and directly interacted with c-di-GMP. Knockdown of DDX41 via short hairpin RNA in mouse or human cells inhibited the induction of genes encoding molecules involved in the innate immune response and resulted in defective activation of STING, TBK1 and IRF3 in response to c-di-GMP or c-di-AMP. Our results suggest a mechanism whereby c-di-GMP and c-di-AMP are detected by DDX41, which forms a complex with STING to signal to TBK1-IRF3 and activate the interferon response.
  Nature Immunology 11/2012; · 26.01 Impact Factor
• Article: On the nature of mycobacteriophage diversity and host preference.

  Deborah Jacobs-Sera, Laura J Marinelli, Charles Bowman, Gregory W Broussard, Carlos Guerrero Bustamante, Michelle M Boyle, Zaritza O Petrova, Rebekah M Dedrick, Welkin H Pope, Robert L Modlin, Roger W Hendrix, Graham F Hatfull
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  ABSTRACT: The complete genome sequences of over 220 mycobacteriophages reveal them to be highly diverse, with numerous types sharing little or no nucleotide sequence identity with each other. We have determined the preferences of these phages for Mycobacterium tuberculosis and for other strains of Mycobacterium smegmatis, and find there is a correlation between genome type (cluster, subcluster, singleton) and host range. For many of the phages, expansion of host range occurs at relatively high frequencies, and we describe several examples in which host constraints occur at early stages of infection (adsorption or DNA injection), and phages have the ability to expand their host range through mutations in tail genes. We present a model in which phage diversity is a function of both the ability of phages to rapidly adapt to new hosts and the richness of the diversity of the bacterial population from which those phages are isolated.
  Virology 10/2012; · 3.35 Impact Factor
• Article: Abelson Tyrosine Kinase Controls Phagosomal Acidification Required for Killing of Mycobacterium tuberculosis in Human Macrophages.

  Heiko Bruns, Frank Stegelmann, Mario Fabri, Konstanze Döhner, Ger van Zandbergen, Manfred Wagner, Mhairi Skinner, Robert L Modlin, Steffen Stenger
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  ABSTRACT: The mechanisms that regulate the acidification of intracellular compartments are key to host defense against pathogens. In this paper, we demonstrate that Abl tyrosine kinase, a master switch for cell growth and trafficking of intracellular organelles, controls the acidification of lysosomes in human macrophages. Pharmacological inhibition by imatinib and gene silencing of Abelson (Abl) tyrosine kinase reduced the lysosomal pH in human macrophages by increasing the transcription and expression of the proton pumping enzyme vacuolar-type H(+)-adenosine triphosphatase. Because lysosomal acidification is required for antimicrobial activity against intracellular bacteria, we determined the effect of imatinib on the growth of the major human pathogen Mycobacterium tuberculosis. Imatinib limited the multiplication of M. tuberculosis, and growth restriction was dependent on acidification of the mycobacterial compartment. The effects of imatinib were also active in vivo because circulating monocytes from imatinib-treated leukemia patients were more acidic than monocytes from control donors. Importantly, sera from imatinib-treated patients triggered acidification and growth restriction of M. tuberculosis in macrophages. In summary, our results identify the control of phagosomal acidification as a novel function of Abl tyrosine kinase and provide evidence that the regulation occurs on the level of the vacuolar-type H(+)-adenosine triphosphatase. Given the efficacy of imatinib in a mouse model of tuberculosis and our finding that orally administered imatinib increased the ability of human serum to trigger growth reduction of intracellular M. tuberculosis, clinical evaluation of imatinib as a complementary therapy of tuberculosis, in particular multidrug or extremely drug-resistant disease, is warranted.
  The Journal of Immunology 09/2012; 189(8):4069-78. · 5.79 Impact Factor
• Article: Isolation of a distinct Mycobacterium tuberculosis mannose-capped lipoarabinomannan isoform responsible for recognition by CD1b-restricted T cells.

  Jordi B Torrelles, Peter A Sieling, Nannan Zhang, Mark A Keen, Michael R McNeil, John T Belisle, Robert L Modlin, Patrick J Brennan, Delphi Chatterjee
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  ABSTRACT: Mannose-capped lipoarabinomannan (ManLAM) is a complex lipoglycan abundantly present in the Mycobacterium tuberculosis cell envelope. Many biological properties have been ascribed to ManLAM, from directly interacting with the host and participating in the intracellular survival of M. tuberculosis, to triggering innate and adaptive immune responses, including the activation of CD1b-restricted T cells. Due to its structural complexity, ManLAM is considered a heterogeneous population of molecules which may explain its different biological properties. The presence of various modifications such as fatty acids, succinates, lactates, phosphoinositides and methylthioxylose in ManLAM have proven to correlate directly with its biological activity and may potentially be involved in the interactions between CD1b and the T cell population. To further delineate the specific ManLAM epitopes involved in CD1b-restricted T cell recognition, and their potential roles in mediating immune responses in M. tuberculosis infection, we established a method to resolve ManLAM into eight different isoforms based on their different isoelectric values. Our results show that a ManLAM isoform with an isoelectric value of 5.8 was the most potent in stimulating the production of interferon-γ in different CD1b-restricted T-cell lines. Compositional analyses of these isoforms of ManLAM revealed a direct relationship between the overall charge of the ManLAM molecule and its capacity to be presented to T cells via the CD1 compartment.
  Glycobiology 04/2012; 22(8):1118-27. · 3.58 Impact Factor
• Article: NOD2 triggers an interleukin-32-dependent human dendritic cell program in leprosy.

  Mirjam Schenk, Stephan R Krutzik, Peter A Sieling, Delphine J Lee, Rosane M B Teles, Maria Teresa Ochoa, Evangelia Komisopoulou, Euzenir N Sarno, Thomas H Rea, Thomas G Graeber, Soohyun Kim, Genhong Cheng, Robert L Modlin
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  ABSTRACT: It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Expression of NOD2 and IL-32 and the frequency of CD1b(+) DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand-induced, IL-32-dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.
  Nature medicine 03/2012; 18(4):555-63. · 27.14 Impact Factor
• Source

  Available from: Philip T Liu

  Article: MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy.

  Philip T Liu, Matthew Wheelwright, Rosane Teles, Evangelia Komisopoulou, Kristina Edfeldt, Benjamin Ferguson, Manali D Mehta, Aria Vazirnia, Thomas H Rea, Euzenir N Sarno, Thomas G Graeber, Robert L Modlin
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  ABSTRACT: Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a spectrum of clinical presentations that correlate with host immune responses. Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) versus the self-limited tuberculoid (T-lep) disease. Bioinformatic analysis revealed a significant enrichment of L-lep-specific miRNAs that preferentially target key immune genes downregulated in L-lep versus T-lep lesions. The most differentially expressed miRNA in L-lep lesions, hsa-mir-21, was upregulated in Mycobacterium leprae-infected monocytes. By directly downregulating Toll-like receptor 2/1 heterodimer (TLR2/1)-induced CYP27B1 and IL1B expression as well as indirectly upregulating interleukin-10 (IL-10), hsa-mir-21 inhibited expression of the genes encoding two vitamin D-dependent antimicrobial peptides, CAMP and DEFB4A. Conversely, knockdown of hsa-mir-21 in M. leprae-infected monocytes enhanced expression of CAMP and DEFB4A and restored TLR2/1-mediated antimicrobial activity against M. leprae. Therefore, the ability of M. leprae to upregulate hsa-mir-21 targets multiple genes associated with the immunologically localized disease form, providing an effective mechanism to escape from the vitamin D-dependent antimicrobial pathway.
  Nature medicine 01/2012; 18(2):267-73. · 27.14 Impact Factor
• Article: Propionibacterium acnes Bacteriophages Display Limited Genetic Diversity and Broad Killing Activity against Bacterial Skin Isolates.

  Laura J Marinelli, Sorel Fitz-Gibbon, Clarmyra Hayes, Charles Bowman, Megan Inkeles, Anya Loncaric, Daniel A Russell, Deborah Jacobs-Sera, Shawn Cokus, Matteo Pellegrini, Jenny Kim, Jeff F Miller, Graham F Hatfull, Robert L Modlin
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  ABSTRACT: ABSTRACT Investigation of the human microbiome has revealed diverse and complex microbial communities at distinct anatomic sites. The microbiome of the human sebaceous follicle provides a tractable model in which to study its dominant bacterial inhabitant, Propionibacterium acnes, which is thought to contribute to the pathogenesis of the human disease acne. To explore the diversity of the bacteriophages that infect P. acnes, 11 P. acnes phages were isolated from the sebaceous follicles of donors with healthy skin or acne and their genomes were sequenced. Comparative genomic analysis of the P. acnes phage population, which spans a 30-year temporal period and a broad geographic range, reveals striking similarity in terms of genome length, percent GC content, nucleotide identity (>85%), and gene content. This was unexpected, given the far-ranging diversity observed in virtually all other phage populations. Although the P. acnes phages display a broad host range against clinical isolates of P. acnes, two bacterial isolates were resistant to many of these phages. Moreover, the patterns of phage resistance correlate closely with the presence of clustered regularly interspaced short palindromic repeat elements in the bacteria that target a specific subset of phages, conferring a system of prokaryotic innate immunity. The limited diversity of the P. acnes bacteriophages, which may relate to the unique evolutionary constraints imposed by the lipid-rich anaerobic environment in which their bacterial hosts reside, points to the potential utility of phage-based antimicrobial therapy for acne. IMPORTANCE Propionibacterium acnes is a dominant member of the skin microflora and has also been implicated in the pathogenesis of acne; however, little is known about the bacteriophages that coexist with and infect this bacterium. Here we present the novel genome sequences of 11 P. acnes phages, thereby substantially increasing the amount of available genomic information about this phage population. Surprisingly, we find that, unlike other well-studied bacteriophages, P. acnes phages are highly homogeneous and show a striking lack of genetic diversity, which is perhaps related to their unique and restricted habitat. They also share a broad ability to kill clinical isolates of P. acnes; phage resistance is not prevalent, but when detected, it appears to be conferred by chromosomally encoded immunity elements within the host genome. We believe that these phages display numerous features that would make them ideal candidates for the development of a phage-based therapy for acne.
  mBio 01/2012; 3(5). · 5.31 Impact Factor
• Source

  Available from: eurekalert.org

  Article: Shedding light on the vitamin D-tuberculosis-HIV connection.

  Susan Realegeno, Robert L Modlin
  Proceedings of the National Academy of Sciences 11/2011; 108(47):18861-2. · 9.68 Impact Factor
• Article: Structural Differences in Lipomannans from Pathogenic and Nonpathogenic Mycobacteria That Impact CD1b-restricted T Cell Responses

  Jordi B. Torrelles, Peter A. Sieling, Jesús Arcos, Rose Knaup, Craig Bartling, Murugesan V. S. Rajaram, Steffen Stenger, Robert L. Modlin, Larry S. Schlesinger
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  ABSTRACT: Mannosylated molecules on the Mycobacterium tuberculosis surface are important determinants in the immunopathogenesis of tuberculosis. To date, much attention has been paid to mannose-capped lipoarabinomannan, which mediates phagocytosis and intracellular trafficking of M. tuberculosis by engaging the macrophage mannose receptor and subsequently binds to intracellular CD1b molecules for presentation to T cells. Another important mannosylated lipoglycan on the M. tuberculosis surface is lipomannan (LM). Comparative structural detail of the LMs from virulent and avirulent strains is limited as is knowledge regarding their differential capacity to be recognized by the adaptive immune response. Here, we purified LM from the avirulent M. smegmatis and the virulent M. tuberculosis H37Rv, performed a comparative structural biochemical analysis, and addressed their ability to stimulate CD1b-restricted T cell clones. We found that M. tuberculosis H37Rv produces a large neutral LM (TB-LM); in contrast, M. smegmatis produces a smaller linear acidic LM (SmegLM) with a high succinate content. Correspondingly, TB-LM was not as efficiently presented to CD1b-restricted T cells as SmegLM. Thus, here we correlate the structure-function relationships for LMs with CD1b-restricted T cell responses and provide evidence that the structural features of TB-LM contribute to its diminished T cell responsiveness.
  Journal of Biological Chemistry 10/2011; 286(41):35438-35446. · 4.77 Impact Factor
• Article: Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages.

  Mario Fabri, Steffen Stenger, Dong-Min Shin, Jae-Min Yuk, Philip T Liu, Susan Realegeno, Hye-Mi Lee, Stephan R Krutzik, Mirjam Schenk, Peter A Sieling, [......], David M Lewinsohn, Bruce W Hollis, Martin Hewison, John S Adams, Andreas Steinmeyer, Ulrich Zügel, Genhong Cheng, Eun-Kyeong Jo, Barry R Bloom, Robert L Modlin
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  ABSTRACT: Control of tuberculosis worldwide depends on our understanding of human immune mechanisms, which combat the infection. Acquired T cell responses are critical for host defense against microbial pathogens, yet the mechanisms by which they act in humans remain unclear. We report that T cells, by the release of interferon-γ (IFN-γ), induce autophagy, phagosomal maturation, the production of antimicrobial peptides such as cathelicidin, and antimicrobial activity against Mycobacterium tuberculosis in human macrophages via a vitamin D-dependent pathway. IFN-γ induced the antimicrobial pathway in human macrophages cultured in vitamin D-sufficient sera, but not in sera from African-Americans that have lower amounts of vitamin D and who are more susceptible to tuberculosis. In vitro supplementation of vitamin D-deficient serum with 25-hydroxyvitamin D3 restored IFN-γ-induced antimicrobial peptide expression, autophagy, phagosome-lysosome fusion, and antimicrobial activity. These results suggest a mechanism in which vitamin D is required for acquired immunity to overcome the ability of intracellular pathogens to evade macrophage-mediated antimicrobial responses. The present findings underscore the importance of adequate amounts of vitamin D in all human populations for sustaining both innate and acquired immunity against infection.
  Science translational medicine 10/2011; 3(104):104ra102. · 7.80 Impact Factor
• Article: Structural differences in lipomannans from pathogenic and nonpathogenic mycobacteria that impact CD1b-restricted T cell responses.

  Jordi B Torrelles, Peter A Sieling, Jesús Arcos, Rose Knaup, Craig Bartling, Murugesan V S Rajaram, Steffen Stenger, Robert L Modlin, Larry S Schlesinger
  [show abstract] [hide abstract]
  ABSTRACT: Mannosylated molecules on the Mycobacterium tuberculosis surface are important determinants in the immunopathogenesis of tuberculosis. To date, much attention has been paid to mannose-capped lipoarabinomannan, which mediates phagocytosis and intracellular trafficking of M. tuberculosis by engaging the macrophage mannose receptor and subsequently binds to intracellular CD1b molecules for presentation to T cells. Another important mannosylated lipoglycan on the M. tuberculosis surface is lipomannan (LM). Comparative structural detail of the LMs from virulent and avirulent strains is limited as is knowledge regarding their differential capacity to be recognized by the adaptive immune response. Here, we purified LM from the avirulent M. smegmatis and the virulent M. tuberculosis H(37)R(v), performed a comparative structural biochemical analysis, and addressed their ability to stimulate CD1b-restricted T cell clones. We found that M. tuberculosis H(37)R(v) produces a large neutral LM (TB-LM); in contrast, M. smegmatis produces a smaller linear acidic LM (SmegLM) with a high succinate content. Correspondingly, TB-LM was not as efficiently presented to CD1b-restricted T cells as SmegLM. Thus, here we correlate the structure-function relationships for LMs with CD1b-restricted T cell responses and provide evidence that the structural features of TB-LM contribute to its diminished T cell responsiveness.
  Journal of Biological Chemistry 08/2011; 286(41):35438-46. · 4.77 Impact Factor
• Article: Cord blood vitamin D status impacts innate immune responses.

  Valencia P Walker, Xiaoran Zhang, Ida Rastegar, Philip T Liu, Bruce W Hollis, John S Adams, Robert L Modlin
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  ABSTRACT: Our objectives were to 1) assess cord blood vitamin D concentrations from healthy term newborns, 2) ascertain whether cord blood vitamin D insufficiency precludes optimal induction of the Toll-like receptor (TLR) antimicrobial pathway in monocytes, and 3) determine whether in vitro supplementation with 25-hydroxyvitamin D(3) [25(OH)D(3)] and/or 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] restores TLR-induced antimicrobial responses. Plasma concentrations of 25(OH)D and 1,25(OH)(2)D were measured from cord blood of 23 newborns. Human monocytes were cultured in cord blood plasma and stimulated with TLR2 and TLR4 ligands, and then antimicrobial gene expression was analyzed using quantitative PCR. Cord blood 25(OH)D and 1,25(OH)(2)D concentrations were positively correlated to each other (r = 0.78; P <0.0001). Compared with those conditioned in vitamin D-sufficient plasma [25(OH)D > 75 nmol/liter], monocytes cultured in severely vitamin D-deficient plasma [25(OH)D < 30 nmol/liter] exhibited decreased TLR-induced cathelicidin expression (P <0.05). Supplementation in vitro of vitamin D-deficient plasma with 25(OH)D(3) increased antimicrobial peptide gene expression. Cord blood vitamin D deficiency, by its effects on TLR-induced antimicrobial production, altered in vitro monocyte responses. The observation that exogenous 25(OH)D(3) in vitro recovered TLR-induced antimicrobial responses suggests the need for additional prospective investigations to further delineate the role of vitamin D in the newborn immune response.
  The Journal of clinical endocrinology and metabolism 04/2011; 96(6):1835-43. · 6.50 Impact Factor
• Article: Noninvasive in vivo imaging to evaluate immune responses and antimicrobial therapy against Staphylococcus aureus and USA300 MRSA skin infections.

  John S Cho, Jamie Zussman, Niles P Donegan, Romela Irene Ramos, Nairy C Garcia, Daniel Z Uslan, Yoichiro Iwakura, Scott I Simon, Ambrose L Cheung, Robert L Modlin, Jenny Kim, Lloyd S Miller
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  ABSTRACT: Staphylococcus aureus skin infections represent a significant public health threat because of the emergence of antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA). As greater understanding of protective immune responses and more effective antimicrobial therapies are needed, a S. aureus skin wound infection model was developed in which full-thickness scalpel cuts on the backs of mice were infected with a bioluminescent S. aureus (methicillin sensitive) or USA300 community-acquired MRSA strain and in vivo imaging was used to noninvasively monitor the bacterial burden. In addition, the infection-induced inflammatory response was quantified using in vivo fluorescence imaging of LysEGFP mice. Using this model, we found that both IL-1α and IL-1β contributed to host defense during a wound infection, whereas IL-1β was more critical during an intradermal S. aureus infection. Furthermore, treatment of a USA300 MRSA skin infection with retapamulin ointment resulted in up to 85-fold reduction in bacterial burden and a 53% decrease in infection-induced inflammation. In contrast, mupirocin ointment had minimal clinical activity against this USA300 strain, resulting in only a 2-fold reduction in bacterial burden. Taken together, this S. aureus wound infection model provides a valuable preclinical screening method to investigate cutaneous immune responses and the efficacy of topical antimicrobial therapies.
  Journal of Investigative Dermatology 12/2010; 131(4):907-15. · 6.31 Impact Factor
• Source

  Available from: Philip T Liu

  Article: T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism.

  Kristina Edfeldt, Philip T Liu, Rene Chun, Mario Fabri, Mirjam Schenk, Matthew Wheelwright, Caroline Keegan, Stephan R Krutzik, John S Adams, Martin Hewison, Robert L Modlin
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  ABSTRACT: We investigated the mechanisms by which T-cell cytokines are able to influence the Toll-like receptor (TLR)-induced, vitamin D-dependent antimicrobial pathway in human monocytes. T-cell cytokines differentially influenced TLR2/1-induced expression of the antimicrobial peptides cathelicidin and DEFB4, being up-regulated by IFN-γ, down-regulated by IL-4, and unaffected by IL-17. The Th1 cytokine IFN-γ up-regulated TLR2/1 induction of 25-hydroxyvitamin D-1α-hydroxylase (i.e., CYP27B1), leading to enhanced bioconversion of 25-hydroxyvitamin D(3) (25D(3)) to its active metabolite 1,25D(3). In contrast, the Th2 cytokine IL-4, by itself and in combination with the TLR2/1 ligand, induced catabolism of 25D(3) to the inactive metabolite 24,25D(3), and was dependent on expression of vitamin D-24-hydroxylase (i.e., CYP24A1). Therefore, the ability of T-cell cytokines to differentially control monocyte vitamin D metabolism represents a mechanism by which cell-mediated immune responses can regulate innate immune mechanisms to defend against microbial pathogens.
  Proceedings of the National Academy of Sciences 12/2010; 107(52):22593-8. · 9.68 Impact Factor
• Article: Role of autophagy in the host response to microbial infection and potential for therapy.

  Mario Fabri, Susan E Realegeno, Eun-Kyeong Jo, Robert L Modlin
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  ABSTRACT: There is compelling evidence demonstrating a key role for autophagy in host defense against microbial infections. Induction and regulation of autophagy involves complex pathways including signaling molecules that have widespread roles in cell biological functions. For example, inhibiting mTOR by rapamycin, the most widely used chemical approach to induce autophagy, can also result in immunosupression. Nevertheless, advances in our understanding of autophagy provide a new opportunity to modulate host cellular responses as a potential therapeutic strategy to combat microbial infections in humans.
  Current opinion in immunology 11/2010; 23(1):65-70. · 10.88 Impact Factor