FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Infect Immun / MyD88-dependent recruitment of monocytes and dendritic cells...
Infection and immunity2011; 80(1); 110-120; doi: 10.1128/IAI.05819-11

MyD88-dependent recruitment of monocytes and dendritic cells required for protection from pulmonary Burkholderia mallei infection.

Abstract: The Gram-negative bacterium Burkholderia mallei causes rapidly fatal illness in equines and humans when contracted by inhalation and also has the potential to be used as a bioweapon. However, little is known regarding the early innate immune responses and signaling mechanisms required to generate protection from pneumonic B. mallei infection. We showed previously that monocyte chemoattractant protein 1 (MCP-1) was a critical chemokine required for protection from pneumonic B. mallei infection. We have now extended those studies to identify key Toll-like receptor (TLR) signaling pathways, effector cells, and cytokines required for protection from respiratory B. mallei infection. We found that MyD88-/- mice were highly susceptible to pulmonary challenge with B. mallei and had significantly short survival times, increased bacterial burdens, and severe organ pathology compared to wild-type mice. Notably, MyD88-/- mice had significantly fewer monocytes and dendritic cells (DCs) in lung tissues and airways than infected wild-type mice despite markedly higher bacterial burdens. The MyD88-/- mice were also completely unable to produce gamma interferon (IFN-γ) at any time points following infection. In wild-type mice, NK cells were the primary cells producing IFN-γ in the lungs following B. mallei infection, while DCs and monocytes were the primary cellular sources of interleukin-12 (IL-12) production. Treatment with recombinant IFN-γ (rIFN-γ) was able to significantly restore protective immunity in MyD88-/- mice. Thus, we conclude that the MyD88-dependent recruitment of inflammatory monocytes and DCs to the lungs and the local production of IL-12, followed by NK cell production of IFN-γ, are the key initial cellular responses required for early protection from B. mallei infection.
Get Full Text
Publication Date: 2011-10-24 PubMed ID: 22025508PubMed Central: PMC3255660DOI: 10.1128/IAI.05819-11Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research study focuses on understanding the early immune responses and signalling mechanisms needed to protect from B. mallei, a potentially deadly bacteria that causes rapid illness in humans and horses. The study identifies the key pathways, cells, and compounds required for protection against B. mallei and also investigates MyD88’s role in the process, finding it necessary for effective immune response.

Significance of Burkholderia mallei and MyD88

  • Burkholderia mallei is a Gram-negative bacterium that, when inhaled, causes rapidly fatal illness in humans and equines. It also has the potential to be weaponized.
  • It is critical to understand how the innate immune system responds to infection and which signaling procedures are required for protection.
  • In this context, this study highlights the key role of MyD88, a signaling protein that helps to regulate the immune response.

The Role of MyD88, Monocytes, and Dendritic Cells

  • The study found that mice without MyD88 were highly susceptible to B. mallei infection, leading to shorter survival times, higher bacterial burdens, and more severe organ pathology than wild-type mice.
  • The MyD88-deficient mice also had significantly fewer monocytes and dendritic cells in their lungs and airways, despite having higher bacterial burdens.
  • This points to the important role of MyD88 in recruiting these critical immune cells to fight off infection.

Effects on Cytokine Production

  • Beyond cell recruitment, MyD88 also impacts cytokine production, which aids in managing the body’s immune response.
  • The study found that MyD88-deficient mice were utterly unable to produce gamma interferon (IFN-γ) at any point post-infection.
  • Among wild-type mice, NK cells were the main source of IFN-γ production in response to B. mallei infection, while dendritic cells and monocytes were primarily responsible for interleukin-12 production.
  • Notably, treating MyD88-deficient mice with recombinant IFN-γ significantly restored their immunity, underlining the potential therapeutic implications of this study.

Conclusion

  • The researchers concluded that the MyD88-dependent recruitment of monocytes and dendritic cells into the respiratory system is crucial for early protection from B. mallei infection.
  • Furthermore, this process works in tandem with the local production of interleukin-12 and the subsequent NK cell-derived production of IFN-γ.

Cite This Article

APA
Goodyear A, Troyer R, Bielefeldt-Ohmann H, Dow S. (2011). MyD88-dependent recruitment of monocytes and dendritic cells required for protection from pulmonary Burkholderia mallei infection. Infect Immun, 80(1), 110-120. https://doi.org/10.1128/IAI.05819-11

Publication

Infection and immunity
ISSN: 1098-5522
NlmUniqueID: 0246127
Country: United States
Language: English
Volume: 80
Issue: 1
Pages: 110-120

Researcher Affiliations

Goodyear, Andrew
  • Rocky Mountain RCE, CO, USA.
Troyer, Ryan
    Bielefeldt-Ohmann, Helle
      Dow, Steven

        MeSH Terms

        • Animals
        • Bacterial Load
        • Burkholderia mallei / immunology
        • Dendritic Cells / immunology
        • Disease Models, Animal
        • Female
        • Glanders / immunology
        • Interferon-gamma / metabolism
        • Interleukin-12 / metabolism
        • Lung / microbiology
        • Lung / pathology
        • Male
        • Mice
        • Mice, Inbred C57BL
        • Mice, Knockout
        • Monocytes / immunology
        • Myeloid Differentiation Factor 88 / immunology
        • Myeloid Differentiation Factor 88 / metabolism
        • Pneumonia, Bacterial / immunology
        • Pneumonia, Bacterial / microbiology
        • Survival Analysis

        Grant Funding

        • U54 AI065357 / NIAID NIH HHS
        • U54 AI065357-01 / NIAID NIH HHS

        References

        This article includes 37 references
        1. Barnes JL, Williams NL, Ketheesan N. Susceptibility to Burkholderia pseudomallei is associated with host immune responses involving tumor necrosis factor receptor-1 (TNFR1) and TNF receptor-2 (TNFR2).. FEMS Immunol Med Microbiol 2008 Apr;52(3):379-88.
          pubmed: 18294191doi: 10.1111/j.1574-695x.2008.00389.xgoogle scholar: lookup
        2. Bielefeldt Ohmann H, Campos M, Snider M, Rapin N, Beskorwayne T, Popowych Y, Lawman MJ, Rossi A, Babiuk LA. Effect of chronic administration of recombinant bovine tumor necrosis factor to cattle.. Vet Pathol 1989 Nov;26(6):462-72.
          pubmed: 2603327doi: 10.1177/030098588902600602google scholar: lookup
        3. Bogdan C, Schleicher U. Production of interferon-gamma by myeloid cells--fact or fancy?. Trends Immunol 2006 Jun;27(6):282-90.
          pubmed: 16698319doi: 10.1016/j.it.2006.04.004google scholar: lookup
        4. Branger J, Knapp S, Weijer S, Leemans JC, Pater JM, Speelman P, Florquin S, van der Poll T. Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice.. Infect Immun 2004 Feb;72(2):788-94.
          pmc: PMC321591pubmed: 14742522doi: 10.1128/iai.72.2.788-794.2004google scholar: lookup
        5. Campbell JS, Riehle KJ, Brooling JT, Bauer RL, Mitchell C, Fausto N. Proinflammatory cytokine production in liver regeneration is Myd88-dependent, but independent of Cd14, Tlr2, and Tlr4.. J Immunol 2006 Feb 15;176(4):2522-8.
          pubmed: 16456013doi: 10.4049/jimmunol.176.4.2522google scholar: lookup
        6. Diehl AM. Cytokine regulation of liver injury and repair.. Immunol Rev 2000 Apr;174:160-71.
          pubmed: 10807515doi: 10.1034/j.1600-0528.2002.017411.xgoogle scholar: lookup
        7. Dvorak GD, Spickler AR. Glanders.. J Am Vet Med Assoc 2008 Aug 15;233(4):570-7.
          pubmed: 18710311doi: 10.2460/javma.233.4.570google scholar: lookup
        8. Easton A, Haque A, Chu K, Lukaszewski R, Bancroft GJ. A critical role for neutrophils in resistance to experimental infection with Burkholderia pseudomallei.. J Infect Dis 2007 Jan 1;195(1):99-107.
          pubmed: 17152013doi: 10.1086/509810google scholar: lookup
        9. Fisher JH, Larson J, Cool C, Dow SW. Lymphocyte activation in the lungs of SP-D null mice.. Am J Respir Cell Mol Biol 2002 Jul;27(1):24-33.
          pubmed: 12091242doi: 10.1165/ajrcmb.27.1.4563google scholar: lookup
        10. Goodyear A, Jones A, Troyer R, Bielefeldt-Ohmann H, Dow S. Critical protective role for MCP-1 in pneumonic Burkholderia mallei infection.. J Immunol 2010 Feb 1;184(3):1445-54.
          pmc: PMC2878842pubmed: 20042590doi: 10.4049/jimmunol.0900411google scholar: lookup
        11. Goodyear A, Kellihan L, Bielefeldt-Ohmann H, Troyer R, Propst K, Dow S. Protection from pneumonic infection with burkholderia species by inhalational immunotherapy.. Infect Immun 2009 Apr;77(4):1579-88.
          pmc: PMC2663177pubmed: 19179415doi: 10.1128/iai.01384-08google scholar: lookup
        12. Haraoka M, Hang L, Frendéus B, Godaly G, Burdick M, Strieter R, Svanborg C. Neutrophil recruitment and resistance to urinary tract infection.. J Infect Dis 1999 Oct;180(4):1220-9.
          pubmed: 10479151doi: 10.1086/315006google scholar: lookup
        13. Jeddeloh JA, Fritz DL, Waag DM, Hartings JM, Andrews GP. Biodefense-driven murine model of pneumonic melioidosis.. Infect Immun 2003 Jan;71(1):584-7.
          pmc: PMC143420pubmed: 12496217doi: 10.1128/iai.71.1.584-587.2003google scholar: lookup
        14. Lertmemongkolchai G, Cai G, Hunter CA, Bancroft GJ. Bystander activation of CD8+ T cells contributes to the rapid production of IFN-gamma in response to bacterial pathogens.. J Immunol 2001 Jan 15;166(2):1097-105.
          pubmed: 11145690doi: 10.4049/jimmunol.166.2.1097google scholar: lookup
        15. Lever MS, Nelson M, Ireland PI, Stagg AJ, Beedham RJ, Hall GA, Knight G, Titball RW. Experimental aerogenic Burkholderia mallei (glanders) infection in the BALB/c mouse.. J Med Microbiol 2003 Dec;52(Pt 12):1109-1115.
          pubmed: 14614070doi: 10.1099/jmm.0.05180-0google scholar: lookup
        16. Mahenthiralingam E, Baldwin A, Dowson CG. Burkholderia cepacia complex bacteria: opportunistic pathogens with important natural biology.. J Appl Microbiol 2008 Jun;104(6):1539-51.
          pubmed: 18217926doi: 10.1111/j.1365-2672.2007.03706.xgoogle scholar: lookup
        17. Mastroeni P, Harrison JA, Robinson JH, Clare S, Khan S, Maskell DJ, Dougan G, Hormaeche CE. Interleukin-12 is required for control of the growth of attenuated aromatic-compound-dependent salmonellae in BALB/c mice: role of gamma interferon and macrophage activation.. Infect Immun 1998 Oct;66(10):4767-76.
          pmc: PMC108588pubmed: 9746577doi: 10.1128/iai.66.10.4767-4776.1998google scholar: lookup
        18. Morici LA, Heang J, Tate T, Didier PJ, Roy CJ. Differential susceptibility of inbred mouse strains to Burkholderia thailandensis aerosol infection.. Microb Pathog 2010 Jan;48(1):9-17.
          pmc: PMC7006035pubmed: 19853031doi: 10.1016/j.micpath.2009.10.004google scholar: lookup
        19. Ohteki T, Fukao T, Suzue K, Maki C, Ito M, Nakamura M, Koyasu S. Interleukin 12-dependent interferon gamma production by CD8alpha+ lymphoid dendritic cells.. J Exp Med 1999 Jun 21;189(12):1981-6.
          pmc: PMC2192968pubmed: 10377194doi: 10.1084/jem.189.12.1981google scholar: lookup
        20. Pietras EM, Miller LS, Johnson CT, O'Connell RM, Dempsey PW, Cheng G. A MyD88-dependent IFNγR-CCR2 signaling circuit is required for mobilization of monocytes and host defense against systemic bacterial challenge.. Cell Res 2011 Jul;21(7):1068-79.
          pmc: PMC3193491pubmed: 21467996doi: 10.1038/cr.2011.59google scholar: lookup
        21. Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. Am. J. Hyg. (Lond.) 1938 27: 493–497.
        22. Rotz LD, Khan AS, Lillibridge SR, Ostroff SM, Hughes JM. Public health assessment of potential biological terrorism agents.. Emerg Infect Dis 2002 Feb;8(2):225-30.
          pmc: PMC2732458pubmed: 11897082doi: 10.3201/eid0802.010164google scholar: lookup
        23. Rowland CA, Lertmemongkolchai G, Bancroft A, Haque A, Lever MS, Griffin KF, Jackson MC, Nelson M, O'Garra A, Grencis R, Bancroft GJ, Lukaszewski RA. Critical role of type 1 cytokines in controlling initial infection with Burkholderia mallei.. Infect Immun 2006 Sep;74(9):5333-40.
          pmc: PMC1594859pubmed: 16926428doi: 10.1128/iai.02046-05google scholar: lookup
        24. Santanirand P, Harley VS, Dance DA, Drasar BS, Bancroft GJ. Obligatory role of gamma interferon for host survival in a murine model of infection with Burkholderia pseudomallei.. Infect Immun 1999 Jul;67(7):3593-600.
          pmc: PMC116549pubmed: 10377144doi: 10.1128/iai.67.7.3593-3600.1999google scholar: lookup
        25. Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update.. Hepatology 2008 Jul;48(1):322-35.
          pubmed: 18506843doi: 10.1002/hep.22306google scholar: lookup
        26. Seki E, Tsutsui H, Iimuro Y, Naka T, Son G, Akira S, Kishimoto T, Nakanishi K, Fujimoto J. Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration.. Hepatology 2005 Mar;41(3):443-50.
          pubmed: 15723296doi: 10.1002/hep.20603google scholar: lookup
        27. Sprague LD, Neubauer H. Melioidosis in animals: a review on epizootiology, diagnosis and clinical presentation.. J Vet Med B Infect Dis Vet Public Health 2004 Sep;51(7):305-20.
          pubmed: 15525357doi: 10.1111/j.1439-0450.2004.00797.xgoogle scholar: lookup
        28. Tilg H. Cytokines and liver diseases.. Can J Gastroenterol 2001 Oct;15(10):661-8.
          pubmed: 11694902doi: 10.1155/2001/746736google scholar: lookup
        29. Titball RW, Russell P, Cuccui J, Easton A, Haque A, Atkins T, Sarkar-Tyson M, Harley V, Wren B, Bancroft GJ. Burkholderia pseudomallei: animal models of infection.. Trans R Soc Trop Med Hyg 2008 Dec;102 Suppl 1:S111-6.
          pubmed: 19121670doi: 10.1016/s0035-9203(08)70026-9google scholar: lookup
        30. Ventura GM, Balloy V, Ramphal R, Khun H, Huerre M, Ryffel B, Plotkowski MC, Chignard M, Si-Tahar M. Lack of MyD88 protects the immunodeficient host against fatal lung inflammation triggered by the opportunistic bacteria Burkholderia cenocepacia.. J Immunol 2009 Jul 1;183(1):670-6.
          pubmed: 19535624doi: 10.4049/jimmunol.0801497google scholar: lookup
        31. Wang X, Moser C, Louboutin JP, Lysenko ES, Weiner DJ, Weiser JN, Wilson JM. Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung.. J Immunol 2002 Jan 15;168(2):810-5.
          pubmed: 11777976doi: 10.4049/jimmunol.168.2.810google scholar: lookup
        32. West TE, Ernst RK, Jansson-Hutson MJ, Skerrett SJ. Activation of Toll-like receptors by Burkholderia pseudomallei.. BMC Immunol 2008 Aug 8;9:46.
          pmc: PMC2527550pubmed: 18691413doi: 10.1186/1471-2172-9-46google scholar: lookup
        33. West TE, Hawn TR, Skerrett SJ. Toll-like receptor signaling in airborne Burkholderia thailandensis infection.. Infect Immun 2009 Dec;77(12):5612-22.
          pmc: PMC2786489pubmed: 19797072doi: 10.1128/iai.00618-09google scholar: lookup
        34. White NJ. Melioidosis.. Lancet 2003 May 17;361(9370):1715-22.
          pubmed: 12767750doi: 10.1016/s0140-6736(03)13374-0google scholar: lookup
        35. Wiersinga WJ, Wieland CW, Dessing MC, Chantratita N, Cheng AC, Limmathurotsakul D, Chierakul W, Leendertse M, Florquin S, de Vos AF, White N, Dondorp AM, Day NP, Peacock SJ, van der Poll T. Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis).. PLoS Med 2007 Jul 31;4(7):e248.
          pmc: PMC1950213pubmed: 17676990doi: 10.1371/journal.pmed.0040248google scholar: lookup
        36. Wiersinga WJ, Wieland CW, Roelofs JJ, van der Poll T. MyD88 dependent signaling contributes to protective host defense against Burkholderia pseudomallei.. PLoS One 2008;3(10):e3494.
          pmc: PMC2566818pubmed: 18946505doi: 10.1371/journal.pone.0003494google scholar: lookup
        37. Zhan Y, Xu Y, Seah S, Brady JL, Carrington EM, Cheers C, Croker BA, Wu L, Villadangos JA, Lew AM. Resident and monocyte-derived dendritic cells become dominant IL-12 producers under different conditions and signaling pathways.. J Immunol 2010 Aug 15;185(4):2125-33.
          pubmed: 20644172doi: 10.4049/jimmunol.0903793google scholar: lookup

        Citations

        This article has been cited 14 times.
        1. Chiang CY, Zhong Y, Ward MD, Lane DJ, Kenny T, Rosario-Acevedo R, Eaton BP, Treviño SR, Chance TB, Hu M, Worsham PL, Waag DM, Moore RT, Cazares LH, Cote CK, Zhou Y, Panchal RG. Proteomic Analysis of Non-human Primate Peripheral Blood Mononuclear Cells During Burkholderia mallei Infection Reveals a Role of Ezrin in Glanders Pathogenesis. Front Microbiol 2021;12:625211.
          doi: 10.3389/fmicb.2021.625211pubmed: 33967974google scholar: lookup
        2. De Pascalis R, Rossi AP, Mittereder L, Takeda K, Akue A, Kurtz SL, Elkins KL. Production of IFN-γ by splenic dendritic cells during innate immune responses against Francisella tularensis LVS depends on MyD88, but not TLR2, TLR4, or TLR9. PLoS One 2020;15(8):e0237034.
          doi: 10.1371/journal.pone.0237034pubmed: 32745117google scholar: lookup
        3. Norris MH, Khan MSR, Chirakul S, Schweizer HP, Tuanyok A. Outer Membrane Vesicle Vaccines from Biosafe Surrogates Prevent Acute Lethal Glanders in Mice. Vaccines (Basel) 2018 Jan 10;6(1).
          doi: 10.3390/vaccines6010005pubmed: 29320408google scholar: lookup
        4. Skyberg JA, Lacey CA. Hematopoietic MyD88 and IL-18 are essential for IFN-γ-dependent restriction of type A Francisella tularensis infection. J Leukoc Biol 2017 Dec;102(6):1441-1450.
          doi: 10.1189/jlb.4A0517-179Rpubmed: 28951422google scholar: lookup
        5. Saikh KU, Mott TM. Innate immune response to Burkholderia mallei. Curr Opin Infect Dis 2017 Jun;30(3):297-302.
          doi: 10.1097/QCO.0000000000000362pubmed: 28177960google scholar: lookup
        6. David J, Bell RE, Clark GC. Mechanisms of Disease: Host-Pathogen Interactions between Burkholderia Species and Lung Epithelial Cells. Front Cell Infect Microbiol 2015;5:80.
          doi: 10.3389/fcimb.2015.00080pubmed: 26636042google scholar: lookup
        7. Chiang CY, Ulrich RL, Ulrich MP, Eaton B, Ojeda JF, Lane DJ, Kota KP, Kenny TA, Ladner JT, Dickson SP, Kuehl K, Raychaudhuri R, Sun M, Bavari S, Wolcott MJ, Covell D, Panchal RG. Characterization of the murine macrophage response to infection with virulent and avirulent Burkholderia species. BMC Microbiol 2015 Nov 6;15:259.
          doi: 10.1186/s12866-015-0593-3pubmed: 26545875google scholar: lookup
        8. Robinson RT. IL12Rβ1: the cytokine receptor that we used to know. Cytokine 2015 Feb;71(2):348-59.
          doi: 10.1016/j.cyto.2014.11.018pubmed: 25516297google scholar: lookup
        9. Su L, Qi Y, Zhang M, Weng M, Zhang X, Su C, Shi HN. Development of fatal intestinal inflammation in MyD88 deficient mice co-infected with helminth and bacterial enteropathogens. PLoS Negl Trop Dis 2014 Jul;8(7):e2987.
          doi: 10.1371/journal.pntd.0002987pubmed: 25010669google scholar: lookup
        10. Olsen CH. Statistics in Infection and immunity revisited. Infect Immun 2014 Mar;82(3):916-20.
          doi: 10.1128/IAI.00811-13pubmed: 24343646google scholar: lookup
        11. Lafontaine ER, Zimmerman SM, Shaffer TL, Michel F, Gao X, Hogan RJ. Use of a safe, reproducible, and rapid aerosol delivery method to study infection by Burkholderia pseudomallei and Burkholderia mallei in mice. PLoS One 2013;8(10):e76804.
          doi: 10.1371/journal.pone.0076804pubmed: 24098563google scholar: lookup
        12. Silva EB, Dow SW. Development of Burkholderia mallei and pseudomallei vaccines. Front Cell Infect Microbiol 2013;3:10.
          doi: 10.3389/fcimb.2013.00010pubmed: 23508691google scholar: lookup
        13. Judy BM, Taylor K, Deeraksa A, Johnston RK, Endsley JJ, Vijayakumar S, Aronson JF, Estes DM, Torres AG. Prophylactic application of CpG oligonucleotides augments the early host response and confers protection in acute melioidosis. PLoS One 2012;7(3):e34176.
          doi: 10.1371/journal.pone.0034176pubmed: 22448290google scholar: lookup
        14. Szulc-Dąbrowska L, Biernacka Z, Koper M, Struzik J, Gieryńska M, Schollenberger A, Lasocka I, Toka FN. Differential Activation of Splenic cDC1 and cDC2 Cell Subsets following Poxvirus Infection of BALB/c and C57BL/6 Mice. Cells 2023 Dec 20;13(1).
          doi: 10.3390/cells13010013pubmed: 38201217google scholar: lookup
        Subscribe to our newsletter
        Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.