My early publications directly addressed the deficit in mechanistic studies of neonatal-specific sepsis pathophysiology. First, I developed and characterized a model of polymicrobial sepsis that recapitulates the pathophysiology of septic peritonitis that is now the ‘gold standard’ of neonatal murine sepsis and is used around the world. The availability of this model allowed a direct comparison of the neonatal and adult host response. We showed neonates manifest a markedly reduced Th1-based inflammatory response to sepsis as compared to adults. We were the first to demonstrate that the adaptive immune system does not play a significant role in neonatal sepsis highlighting a dependence on innate immunity. Using specific TLR agonists, we demonstrated that innate immune priming (trained immunity) was associated with enhanced innate immune function and reduced neonatal sepsis mortality. We demonstrated that neonates, in contrast to adults, are dependent upon TRIF signaling for survival to Gram negative sepsis. We showed murine neonatal CD71erythroid cells, although immunomodulatory ex vivo, had no impact on murine neonatal sepsis survival. We uncovered a novel IL-18, IL-1, IL-17A axis that significantly contributes to sepsis mortality. Unexpectedly, we discovered that IL-1β is unnecessary for lethal neonatal sepsis; rather, IL-1α is the predominant IL-1R1–dependent determinant of mortality.

  1. Wynn JL, Scumpia PO, Delano MJ, O’Malley K, Abouhamze A, Ungaro R, Moldawer LL. (2007) Increased mortality and altered immunity in neonatal sepsis produced by generalize peritonitis. Shock.  2007 Dec;28(6):675-683. PMID: 17621256
  2. Wynn, JL, Scumpia, PO, Winfeld, RD, Delano, MJ, Barker, T, Satoh, M, Levy, O, Moldawer, LL. (2008). Defective innate immunity predisposes neonates to poor sepsis outcome, but is reversed by TLR agonists. Blood. 2008 Sep 1;112(5):1750-8. PMCID: PMC2518883
  3. Cuenca AG, Wynn JL, Kelly-Scumpia KM, Scumpia PO, Vila L, Delano MJ, Mathews CE, Wallet SM, Reeves WH, Behrns KE, Nacionales DC, Efron PA, Kunkel SL, Moldawer LL. (2011).  Critical role for CXC Ligand 10 (IP-10)/CXCR3 signaling in the murine neonatal response to sepsis. Infect Immun. 2011 Jul;79(7):2746-54. PMCID: PMC3191971
  4. Cuenca AG, Joiner DN, Gentile LF, Cuenca AL, Wynn JL, Kelly-Scumpia KM, Scumpia PO, Behrns KE, Efron PA, Nacionales D, Wallet SM, Reeves WH, Mathews CE, Moldawer LL. TRIF-Dependent Innate Immune Activation Is Critical for Survival to Neonatal Gram-Negative Sepsis. J Immunol. 2015 Feb 1;194(3):1169-77. PMID: 25548220, PMCID: PMC4297742.
  5. Wynn JL, Scumpia PO, Stocks BT, Romano-Keeler J, Alrifai MW, Liu JH, Kim AS, Alford CE, Matta P, Weitkamp JH, Moore DJ. Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality. J Immunol. 2015 Aug 1;195(3):1064-70. PMID: 26101326, PMCID PMC4506905.
  6. Wynn JL, Wilson CS, Scumpia PO, Liu J, Zharkikh I, Wong HR, Lahni P, Benjamin JT, Plosa EJ, Weitkamp JH, Hawiger J, Sherwood ER, Moldawer LL, Ungaro R, Baker HV, Lopez MC, McElroy SJ, Colliou N, Mohamadzadeh M, Moore DJ. Targeting IL-17A A attenuates neonatal sepsis mortality induced by IL-18. Proc Natl Acad Sci U S A. 2016 Apr 25. PMID 27114524. PMCID pending.
  7. Benjamin JT, Moore DJ, Bennett C, van der Meer R, Royce A, Loveland R, Wynn JL. IL1α and not IL-1β drives IL-1R1-dependent neonatal murine sepsis lethality. J Immune. October 2018. PMID 30305325

In parallel with the novel mechanistic investigations into the pathophysiology of sepsis in murine neonates described above, I have also led several studies of human neonates that have significantly improved our understanding neonatal-specific sepsis pathophysiology. Using genome-wide expression profiling on peripheral blood, we showed that human neonates manifest a unique host immune response among pediatric patients with septic shock. Our examination of the impact of candiduria in extremely low birth weight infants led to a change in practice. In a series of three investigations, we presented evidence that neonates do not manifest clinically-apparent immunoparalysis as seen in older children and adults after sepsis and that neonates with sepsis have altered vaccine responses manifested months after the episode. We demonstrated an effective method to safely reduce antimicrobial exposure in preterm infants. We have worked to align the efforts of neonatal sepsis investigators by working towards a consensus definition for neonatal sepsis. In parallel, we showed that timing of sepsis after birth is a critical determinant of the host response to sepsis in preterm neonates and showed the timing and progression of organ failure in neonates with fatal sepsis. Using transcriptomic approaches, we demonstrated unique profiles for patients with sepsis across the human life span, showed the sepsis MetaScore had great utility to identify infected neonates at the time of evaluation among those at risk, and highlighted the single-nucleotide polymorphisms associated with late-onset sepsis in extremely premature infants. Most recently, we developed and validated a neonatal sequential organ failure assessment (nSOFA) to serve as an operational definition of organ dysfunction specific to the preterm population.

  1. Wynn JL, Cvijanovich NZ, Allen GL, Thomas NJ, Freishtat RJ, Anas N, Meyer K, Checchia PA, Lin R, Shanley TP, Bigham MT, Wong HR. The influence of developmental age on the early transcriptomic response of children with septic shock. Mol Med. 2011;17(11-12):1146-56. PMID: 21738952, PMCID: PMC3321808
  2. Wynn JL, Tan S, Gantz MG, Das A, Goldberg RN, Adams-Chapman I, Stoll BJ, Shankaran S, Walsh MC, Auten KJ, Miller NA, Sánchez PJ, Higgins RD, Cotten CM, Smith PB, Benjamin Jr DK, Neonatal Research Network. Outcomes following candiduria in extremely low birth weight infants. Clin Infect Dis. 2012 Feb 1;54(3):331-9. PMID: 22144537,PMCID: PMC3258271
  3. Wynn JL, Hansen NI, Das A, Cotton CM, Goldberg RN, Sanchez PJ, Bell EF, Van Meurs KP, Carlo WA, Laptook AR, Higgins RD, Benjamin Jr DK, and Stoll BJ for the NICHD Neonatal Research Network (NRN). Early sepsis does not increase the risk of late sepsis in very low birth weight neonates. J Pediatr. 2013 May;162(5):942-8.e1-3. PMID: 23295144, PMCID: PMC3622770
  4. Lin CB, Hornik CP, Clark R, Cotten CM, Benjamin Jr. DK, Cohen-Wolkoweiz M, Smith PB, Wynn JL. Very low birth weight neonates who survive early-onset sepsis do not have an increased risk of developing late-onset sepsis. Early Hum Dev. 2012 Nov;88(11):905-9. PMID: 22840605, PMCID: PMC3462255
  5. Wynn JL, Li L, Cotten CM, Phelps DL, Shankaran S, Goldberg RN, Carlo WA, Van Meurs KP, Das A, Vohr BR, Higgins RD, Stoll BJ, and D’Angio CT for the NICHD NRN.  Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants. J Perinatol. 2013 Aug;33(8):613-8. PMID: 23370608, PMCID: PMC3722279
  6. Coggins SA*, Wynn JL*, Hill ML, Slaughter JC, Ozdas-Weitkamp A, L. Waitman LR, Carnevale RJ, Matta A, Weitkamp JH. Use of a computerized C-reactive protein based sepsis evaluation in the NICU: A five-year experience. PLoS One. 2013 Nov 11;8(11):e78602. PMID: 24244325, PMCID: PMC3823853 *co-first authors
  7. Coggins SA, Weitkamp JH, Grunswald L, Reese J, Walsh W, Wynn JL. Heart Rate Characteristic index monitoring for blood stream infection in the NICU: A 3-year experience. Arch Dis Child Fetal Neonatal Ed. 2015 Oct 30. PMID: 26518312, PMCID: PMC4851911
  8. Wynn JL, Wong HR, Shanley TP, Bizzarro M, Saiman L, Polin RA. Time for a neonatal–specific consensus definition for sepsis. Pediatr Crit Care Med. 2014 Apr 18. PMID: 24751791, PMCID: PMC4087075.
  9. Benitz WE, Wynn JL, Polin RA. Reappraisal of Guidelines for Management of Neonates with Suspected Early-Onset Sepsis. J Pediatr. 2015 Apr;166(4):1070-4. PMID: 25641240. PMCID pending.
  10. Wynn JL, Guthrie SO, Wong HR, Lahni P, Ungaro R, Lopez MC, Baker HV, Moldawer LL. Post-natal age is a critical determinant of the neonatal host response to sepsis. Mol Med. 2015 Jun 2. PMID: 26052715, PMCID pending.
  11. Wynn JL, Kelly MS, Benjamin DK, Clark R, Greenberg R, Benjamin DK Jr, Smith PB. Timing of Multi-Organ Dysfunction Among Premature Infants with Fatal Sepsis. Am J Perinatol. 2016 Dec 6. [Epub ahead of print]. PMID: 27923248. PMCID pending.
  12. Raymond SL, Lopez C, Baker HV, Larson SD, Sweeney TE, Moldawer LL, Wynn JL. Unique transcriptomic response to sepsis is observed among patients of different age groups. PLoS One. 2017 Sep 8;12(9):e0184159. PMID: 28886074, PMCID: PMC5590890
  13. Srinivasan L, Page G, Kirpalani H, Murray JC, Das A, Higgins RD, Wynn JL, Cotten CM, Carlo WA, Bell EF, Goldberg RN, Schibler K, Sood BG, Stevenson DK, Stoll BJ, Van Meurs KP, Johnson KJ, McDonald SA, Zaterka-Baxter KM, Kennedy KA, Sánchez PJ, Duara S, Walsh MC, Shankaran S, Korones SB, Finer NN, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Genome Wide Association Study of Sepsis in Extremely Premature Infants. Arch Dis Child Fetal Neonatal Ed. 2017 Sep;102(5):F439-F445. PMID: 28283553. PMCID: PMC5563277
  14. Sweeney, TE*, Wynn JL*, Cernada M, Serna E, Wong HR, Moldawer LL, Vento M, Khatri P. Validation of the Sepsis MetaScore for Diagnosis of Neonatal Sepsis. J Pediatric Infect Dis Soc. 2018 May 15;7(2):129-135. PMID: 28419265, PMCID: PMC5954302
    *co-first authors
  15. Wynn JL, Polin RA. Development and Validation of a Neonatal Sequential Organ Failure Assessment Score. Pediatr Res. 2019 Aug 8. doi: 10.1038/s41390-019-0517-2. [Epub ahead of print] PMID: 31394566

In addition to the contributions described above, with a number of collaborators at UF, Cincinnati Children’s Hospital, and Vanderbilt, I directly addressed the impact of multiple facets of the immune system on the outcome of sepsis including CD4+ T cells, T regulatory cells, B cells, myeloid suppressor cells, type I interferon signaling, MMP-8, sepsis-associated PDA, and nuclear transport blockade.

  1. Scumpia PO, Delano MJ, Kelly-Scumpia KM, Weinstein JS, Wynn JL, Winfield RD, Xia C, Chung CS, Ayala A, Atkinson MA, Reeves WH, Clare-Salzler MJ, Moldawer LL. Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis. Blood. 2007 Nov 15;110(10):3673-81. PMCID: PMC2077315
  2. Scumpia PO, Delano MJ, Kelly KM, O’Malley K, Efron PA, McAuliffe PF, Brusko T, Ungaro R, Barker T, Wynn JL, Atkinson MA, Reeves WH, Clare Salzler MJ, and Moldawer LL.  Increased natural CD4+CD25+ regulatory T cells and their suppressor activity does not contribute to mortality in murine polymicrobial sepsis. J Immunol 2006 Dec 1;177(11):7943-9. PMID: 17114466
  3. Kelly-Scumpia KM, Scumpia PO, Weinstein JS, Delano MJ, Cuenca AG, Nacionales DC, Wynn JL, Lee PY, Kumagai Y, Efron PA, Akira S, Wasserfall C, Atkinson MA, and Moldawer LL. B cells enhance early innate immune responses during bacterial sepsis. J Exp Med. 2011 Aug 1;208(8):1673-82. PMCID: PMC3149216
  4. Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia K, O’Malley K, Wynn JL, Antonenko S, Al-Quran S, Swam R, Chung C, Atkinson MA, Ramphal R, Gabrilovich D, Reeves W, Ayala A, Philips J, Laface D, Heyworth P, Clare-Salzer M, Moldawer LL. MyD88-Dependent expansion of an immature Gr1+CD11b+ population induces T-cell suppression and TH2 polarization in sepsis. J Ex Med. 2007 Jun 11;204(6):1463-74. PMCID: PMC2118626
  5. Kelly-Scumpia KM, Scumpia PO, Delano MJ, Weinstein J, Cuenca AG, Wynn JL, Moldawer LL. Type I interferon signaling in hematopoietic cells is required for survival in murine polymicrobial sepsis by regulating CXCL10. J Exp Med. 2010 Feb 15;207(2):319-26. PMCID: PMC2822595
  6. Kelly-Scumpia KM, Scumpia PO, Weinstein JS, Delano MJ, Cuenca AG, Nacionales DC, Wynn JL, Lee PY, Kumagai Y, Efron PA, Akira S, Wasserfall C, Atkinson MA, and Moldawer LL. B cells enhance early innate immune responses during bacterial sepsis. J Exp Med. 2011 Aug 1;208(8):1673-82. PMCID: PMC3149216
  7. Vucovich M, Cotton R, Shelton E, Goettel J, Ehinger N, Poole S, Brown N, Wynn JL, Paria B, Slaughter J, Clark R, Rojas M, and Reese J. Amnioglycoside-Mediated Relaxation of the Ductus Arteriosus in Sepsis-Associated PDA. Am J Physiol Heart Circ Physiol. 2014 Sep 1;307(5):H732-40. PMID: 24993047, PMCID: PMC4187398
  8. Atkinson SJ, Varisco BM, Sandquist M, Daly MN, Klingbeil L, Kuethe JW, Midura EF, Caldwell CC, Harmon K, Lahni P, Piraino G, Hake P, Zingarelli B, Mortensen JE, Wynn JL, Wong HR. Matrix metalloproteinase-8 (MMP-8) augments bacterial clearance in juvenile mice. Mol Med. 2016 Aug 8;22. PMID: 27506554, PMCID: PMC5072408
  9. Veach RA, Liu Y, Zienkiewicz J, Wylezinski LS, Boyd K, Wynn JL, Hawiger J. Survival, Bacterial Clearance and Thrombocytopenia are Improved in Polymicrobial Sepsis by Targeting Nuclear Transport Shuttles Importins α5 and β1. PLoS One. 2017 Jun 19;12(6):e0179468. PMID: 28628637, PMCID: PMC5476269