Current understanding of innate immune cell dysfunction in childhood undernutrition

Frontiers in Immunology

Volumn 10, Issue , 2019, Pages

  Bourke, Claire D ^a,b   Jones, Kelsey D J ^c,d   Prendergast, Andrew J ^a,b  

^a QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^b Zvitambo Institute for Maternal and Child Health Research   (Zimbabwe)

^c UNIVERSITY OF OXFORD   (United Kingdom)

^d UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Children; Enteropathy; Infections; Inflammation; Innate immune cells; Low and middle income countries (LMIC); Malnutrition; Undernutrition

Indexed keywords

BIOLOGICAL MARKER;

ANIMAL; ANIMAL MODEL; BONE MARROW CELL; CHILD; COHORT ANALYSIS; COMPLICATION; DEVELOPING COUNTRY; DYSBIOSIS; EPITHELIUM CELL; GROWTH DISORDER; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOCOMPROMISED PATIENT; IMMUNOLOGICAL MEMORY; IMMUNOLOGY; INCOME; INFANT; INFLAMMATION; INNATE IMMUNITY; INTESTINE FLORA; INTESTINE MUCOSA; LYMPHOCYTE SUBPOPULATION; MICROBIOLOGY; NUTRITIONAL DISORDER; PATHOLOGY; PRESCHOOL CHILD; WASTING SYNDROME;

ANIMALS; BIOMARKERS; CHILD; CHILD NUTRITION DISORDERS; CHILD, PRESCHOOL; COHORT STUDIES; DEVELOPING COUNTRIES; DYSBIOSIS; EPITHELIAL CELLS; GASTROINTESTINAL MICROBIOME; GROWTH DISORDERS; HIV INFECTIONS; HUMANS; IMMUNITY, INNATE; IMMUNOCOMPROMISED HOST; IMMUNOLOGIC MEMORY; INCOME; INFANT; INFECTIONS; INFLAMMATION; INTESTINAL MUCOSA; LYMPHOCYTE SUBSETS; MODELS, ANIMAL; MYELOID CELLS; WASTING SYNDROME;

EID: 85071538007     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2019.01728     Document Type: Review

References (141)

1. Olofin I, McDonald CM, Ezzati M, Flaxman S, Black RE, Fawzi WW, et al. Associations of suboptimal growth with all-cause and cause-specific mortality in children under five years: a pooled analysis of ten prospective studies.PLoSONE.(2013)8:e64636.doi:10.1371/journal.pone.0064636
2. Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, et al. Maternal and child undernutrition and overweight in lowincome and middle-income countries. Lancet. (2013) 382:427–51. doi:10.1016/S0140-6736(13)60937-X
3. UNICEF, WHO, and W Bank. UNICEF-WHO-The World Bank: Joint child MalnutritionEstimates—LevelsandTrends–2019edition,(2019).
4. Osgood-Zimmerman A, Millear AI, Stubbs RW, Shields C, Pickering BV, EarlL,etal.MappingchildgrowthfailureinAfricabetween2000and2015. Nature.(2018)555:41.doi:10.1038/nature25760
5. Bourke CD, Berkley JA, Prendergast AJ. Immune dysfunction as a cause and consequence of malnutrition. Trends Immunol. (2016) 37:386–98. doi:10.1016/j.it.2016.04.003
6. Page AL, de Rekeneire N, Sayadi S, Aberrane S, Janssens AC, Rieux C, et al. Infections in children admitted with complicated severe acute malnutrition inNiger.PLoSONE.(2013)8:e68699.doi:10.1371/journal.pone.0068699
7. Berkley JA, Ngari M, Thitiri J, Mwalekwa L, Timbwa M, Hamid F, et al. Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial. Lancet Global Health. (2016) 4:e464– e473.doi:10.1016/S2214-109X(16)30096-1
8. AttiaS,VerslootCJ,VoskuijlW,vanVlietSJ,DiGiovanniV,ZhangL,etal. Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study. Am JClinNutr.(2016)104:1441–9.doi:10.3945/ajcn.116.130518
9. Njunge J, Gwela A, Kibinge NK, Ngari M, Nyamako L, Nyatichi E, et al. Biomarkers of post-discharge mortality among children with complicated severe acute malnutrition. Sci Rep. (2019) 9:5981. doi:10.1038/s41598-019-42436-y
10. Versloot CJ, Attia S, Bourdon C, Richardson SE, Potani I, Bandsma R, et al. Intestinal pathogen clearance in children with severe acute malnutrition is unrelated to inpatient morbidity. Clin Nutr ESPEN. (2018) 24:109–13. doi:10.1016/j.clnesp.2018.01.004
11. UNICEF, WHO, and W Bank, Levels and Trends in Child Malnutriton: UNICEF/WHO/World Bank Group Joint Child Malnutrition Estimates; Key findingsofthe2017edition,(2017).
12. Harper KM, Mutasa M, Prendergast AJ, Humphrey J, Manges AR. Environmental enteric dysfunction pathways and child stunting: a systematic review. PLoS Neglec Trop Dis. (2018) 12:e0006205. doi:10.1371/journal.pntd.0006205
13. Robertson RC, Manges AR, Finlay BB, Prendergast AJ. The human microbiome and child growth; first 1000 days and beyond. Trends Microbiol. (2018). 27:131–47. doi: 10.1016/j.tim.2018. 09.008
14. Golden M.Theeffectsofmalnutritioninthemetabolismofchildren.Transac R Soc Trop Med Hygiene. (1988) 82:3–6. doi: 10.1016/0035-9203(88)9 0245-3
15. Semba RD, Shardell M, Trehan I, Moaddel R, Maleta KM, Ordiz MI, et al. Metabolicalterationsinchildrenwithenvironmentalentericdysfunction.Sci Rep.(2016)6:28009.doi:10.1038/srep28009
16. PrendergastAJ,RukoboS,ChasekwaB,MutasaK,NtoziniR,MbuyaMNN, et al. Stunting is characterized by chronic inflammation in zimbabwean infants. PLoS ONE. (2014) 9:e86928. doi: 10.1371/journal.pone.00 86928
17. Jones KDJ, Hünten-Kirsch B, Laving AMR, Munyi CW, Ngari M, Mikusa J, etal.Mesalazineintheinitialmanagementofseverelyacutelymalnourished children with environmental enteric dysfunction: a pilot randomized controlledtrial.BMCMed.(2014)12:133.doi:10.1186/s12916-014-0133-2
18. Paul KH, Muti M, Chasekwa B, Mbuya MN, Madzima RC, Humphrey JH, et al. Complementary feeding messages that target cultural barriers enhance both the use of lipid-based nutrient supplements and underlying feeding practices to improve infant diets in rural Zimbabwe. Matern Child Nutr. (2012) 8:225–38. doi: 10.1111/j.1740-8709.2010. 00265.x
19. Prendergast AJ, Humphrey JH. The stunting syndrome in developing countries. Paediatr Int Child Health. (2014) 34:250–65. doi:10.1179/2046905514Y.0000000158
20. Prentice AM, Ward KA, Goldberg GR, Jarjou LM, Moore SE, Fulford AJ, et al. Critical windows for nutritional interventions against stunting. Am J ClinNutr.(2013)97:911–8.doi:10.3945/ajcn.112.052332
21. Shattuck-Heidorn H, Reiches MW, Prentice AM, Moore SE, Ellison PT. Energetics and the immune system: trade-offs associated with non-acute levels of CRP in adolescent Gambian girls. Evol Med Public Health. (2016) 2017:27–38.doi:10.1093/emph/eow034
22. Nairz M, Haschka D, Demetz E, Weiss G. Iron at the interface of immunity and infection. Front Pharmacol. (2014) 5:00152. doi:10.3389/fphar.2014.00152
23. Barratt MJ, Lebrilla C, Shapiro H-Y, Gordon JI. The gut microbiota, food science, and human nutrition: a timely marriage. Cell Host Microbe. (2017) 22:134–41.doi:10.1016/j.chom.2017.07.006
24. Netea MG, Schlitzer A, Placek K, Joosten LAB, Schultze JL. Innate and adaptive immune memory: an evolutionary continuum in the host’s response to pathogens. Cell Host Microbe. (2019) 25:13–26. doi:10.1016/j.chom.2018.12.006
25. Benn CS, Netea MG, Selin LK, Aaby P. A small jab – a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. (2013) 34:431–9.doi:10.1016/j.it.2013.04.004
26. ArtsRJ, Blok BA, van Crevel R, Joosten LA, Aaby P, Benn CS, et al. Vitamin Ainducesinhibitoryhistonemethylationmodificationsanddown-regulates trained immunity in human monocytes. J Leukocyte Biol. (2015) 98:129–36. doi:10.1189/jlb.6AB0914-416R
27. Ordovas-Montanes J, Dwyer DF, Nyquist SK, Buchheit KM, Vukovic M, DebC,etal.Allergicinflammatorymemoryinhumanrespiratoryepithelial progenitorcells.Nature.(2018)560:649–54.doi:10.1038/s41586-018-0449-8
28. Cassone A. The case for an expanded concept of trained immunity. mBio. (2018)9:e00570–18.doi:10.1128/mBio.00570-18
29. Naik S, Larsen SB, Gomez NC, Alaverdyan K, Sendoel A, Yuan S, et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature.(2017)550:475–80.doi:10.1038/nature24271
30. Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest. (2016) 126:23–31. doi:10.1172/JCI82224
31. Grondman I, Arts RJW, Koch RM, Leijte GP, Gerretsen J, Bruse N, et al. Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst. J Leukoc Biol. (2019) 106:11–25.doi:10.1002/JLB.5HI0119-018R
32. Shalova IN, Lim JY, Chittezhath M, Zinkernagel AS, Beasley F, Hernandez Jimenez E, et al. Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1alpha. Immunity. (2015)42:484–98.doi:10.1016/j.immuni.2015.02.001
33. van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol.(2017)17:407.doi:10.1038/nri.2017.36
34. Uchiyama R, Kupkova K, Shetty SJ, Linford AS, Pray-Grant MG, Wagar LE, et al. Histone H3 lysine 4 methylation signature associated with humanundernutrition.ProcNatlAcadSciUSA.(2018).115:E11264–E11273. doi:10.1073/pnas.1722125115
35. Lima AAM, Leite ÁM, Di Moura A, Lima NL, Soares AM, Abreu CB, et al. Determinantvariables,entericpathogenburden,gutfunctionandimmunerelated inflammatory biomarkers associated with childhood malnutrition: a prospective case-control study in Northeastern Brazil. Pediatric Infec Dis J. (2017)36:1177–85.doi:10.1097/INF.0000000000001569
36. ZhangL,VoskuijlW,MouzakiM,GroenAK,AlexanderJ,BourdonC,etal. Impaired bile acid homeostasis in children with severe acute malnutrition. PLoSOne.(2016)11:e0155143.doi:10.1371/journal.pone.0155143
37. Lee SE, Stewart CP, Schulze KJ, Cole RN, Wu LS, Yager JD, et al. The plasma proteome is associated with anthropometric status of undernourished nepalese school-aged children. J Nutr. (2017) 147:304–13. doi:10.3945/jn.116.243014
38. Guerrant RL, Leite AM, Pinkerton R, Medeiros PHQS, Cavalcante PA, DeBoer M, et al. Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in Northeast Brazil. PLoS ONE. (2016)11:e0158772.doi:10.1371/journal.pone.0158772
39. Kosek MN, Team M-E. Causal pathways from enteropathogens to environmental enteropathy: findings from the MAL-ED birth cohort study. EBioMed.(2017)18:109–17.doi:10.1016/j.ebiom.2017.02.024
40. Donowitz J, Cook H, Alam M, Tofail F, Kabir MM, Colgate ER, et al. Role of maternal health and infant inflammation in nutritional and neurodevelopmental outcomes of two-year-old Bangladeshi children. PLoS NeglTropDis.(2018)12:e0006363.doi:10.1371/journal.pntd.0006363
41. FarràsM,ChandweK,Mayneris-perxachsJ,AmadiB,Louis-AugusteJ,Besa E, et al. Characterizing the metabolic phenotype of intestinal villus blunting inZambianchildrenwithsevereacutemalnutritionandpersistentdiarrhea. PLoSOne.(2018)13:e0192092.doi:10.1371/journal.pone.0192092
42. Delamare G, Chandwe K, Lee W, Drake L, Frost G, Holmes E, et al. Health OutcomesinUndernutrition:TheRoleofNutrients,GutDysfunctionandthe GutMicrobiome(HUNGer)Consortium:WhitePaper,(2019).
43. Page AL, de Rekeneire N, Sayadi S, Aberrane S, Janssens AC, Dehoux M, et al. Diagnostic and prognostic value of procalcitonin and Creactive protein in malnourished children. Pediatrics. (2014) 133:e363–70. doi:10.1542/peds.2013-2112
44. RytterMJ,Babirekere-IrisoE,NamusokeH,ChristensenVB,MichaelsenKF, RitzC,etal.Riskfactorsfordeathinchildrenduringinpatient treatmentof severeacutemalnutrition:aprospectivecohortstudy.AmJClinNutr.(2017) 105:494–502.doi:10.3945/ajcn.116.140822
45. Rytter MJ, Kolte L, Briend A, Friis H, Christensen VB. The immune systeminchildrenwithmalnutrition–asystematicreview.PLoSONE.(2014) 9:e105017.doi:10.1371/journal.pone.0105017
46. Morgan G. What, if any, is the effect of malnutrition on immunological competence? Lancet. (1997) 349:1693–5. doi:10.1016/S0140-6736(96)12038-9
47. QiR,HuangY-T,LiuJ-W,SunY,SunX-F,HanH-J,etal.Globalprevalence of asymptomatic norovirus infection: a meta-analysis. EClinicalMed. (2018) 2:50–8.doi:10.1016/j.eclinm.2018.09.001
48. Piriou E, Asito AS, Sumba PO, Fiore N, Middeldorp JM, Moormann AM, et al. Early age at time of primary Epstein-Barr virus infection results in poorly controlled viral infection in infants from Western Kenya: clues to the etiology of endemic Burkitt lymphoma. J Infec Dis. (2012) 205:906–13. doi:10.1093/infdis/jir872
49. EibachD,KrumkampR,HahnA,SarpongN,Adu-SarkodieY,LevaA,etal. Application of a multiplex PCR assay for the detection of gastrointestinal pathogens in a rural African setting. BMC Infec Dis. (2016) 16:150. doi:10.1186/s12879-016-1481-7
50. Marie C, Ali A, Chandwe K, Petri WA, Kelly P. Pathophysiology of environmental enteric dysfunction and its impact on oral vaccine efficacy. MucosalImmunol.(2018)11:1290–8.doi:10.1038/s41385-018-0036-1
51. Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M, et al. Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med. (2009) 206:1395–408.doi:10.1084/jem.20082779
52. Ferrer-Admetlla A, Bosch E, Sikora M, Marquès-Bonet T, Ramírez-Soriano A, Muntasell A, et al. Balancing selection is the main force shaping the evolution of innate immunity genes. J Immunol. (2008) 181:1315–22. doi:10.4049/jimmunol.181.2.1315
53. Duchene J, Novitzky-Basso I, Thiriot A, Casanova-Acebes M, Bianchini M, Etheridge SL, et al. Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis. Nat Immunol. (2017) 18:753–61. doi:10.1038/ni.3763
54. Kerac M, Bunn J, Chagaluka G, Bahwere P, Tomkins A, Collins S, et al. Follow-upofpost-dischargegrowthandmortalityaftertreatmentforsevere acute malnutrition (FuSAM Study): a prospective cohort study PLoS One. (2014)9:e96030.doi:10.1371/journal.pone.0096030
55. Bwakura-Dangarembizi M, Amadi B, Bourke C, Robertson R, Mwapenya B, Chandwe K, et al. Health outcomes, pathogenesis and epidemiology of severe acute malnutrition (HOPE-SAM): rationale and methods of a longitudinal observational study. BMJ Open. (2018) 9:e023077. doi:10.1136/bmjopen-2018-023077
56. PrendergastAJ,BerejenaC,PimunduG,ShonhaiA,Bwakura-Dangarembizi M, Musiime V, et al. Inflammatory biomarkers in HIV-infected children hospitalizedforseveremalnutritioninUgandaandZimbabwe.AIDS.(2019) 33:1485–90.doi:10.1097/QAD.0000000000002231
57. DouglasSD,SchopferK.Phagocytefunctioninprotein-caloriemalnutrition. ClinExpImmunol.(1974)17:121–8.
58. Jose DG, Shelton M, Tauro GP, Belbin R, Hosking CS. Deficiency of immunologicalandphagocyticfunctioninaboriginalchildrenwithproteincaloriemalnutrition.MedJAustr.(1975)2:699–705.
59. Ford GW, Belbin R, Jose DG, Vorbach EA, Kirke DK. Growth and immune function in aboriginal children during recovery from malnutrition and infection. Austral N Zealand J Med. (1976) 6:321–8. doi:10.1111/imj.1976.6.4.321
60. Keusch GT, Urrutia JJ, Guerrero O, Castaneda G, and Smith H. Serum opsonic activity in acute protein-energy malnutrition. Bull World Health Organ.(1981)59:923–929.
61. Shilotri PG. Hydrogen peroxide production by leukocytes in proteincalorie malnutrition. Clin Chim Acta Int J Clin Chem. (1976) 71:511–4. doi:10.1016/0009-8981(76)90103-0
62. Rosen EU, Geefhuysen J, Anderson R, Joffe M, Rabson AR. Leucocyte functioninchildrenwithkwashiorkor.ArchDisChildhood.(1975)50:220–4. doi:10.1136/adc.50.3.220
63. Schopfer K, Douglas SD.Neutrophilfunctioninchildrenwithkwashiorkor. JLabClinMed.(1976)88:450–61.
64. Shousha S, Kamel K.Nitrobluetetrazoliumtestinchildrenwithkwashiorkor withacommentontheuseoflatexparticlesinthetest.JClinPathol.(1972) 25:494–7.doi:10.1136/jcp.25.6.494
65. Selvaraj RJ, Bhat KS. Phagocytosis and leucocyte enzymes in protein-calorie malnutrition.Biochem.J.(1972)127:255–9.doi:10.1042/bj1270255
66. Hughes SM, Amadi B, Mwiya M, Nkamba H, Tomkins A, and Goldblatt D. Dendritic cell anergy results from endotoxemia in severe malnutrition. JImmunol.(2009)183:2818–26.doi:10.4049/jimmunol.0803518
67. Singh VV, Chauhan SK, Rai R, Kumar A, Singh SM, Rai G. Decreased pattern recognition receptor signaling, interferon-signature, and bactericidal/permeability-increasing protein gene expression in cord blood of term low birth weight human newborns. PLoS ONE. (2013) 8:e62845.doi:10.1371/journal.pone.0062845
68. Heikens GT, Bunn J, Amadi B, Manary M, Chhagan M, Berkley JA, et al. Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet. (2008) 371:1305–7. doi:10.1016/S0140-6736(08)60565-6
69. Amadi B, Besa E, Zyambo K, Kaonga P, Louis-Auguste J, Chandwe K, et al. Impaired barrier function and autoantibody generation in malnutrition enteropathy in zambia. EBioMed. (2017) 22:191–9. doi:10.1016/j.ebiom.2017.07.017
70. Welsh FKS, Farmery SM, MacLennan K, Sheridan MB, Barclay GR, Guillou PJ,etal.Gutbarrierfunctioninmalnourishedpatients.Gut.(1998)42:396– 401.doi:10.1136/gut.42.3.396
71. Sturgeon JP, Bourke CD, Prendergast AJ.Childrenwithnoncriticalinfections have increased intestinal permeability, endotoxemia and altered innate immune responses. Pediatr Infec Dis J Online First. (2019) 38:741–8. doi:10.1097/INF.0000000000002311
72. Campbell DI, Murch SH, Elia M, Sullivan PB, Sanyang MS, Jobarteh B, et al. Chronic T cell-mediated enteropathy in rural west african children: relationship with nutritional status and small bowel function. Pediatric Res. (2003)54:306.doi:10.1203/01.PDR.0000076666.16021.5E
73. Liu J, Bolick DT, Kolling GL, Fu Z, Guerrant RL. Protein malnutrition impairsintestinalepithelialcellturnover,apotentialmechanismofincreased cryptosporidiosis in a murine model. Infec Immunity. (2016) 84:3542–9. doi:10.1128/IAI.00705-16
74. Ueno PM, Ori,á RB, Maier EA, Guedes M, Azevedo OGD, Wu D, et al. Alanyl-glutaminepromotesintestinalepithelialcellhomeostasisinvitroand inamurinemodelofweanlingundernutrition.AmJPhysiolGastrointestinal LiverPhysiol.(2011)301:G612–22.doi:10.1152/ajpgi.00531.2010
75. Vlasova AN, Paim FC, Kandasamy S, Alhamo MA, Fischer DD, Langel SN, et al. Protein malnutrition modifies innate immunity and gene expression by intestinal epithelial cells and human rotavirus infection in neonatal gnotobiotic pigs. mSphere. (2017) 2:e00046–17. doi:10.1128/mSphere.00046-17
76. Brown EM, Wlodarska M, Willing BP, Vonaesch P, Han J, Reynolds LA, et al. Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model. Nat Commun. (2015) 6:7806. doi:10.1038/ncomms8806
77. Yang WH, Heithoff DM, Aziz PV, Sperandio M, Nizet V, Mahan MJ, et al. Recurrent infection progressively disables host protection against intestinal inflammation. Science. (2017) 358:eaao5610. doi: 10.1126/science. aao5610
78. D’Addio F, La Rosa S, Maestroni A, Jung P, Orsenigo E, Ben Nasr M, et al. Circulating IGF-I and IGFBP3 levels control human colonic stem cell function and are disrupted in diabetic enteropathy. Cell Stem Cell. (2015) 17:486–98.doi:10.1016/j.stem.2015.07.010
79. Liang S, Guo X-K, Ou J, Huang R, Xue Q, and Hu X. Nutrient sensing by the intestinal epithelium orchestrates mucosal antimicrobial defense via translational control of Hes1. Cell Host Microbe. (2019) 25:706–18.e7. doi:10.1016/j.chom.2019.03.012
80. Soehnlein O, Steffens S, Hidalgo A, Weber C. Neutrophils as protagonists and targets in chronic inflammation. Nat Rev Immunol. (2017) 17:248. doi:10.1038/nri.2017.10
81. Kumar V, Bimal S, Singh SK, Chaudhary R, Das S, Lal C, et al. Leishmania donovani: dynamics of L. donovani evasion of innate immune cell attack due to malnutrition in visceral leishmaniasis. Nutrition. (2014) 30:449–58. doi:10.1016/j.nut.2013.10.003
82. Vasquez-Garibay E, Campollo-Rivas O, Romero-Velarde E, Mendez Estrada C, Garcia-Iglesias T, Alvizo-Mora JG, et al. Effect of renutrition on natural and cell-mediated immune response in infants with severe malnutrition. J Pediatric Gastroenterol Nutr. (2002) 34:296–301. doi:10.1097/00005176-200203000-00015
83. TakeleY,AdemE,GetahunM,TajebeF,KiflieA,HailuA,etal.Malnutrition in Healthy individuals results in increased mixed cytokine profiles, altered neutrophil subsets and function. PLoS ONE. (2016) 11:e0157919. doi:10.1371/journal.pone.0157919
84. Youinou PY, Garre MA, Menez JF, Boles JM, Morin JF, Pennec Y, et al. Folicaciddeficiencyandneutrophildysfunction.AmJMed.(1982)73:652–7. doi:10.1016/0002-9343(82)90406-5
85. Nayak KC, Sethi AS, Aggarwal TD, Chadda VS, Kumar KK. Bactericidal powerofneutrophilsinproteincaloriemalnutrition.IndJPediatrics.(1989) 56:371–7.doi:10.1007/BF02722303
86. Gause WC, Wynn TA, Allen JE. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol.(2013)13:607–14.doi:10.1038/nri3476
87. Bourke CD, Maizels RM, Mutapi F. Acquired immune heterogeneity and its sources in human helminth infection. Parasitology. (2011) 138:139–59. doi:10.1017/S0031182010001216
88. Yap P, Utzinger J, Hattendorf J, Steinmann P. Influence of nutrition on infection and re-infection with soil-transmitted helminths: a systematic review.ParasitesVectors.(2014)7:229.doi:10.1186/1756-3305-7-229
89. Vila CC, Saracino MP, Falduto GH, Calcagno MA, Venturiello SM, Pallaro AN, et al. Protein malnutrition impairs the immune control of Trichinella spiralisinfection.Nutrition.(2019)60:161–9.doi:10.1016/j.nut.2018.10.024
90. Lu H, Xie RD, Lin R, Zhang C, Xiao XJ, Li LJ, et al. Vitamin D-deficiency induceseosinophilspontaneousactivation.CellImmunol.(2017)322:56–63. doi:10.1016/j.cellimm.2017.10.003
91. Silverberg JI.Associationbetweenchildhoodatopicdermatitis,malnutrition, and low bone mineral density: a US population-based study. Pediatric AllergyImmunol.OfficPublicationEurSocPediatricAllergyImmunol.(2015) 26:54–61.doi:10.1111/pai.12315
92. Takemoto S, Yamamoto A, Tomonaga S, Funaba M, Matsui T. Magnesium deficiency induces the emergence of mast cells in the liver of rats. J Nutr Sci Vitaminol.(2013)59:560–3.doi:10.3177/jnsv.59.560
93. Faivre V, Lukaszewicz AC, Alves A, Charron D, Payen D, Haziot A. Accelerated in vitro differentiation of blood monocytes into dendritic cells in human sepsis. Clin Exp Immunol. (2007) 147:426–39. doi:10.1111/j.1365-2249.2006.03287.x
94. Leentjens J, Kox M, Koch RM, Preijers F, Joosten LA, van der Hoeven JG, et al. (2012). Reversal of immunoparalysis in humans in vivo. Am J Respir CritCareMed.186:838–45.doi:10.1164/rccm.201204-0645OC
95. Patel AA, Zhang Y, Fullerton JN, Boelen L, Rongvaux A, Maini AA, et al. The fate and lifespan of human monocyte subsets in steady state and systemicinflammation.JExpMed.(2017)214:1913–23.doi:10.1084/jem.201 70355
96. WongKL,YeapWH,TaiJJ,OngSM,DangTM,WongSC.Thethreehuman monocyte subsets: implications for health and disease. Immunol Res. (2012) 53:41–57.doi:10.1007/s12026-012-8297-3
97. PeixotoPaes-SilvaR,CorreiadeMacedoEM,OliveiraTomiyaMT,Machado Barbosa de Castro CM. Immune response of severe malnutrition children treated according to the protocol of the World Health Organization. Nutr Hospital.(2015)32:638–44.doi:10.3305/nh.2015.32.2.9048
98. Lotfy OA, Saleh WA, el-Barbari M. A study of some changes of cellmediated immunity in protein energy malnutrition. J Egyp Soc Parasitol. (1998)28:413–28.
99. Niiya T, Akbar SM, Yoshida O, Miyake T, Matsuura B, Murakami H, etal.Impaireddendriticcellfunctionresultingfromchronicundernutrition disrupts the antigen-specific immune response in mice. J Nutr. (2007) 137:671–5.doi:10.1093/jn/137.3.671
100. Hillyer LM, Woodward B. Acutely malnourished weanling mice administered Flt3 ligand can support a cell-mediated inflammatory response.Cytokine.(2019)113:39–49.doi:10.1016/j.cyto.2018.06.004
101. Ibrahim M, Barnes J, Osorio E, Anstead G, Jimenez FJ, Melby P. Deficiency of lymph node-resident Dendritic Cells (DCs) and dysregulation of DC chemoattractants in a malnourished mouse model of leishmania donovani infection.InfectImmun.(2014)82:3098–112.doi:10.1128/IAI.01778-14
102. Epelman S, Kory Lavine J, Gwendalyn Randolph J. Origin and functions of tissue macrophages. Immunity. (2014) 41:21–35. doi:10.1016/j.immuni.2014.06.013
103. Ibrahim MK, Zambruni M, Melby CL, Melby PC. Impact of childhood malnutrition on host defense and infection. Clin Microbiol Rev. (2017) 30:919–71.doi:10.1128/CMR.00119-16
104. Morais NGD, Costa TBD, Ferreira de Lima LF, Basílio DDS, Morais, NNGD, Paiva Cavalcanti MD, et al. Impact of neonatal malnutrition on expression TLR-9, NF-kB and cytokines of macrophages infected in vitro with methicillin resistant Staphylococcus aureus. Microb Pathogen. (2019) 132:254–60.doi:10.1016/j.micpath.2019.05.009
105. Kundu R, Theodoraki A, Haas CT, Zhang Y, Chain B, Kriston-Vizi J, et al. Cell-type-specific modulation of innate immune signalling by vitamin D in human mononuclear phagocytes. Immunology. (2017) 150:55–63. doi:10.1111/imm.12669
106. DesaiA,SmithLE,MbuyaMN,ChigumiraA,FundiraD,TavengwaNV.The SHINE trial infant feeding intervention: pilot study of effects on maternal learning and infant diet quality in rural zimbabwe. Clin Infect Dis. (2015) 61:S710–5.doi:10.1093/cid/civ846
107. Najera-Medina O, Valencia-Chavarria F, Cortes-Bejar C, Palacios Martinez M, Rodriguez-Lopez CP, Gonzalez-Torres MC. Infected malnourished children displayed changes in early activation and lymphocyte subpopulations. Acta paediatrica. (2017) 106:1499–506. doi:10.1111/apa.13930
108. Salimonu LS, Ojo-Amaize E, Williams AIO, Johnson AOK, Cooke AR, Adekunle FA, et al. Depressed natural killer cell activity in children with protein-calorie malnutrition. Clin Immunol Immunopathol. (1982) 24:1–7. doi:10.1016/0090-1229(82)90082-4
109. Salimonu LS, Ojo-Amaize E, Johnson AO, Laditan AA, Akinwolere OA, Wigzell H. Depressed natural killer cell activity in children with protein–calorie malnutrition. II Correction of the impaired activity after nutritional recovery. Cell Immunol. (1983) 82:210–5. doi:10.1016/0008-8749(83)90154-5
110. Gilchrist JJ, Rautanen A, Fairfax B, Mills TC, Naranbhai V, Trochet H, et al. RiskofnontyphoidalSalmonellabacteraemiainAfricanchildrenismodified bySTAT4.(2018)9:1014.doi:10.1038/s41467-017-02398-z
111. Di Francesco A, Di Germanio C, Bernier M, de Cabo R. A time to fast. Science.(2018)362:770–5.doi:10.1126/science.aau2095
112. Clinthorne JF, Beli E, Duriancik DM, Gardner EM. NK cell maturation and function in C57BL/6 mice are altered by caloric restriction. J Immunol. (2013)190:712–22.doi:10.4049/jimmunol.1201837
113. Ritz BW, Aktan I, Nogusa S, Gardner EM. Energy restriction impairs natural killer cell function and increases the severity of influenza infection in young adult male C57BL/6 mice. J Nutr. (2008) 138:2269–75. doi:10.3945/jn.108.093633
114. Clinthorne JF, Adams DJ, Fenton JI, Ritz BW, Gardner EM. Short-Term Re-feeding of previously energy-restricted C57BL/6 male mice restores body weight and body fat and attenuates the decline in natural killer cell function after primary influenza infection. J Nutr. (2010) 140:1495–501. doi:10.3945/jn.110.122408
115. Eberl G, Colonna M, Di Santo JP, McKenzie ANJ. Innate lymphoid cells: a new paradigm in immunology. Science. (2015) 348:aaa6566. doi:10.1126/science.aaa6566
116. Wilhelm C, Kharabi Masouleh S, Kazakov A. Metabolic regulation of innate lymphoid cell-mediated tissue protection-linking the nutritional state to barrier immunity. Front Immunol. (2017) 8:1742–1742. doi:10.3389/fimmu.2017.01742
117. Spencer SP, Wilhelm C, Yang Q, Hall JA, Bouladoux N, Boyd A, et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science. (2014) 343:432–7. doi:10.1126/science.1247606
118. Goverse G, Labao-Almeida C, Ferreira M, Molenaar R, Wahlen S, Konijn T, et al. Vitamin A controls the presence of RORgamma+ innate lymphoid cells and lymphoid tissue in the small intestine. J Immunol. 196:5148–55. doi:10.4049/jimmunol.1501106
119. Li S, Bostick JW, Ye J, Qiu J, Zhang B, Urban JFJr, et al. Aryl hydrocarbon receptor signaling cell intrinsically inhibits intestinal group 2 innate lymphoid cell function. Immunity. (2018) 49:915–28.e5. doi:10.1016/j.immuni.2018.09.015
120. WilhelmC,HarrisonOJ,SchmittV,PelletierM,SpencerSP,UrbanJFJr,etal. Critical role of fatty acid metabolism in ILC2-mediated barrier protection duringmalnutritionandhelminthinfection.JExpMed.(2016)213:1409–18. doi:10.1084/jem.20151448
121. Spencer SP, Belkaid Y. Dietary and commensal derived nutrients: shaping mucosal and systemic immunity. Curr Opin Immunol. (2012) 24:379–84. doi:10.1016/j.coi.2012.07.006
122. DiGiovanniV,BourdonC,WangDX,SeshadriS,SengaE,VerslootCJ,etal. Metabolomic changes in serum of children with different clinical diagnoses ofmalnutrition.JNutr.(2016)146:2436–44.doi:10.3945/jn.116.239145
123. Saleh M, Elson CO. Experimental inflammatory bowel disease: insights into the host-microbiota dialog. Immunity. (2011) 34:293–302. doi:10.1016/j.immuni.2011.03.008
124. Morlese JF, Forrester T, Del Rosario M, Frazer M, Jahoor F. Transferrin kinetics are altered in children with severe protein-energy malnutrition. J Nutr.(1997)127:1469–74.doi:10.1093/jn/127.8.1469
125. Hassanein E-SA, Assem HM, Rezk MM, El-Maghraby RM. Study of plasma albumin, transferrin, and fibronectin in children with mild to moderate protein-energy malnutrition. J Trop Pediatr. (1998) 44:362–5. doi:10.1093/tropej/44.6.362
126. Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, Cheng J, et al. Gut microbiomes of malawian twin pairs discordant for kwashiorkor. Science. (2013) 339:548–54. doi: 10.1126/science.12 29000
127. Wagner VE, Dey N, Guruge J, Hsiao A, Ahern PP, Semenkovich NP, et al. Effects of a gut pathobiont in a gnotobiotic mouse model of childhood undernutrition. Sci Transl Med. (2016) 8:366ra164. doi:10.1126/scitranslmed.aah4669
128. Mark Charbonneau R, O’Donnell D, Laura Blanton V, Sarah Totten M, Jasmine Davis CC, Michael Barratt J, et al. Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition. Cell.(2016)164:859–71.doi:10.1016/j.cell.2016.01.024
129. CoatesJC,ColaiezziBA,BellW,CharrondiereUR,LeclercqC.Overcoming dietary assessment challenges in low-income countries: technological solutionsproposedbytheInternationalDietaryDataExpansion(INDDEX) Project.Nutrients.(2017)9:289.doi:10.3390/nu9030289
130. DaoDT,Anez-BustillosL,ChoBS,LiZ,PuderM,GuraKM.Assessmentof micronutrient status in critically Ill children: challenges and opportunities. Nutrients.(2017)9:1185.doi:10.3390/nu9111185
131. Rakoff-Nahoum S, Kong Y, Kleinstein SH, Subramanian S, Ahern PP, Gordon JI, et al. Analysis of gene-environment interactions in postnatal development of the mammalian intestine. Proc Natl Acad Sci USA. (2015) 112:1929–36.doi:10.1073/pnas.1424886112
132. Schulfer AF, Battaglia T, Alvarez Y, Bijnens L, Ruiz VE, Ho M, et al. Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat Microbiol. (2018) 3:234–42. doi:10.1038/s41564-017-0075-5
133. Yasuda K, Oh K, Ren B, Tickle TL, Franzosa EA, Wachtman LM, et al. Biogeography of the intestinal mucosal and lumenal microbiome in the rhesus macaque. Cell Host Microbe. (2015) 17:385–91. doi:10.1016/j.chom.2015.01.015
134. Smith LE, Prendergast AJ, Turner PC, Mbuya MNN, Mutasa K, Kembo G, et al. The potential role of mycotoxins as a contributorto stunting in the SHINE trial. Clin Infec Dis. (2015) 61(Suppl. 7):S733–7. doi:10.1093/cid/civ849
135. Marin DE, Taranu I, Burlacu R, Tudor DS. Effects of zearalenone and its derivatives on the innate immune response of swine. Toxicon. (2010) 56:956–63.doi:10.1016/j.toxicon.2010.06.020
136. Mehrzad J, Klein G, Kamphues J, Wolf P, Grabowski N, Schuberth HJ. In vitro effects of very low levels of aflatoxin B(1) on free radicals production and bactericidal activity of bovine blood neutrophils. Vet Immunol Immunopathol. (2011) 141:16–25. doi: 10.1016/j.vetimm.2011. 01.010
137. Vandenbroucke V, Croubels S, Verbrugghe E, Boyen F, De Backer P, Ducatelle R, et al. The mycotoxin deoxynivalenol promotes uptake of Salmonella Typhimurium in porcine macrophages, associated with ERK1/2 induced cytoskeleton reorganization. Vet Res. (2009) 40:64. doi:10.1051/vetres/2009045
138. Bol-SchoenmakersM,BraberS,AkbariP,deGraaffP,vanRoestM,Kruijssen L, et al. The mycotoxin deoxynivalenol facilitates allergic sensitization to whey in mice. Mucosal Immunol. (2016) 9:1477–86. doi: 10.1038/mi. 2016.13
139. Dhabhar FS. The short-term stress response – Mother nature’s mechanism for enhancing protection and performance under conditions of threat, challenge, and opportunity. Front Neuroendocrinol. (2018) 49:175–92. doi:10.1016/j.yfrne.2018.03.004
140. Matare CR, Mbuya MNN, Pelto G, Dickin KL, Stoltzfus RJ. Assessing maternal capabilities in the SHINE trial: highlighting a hidden link in the causal pathway to child health. Clin Infect Dis.(2015)61(Suppl.7):S745–51. doi:10.1093/cid/civ851
141. Bourke CD, Gough EK, Pimundu G, Shonhai A, Berejena C, Terry L, et al. Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gutmicrobiome and immune activation. Sci Transl Med. (2019) 11:eaav0537.doi:10.1126/scitranslmed.aav0537