Invasive Nontyphoidal Salmonella Disease in Africa

James J. Gilchrist; Calman A. MacLennan

doi:10.1128/ecosalplus.ESP-0007-2018

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Invasive Nontyphoidal Salmonella Disease in Africa

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Authors: James J. Gilchrist¹, and Calman A. MacLennan³
Editors: Michael S. Donnenberg⁶, Andreas J. Bäumler⁷
VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: Department of Paediatrics, University of Oxford, Oxford, UK; 2: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; 3: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 4: Bill and Melinda Gates Foundation, London, UK; 5: Institute of Immunology and Immunotherapy, University of Birmingham, UK; 6: Virginia Commonwealth University School of Medicine, Richmond, VA; 7: University of California—Davis, Davis, CA
Received 13 June 2018 Accepted 14 November 2018 Published 18 January 2019
Address correspondence to Calman A. MacLennan, [email protected]

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Abstract:

Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis. Available epidemiological data indicate that iNTS disease is endemic in much of the region. Antimicrobial resistance is common and case fatality rates are high. There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease. However, the clinical presentation of iNTS disease is often with fever alone, so clinical diagnosis is impossible without blood culture confirmation. No vaccine is currently available, making this a priority area for global health research. Over the past ten years, it has emerged that iNTS disease in Africa is caused by distinct pathovars of Salmonella Typhimurium, belonging to sequence type ST313, and Salmonella Enteritidis. These are characterized by genome degradation and appear to be adapting to an invasive lifestyle. Investigation of rare patients with primary immunodeficiencies has suggested a key role for interferon gamma–mediated immunity in host defense against NTS. This concept has been supported by recent population-based host genetic studies in African children. In contrast, immunoepidemiological studies from Africa indicate an important role for antibody for protective immunity, supporting the development of antibody-inducing vaccines against iNTS disease. With candidate O-antigen–based vaccines due to enter clinical trials in the near future, research efforts should focus on understanding the relative contributions of antibody and cell-mediated immunity to protection against iNTS disease in humans.
Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

Article Version

This article is an updated version of the following content:

Invasive Salmonellosis in Humans

References

1. Doolittle RF, Feng DF, Tsang S, Cho G, Little E. 1996. Determining divergence times of the major kingdoms of living organisms with a protein clock. Science 271:470–477.

2. Giammanco GM, Pignato S, Mammina C, Grimont F, Grimont PAD, Nastasi A, Giammanco G. 2002. Persistent endemicity of Salmonella bongori 48:z(35):–in Southern Italy: molecular characterization of human, animal, and environmental isolates. J Clin Microbiol 40:3502–3505.

3. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. 2002. Typhoid fever. N Engl J Med 347:1770–1782.

4. Hohmann EL. 2001. Nontyphoidal salmonellosis. Clin Infect Dis 32:263–269.

5. Voetsch AC, Van Gilder TJ, Angulo FJ, Farley MM, Shallow S, Marcus R, Cieslak PR, Deneen VC, Tauxe RV, Emerging Infections Program FoodNet Working Group. 2004. FoodNet estimate of the burden of illness caused by nontyphoidal Salmonella infections in the United States. Clin Infect Dis 38(Suppl 3) :S127–S134.

6. Adak GK, Long SM, O’Brien SJ. 2002. Trends in indigenous foodborne disease and deaths, England and Wales: 1992 to 2000. Gut 51:832–841.

7. Reddy EA, Shaw AV, Crump JA. 2010. Community-acquired bloodstream infections in Africa: a systematic review and meta-analysis. Lancet Infect Dis 10:417–432.

8. Ao TT, Feasey NA, Gordon MA, Keddy KH, Angulo FJ, Crump JA. 2015. Global burden of invasive nontyphoidal Salmonella disease, 2010(1). Emerg Infect Dis 21:941–949.

9. Muthumbi E, Morpeth SC, Ooko M, Mwanzu A, Mwarumba S, Mturi N, Etyang AO, Berkley JA, Williams TN, Kariuki S, Scott JAG. 2015. Invasive Salmonellosis in Kilifi, Kenya. Clin Infect Dis 61(Suppl 4) :S290–S301.

10. Tabu C, Breiman RF, Ochieng B, Aura B, Cosmas L, Audi A, Olack B, Bigogo G, Ongus JR, Fields P, Mintz E, Burton D, Oundo J, Feikin DR. 2012. Differing burden and epidemiology of non-Typhi Salmonella bacteremia in rural and urban Kenya, 2006–2009. PLoS One 7:e31237. doi:10.1371/journal.pone.0031237.

11. Verani JR, Toroitich S, Auko J, Kiplang’at S, Cosmas L, Audi A, Mogeni OD, Aol G, Oketch D, Odiembo H, Katieno J, Wamola N, Onyango CO, Juma BW, Fields BS, Bigogo G, Montgomery JM. 2015. Burden of invasive nontyphoidal Salmonella disease in a rural and urban site in Kenya, 2009–2014. Clin Infect Dis 61(Suppl 4) :S302–S309.

12. Oneko M, Kariuki S, Muturi-Kioi V, Otieno K, Otieno VO, Williamson JM, Folster J, Parsons MB, Slutsker L, Mahon BE, Hamel MJ. 2015. Emergence of community-acquired, multidrug-resistant invasive nontyphoidal Salmonella disease in rural western Kenya, 2009–2013. Clin Infect Dis 61(Suppl 4) :S310–S316.

13. Mandomando I, Bassat Q, Sigaúque B, Massora S, Quintó L, Ácacio S, Nhampossa T, Vubil D, Garrine M, Macete E, Aide P, Sacoor C, Herrera-León S, Ruiz J, Tennant SM, Menéndez C, Alonso PL. 2015. Invasive Salmonella infections among children from rural Mozambique, 2001–2014. Clin Infect Dis 61(Suppl 4) :S339–S345.

14. Mtove G, Amos B, Nadjm B, Hendriksen ICE, Dondorp AM, Mwambuli A, Kim DR, Ochiai RL, Clemens JD, von Seidlein L, Reyburn H, Deen J. 2011. Decreasing incidence of severe malaria and community-acquired bacteraemia among hospitalized children in Muheza, north-eastern Tanzania, 2006–2010. Malar J 10:320. doi:10.1186/1475-2875-10-320.

15. Enwere G, Biney E, Cheung YB, Zaman SMA, Okoko B, Oluwalana C, Vaughan A, Greenwood B, Adegbola R, Cutts FT. 2006. Epidemiologic and clinical characteristics of community-acquired invasive bacterial infections in children aged 2-29 months in The Gambia. Pediatr Infect Dis J 25:700–705.

16. Marks F, et al. 2017. Incidence of invasive salmonella disease in sub-Saharan Africa: a multicentre population-based surveillance study. Lancet Glob Health 5:e310–e323.

17. Gilks CF. 1998. Acute bacterial infections and HIV disease. Br Med Bull 54:383–393.

18. Keddy KH, Musekiwa A, Sooka A, Karstaedt A, Nana T, Seetharam S, Nchabaleng M, Lekalakala R, Angulo FJ, Klugman KP, for GERMS-SA. 2017. Clinical and microbiological features of invasive nontyphoidal Salmonella associated with HIV-infected patients, Gauteng Province, South Africa. Medicine (Baltimore) 96:e6448. doi:10.1097/MD.0000000000006448.

19. Gordon MA, Banda HT, Gondwe M, Gordon SB, Boeree MJ, Walsh AL, Corkill JE, Hart CA, Gilks CF, Molyneux ME. 2002. Non-typhoidal salmonella bacteraemia among HIV-infected Malawian adults: high mortality and frequent recrudescence. AIDS 16:1633–1641.

20. Feasey NA, Houston A, Mukaka M, Komrower D, Mwalukomo T, Tenthani L, Jahn A, Moore M, Peters RPH, Gordon MA, Everett DB, French N, van Oosterhout JJ, Allain TJ, Heyderman RS. 2014. A reduction in adult blood stream infection and case fatality at a large African hospital following antiretroviral therapy roll-out. PLoS One 9:e92226. doi:10.1371/journal.pone.0092226.

21. Graham SM, Walsh AL, Molyneux EM, Phiri AJ, Molyneux ME. 2000. Clinical presentation of non-typhoidal Salmonella bacteraemia in Malawian children. Trans R Soc Trop Med Hyg 94:310–314.

22. Keddy KH, Sooka A, Musekiwa A, Smith AM, Ismail H, Tau NP, Crowther-Gibson P, Angulo FJ, Klugman KP, Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). 2015. Clinical and microbiological features of Salmonella meningitis in a South African population, 2003–2013. Clin Infect Dis 61(Suppl 4) :S272–S282.

23. Molyneux EM, Mankhambo LA, Phiri A, Graham SM, Forsyth H, Phiri A, Walsh AL, Wilson LK, Molyneux ME. 2009. The outcome of non-typhoidal salmonella meningitis in Malawian children, 1997–2006. Ann Trop Paediatr 29:13–22.

24. Molyneux EM, Walsh AL, Forsyth H, Tembo M, Mwenechanya J, Kayira K, Bwanaisa L, Njobvu A, Rogerson S, Malenga G. 2002. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 360:211–218.

25. Gordon MA, Graham SM, Walsh AL, Wilson L, Phiri A, Molyneux E, Zijlstra EE, Heyderman RS, Hart CA, Molyneux ME. 2008. Epidemics of invasive Salmonella enterica serovar enteritidis and S. enterica serovar typhimurium infection associated with multidrug resistance among adults and children in Malawi. Clin Infect Dis 46:963–969.

26. Okoro CK, Kingsley RA, Connor TR, Harris SR, Parry CM, Al-Mashhadani MN, Kariuki S, Msefula CL, Gordon MA, de Pinna E, Wain J, Heyderman RS, Obaro S, Alonso PL, Mandomando I, MacLennan CA, Tapia MD, Levine MM, Tennant SM, Parkhill J, Dougan G. 2012. Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa. Nat Genet 44:1215–1221.

27. Berkley JA, Lowe BS, Mwangi I, Williams T, Bauni E, Mwarumba S, Ngetsa C, Slack MPE, Njenga S, Hart CA, Maitland K, English M, Marsh K, Scott JAG. 2005. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med 352:39–47.

28. Scott JAG, Berkley JA, Mwangi I, Ochola L, Uyoga S, Macharia A, Ndila C, Lowe BS, Mwarumba S, Bauni E, Marsh K, Williams TN. 2011. Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study. Lancet 378:1316–1323.

29. Berkley JA, Bejon P, Mwangi T, Gwer S, Maitland K, Williams TN, Mohammed S, Osier F, Kinyanjui S, Fegan G, Lowe BS, English M, Peshu N, Marsh K, Newton CRJC. 2009. HIV infection, malnutrition, and invasive bacterial infection among children with severe malaria. Clin Infect Dis 49:336–343.

30. Brent AJ, Oundo JO, Mwangi I, Ochola L, Lowe B, Berkley JA. 2006. Salmonella bacteremia in Kenyan children. Pediatr Infect Dis J 25:230–236.

31. Bronzan RN, Taylor TE, Mwenechanya J, Tembo M, Kayira K, Bwanaisa L, Njobvu A, Kondowe W, Chalira C, Walsh AL, Phiri A, Wilson LK, Molyneux ME, Graham SM. 2007. Bacteremia in Malawian children with severe malaria: prevalence, etiology, HIV coinfection, and outcome. J Infect Dis 195:895–904.

32. Falay D, Kuijpers LMF, Phoba M-F, De Boeck H, Lunguya O, Vakaniaki E, Bertrand S, Mattheus W, Ceyssens P-J, Vanhoof R, Devlieger H, Van Geet C, Verheyen E, Ngbonda D, Jacobs J. 2016. Microbiological, clinical and molecular findings of non-typhoidal Salmonella bloodstream infections associated with malaria, Oriental Province, Democratic Republic of the Congo. BMC Infect Dis 16:271. doi:10.1186/s12879-016-1604-1.

33. Threlfall EJ, Hall ML, Rowe B. 1992. Salmonella bacteraemia in England and Wales, 1981–1990. J Clin Pathol 45:34–36.

34. Tsai M-H, Huang Y-C, Chiu C-H, Yen M-H, Chang L-Y, Lin P-Y, Lin T-Y. 2007. Nontyphoidal Salmonella bacteremia in previously healthy children: analysis of 199 episodes. Pediatr Infect Dis J 26:909–913.

35. Angelo KM, Reynolds J, Karp BE, Hoekstra RM, Scheel CM, Friedman C. 2016. Antimicrobial resistance among nontyphoidal Salmonella isolated from blood in the United States, 2003–2013. J Infect Dis 214:1565–1570.

36. Parry CM, Thomas S, Aspinall EJ, Cooke RPD, Rogerson SJ, Harries AD, Beeching NJ. 2013. A retrospective study of secondary bacteraemia in hospitalised adults with community acquired non-typhoidal Salmonella gastroenteritis. BMC Infect Dis 13:107. doi:10.1186/1471-2334-13-107.

37. Varma JK, Molbak K, Barrett TJ, Beebe JL, Jones TF, Rabatsky-Ehr T, Smith KE, Vugia DJ, Chang H-GH, Angulo FJ. 2005. Antimicrobial-resistant nontyphoidal Salmonella is associated with excess bloodstream infections and hospitalizations. J Infect Dis 191:554–561.

38. Mandal BK, Brennand J. 1988. Bacteraemia in salmonellosis: a 15 year retrospective study from a regional infectious diseases unit. BMJ 297:1242–1243.

39. Laupland KB, Schønheyder HC, Kennedy KJ, Lyytikäinen O, Valiquette L, Galbraith J, Collignon P, International Bacteremia Surveillance Collaborative. 2010. Salmonella enterica bacteraemia: a multi-national population-based cohort study. BMC Infect Dis 10:95. doi:10.1186/1471-2334-10-95.

40. Hsu R-B, Tsay Y-G, Chen RJ, Chu S-H. 2003. Risk factors for primary bacteremia and endovascular infection in patients without acquired immunodeficiency syndrome who have nontyphoid salmonellosis. Clin Infect Dis 36:829–834.

41. Fisker N, Vinding K, Molbak K, Hornstrup MK. 2003. Clinical review of nontyphoid Salmonella infections from 1991 to 1999 in a Danish county. Clin Infect Dis 37:e47–e52.

42. Shimoni Z, Pitlik S, Leibovici L, Samra Z, Konigsberger H, Drucker M, Agmon V, Ashkenazi S, Weinberger M. 1999. Nontyphoid Salmonella bacteremia: age-related differences in clinical presentation, bacteriology, and outcome. Clin Infect Dis 28:822–827.

43. Gordon MA. 2008. Salmonella infections in immunocompromised adults. J Infect 56:413–422.

44. Keddy KH, Takuva S, Musekiwa A, Puren AJ, Sooka A, Karstaedt A, Klugman KP, Angulo FJ. 2017. An association between decreasing incidence of invasive non-typhoidal salmonellosis and increased use of antiretroviral therapy, Gauteng Province, South Africa, 2003–2013. PLoS One 12:e0173091. doi:10.1371/journal.pone.0173091.

45. Feasey NA, Everett D, Faragher EB, Roca-Feltrer A, Kang’ombe A, Denis B, Kerac M, Molyneux E, Molyneux M, Jahn A, Gordon MA, Heyderman RS. 2015. Modelling the contributions of malaria, HIV, malnutrition and rainfall to the decline in paediatric invasive non-typhoidal Salmonella disease in Malawi. PLoS Negl Trop Dis 9:e0003979. doi:10.1371/journal.pntd.0003979.

46. Mackenzie G, Ceesay SJ, Hill PC, Walther M, Bojang KA, Satoguina J, Enwere G, D’Alessandro U, Saha D, Ikumapayi UNA, O’Dempsey T, Mabey DCW, Corrah T, Conway DJ, Adegbola RA, Greenwood BM. 2010. A decline in the incidence of invasive non-typhoidal Salmonella infection in The Gambia temporally associated with a decline in malaria infection. PLoS One 5:e10568. doi:10.1371/journal.pone.0010568.

47. Peters RPH, Zijlstra EE, Schijffelen MJ, Walsh AL, Joaki G, Kumwenda JJ, Kublin JG, Molyneux ME, Lewis DK. 2004. A prospective study of bloodstream infections as cause of fever in Malawi: clinical predictors and implications for management. Trop Med Int Health 9:928–934.

48. MacLennan CA, Msefula CL, Gondwe EN, Gilchrist JJ, Pensulo P, Mandala WL, Mwimaniwa G, Banda M, Kenny J, Wilson LK, Phiri A, MacLennan JM, Molyneux EM, Molyneux ME, Graham SM. 2017. Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: a prospective observational study. PLoS Negl Trop Dis 11:e0006027. doi:10.1371/journal.pntd.0006027.

49. Lane CR, LeBaigue S, Esan OB, Awofisyo AA, Adams NL, Fisher IST, Grant KA, Peters TM, Larkin L, Davies RH, Adak GK. 2014. Salmonella enterica serovar Enteritidis, England and Wales, 1945–2011. Emerg Infect Dis 20:1097–1104.

50. Feasey NA, Masesa C, Jassi C, Faragher EB, Mallewa J, Mallewa M, MacLennan CA, Msefula C, Heyderman RS, Gordon MA. 2015. Three epidemics of invasive multidrug-resistant Salmonella bloodstream infection in Blantyre, Malawi, 1998–2014. Clin Infect Dis 61(Suppl 4) :S363–S371.

51. Feasey NA, Cain AK, Msefula CL, Pickard D, Alaerts M, Aslett M, Everett DB, Allain TJ, Dougan G, Gordon MA, Heyderman RS, Kingsley RA. 2014. Drug resistance in Salmonella enterica ser. Typhimurium bloodstream infection, Malawi. Emerg Infect Dis 20:1957–1959.

52. Kalonji LM, Post A, Phoba M-F, Falay D, Ngbonda D, Muyembe J-J, Bertrand S, Ceyssens P-J, Mattheus W, Verhaegen J, Barbé B, Kuijpers L, Van Geet C, Lunguya O, Jacobs J. 2015. Invasive Salmonella infections at multiple surveillance sites in the Democratic Republic of the Congo, 2011–2014. Clin Infect Dis 61(Suppl 4) :S346–S353.

53. Kingsley RA, Msefula CL, Thomson NR, Kariuki S, Holt KE, Gordon MA, Harris D, Clarke L, Whitehead S, Sangal V, Marsh K, Achtman M, Molyneux ME, Cormican M, Parkhill J, MacLennan CA, Heyderman RS, Dougan G. 2009. Epidemic multiple drug resistant Salmonella Typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype. Genome Res 19:2279–2287.

54. Msefula CL, Kingsley RA, Gordon MA, Molyneux E, Molyneux ME, MacLennan CA, Dougan G, Heyderman RS. 2012. Genotypic homogeneity of multidrug resistant S. Typhimurium infecting distinct adult and childhood susceptibility groups in Blantyre, Malawi. PLoS One 7:e42085. doi:10.1371/journal.pone.0042085.

55. Paglietti B, Falchi G, Mason P, Chitsatso O, Nair S, Gwanzura L, Uzzau S, Cappuccinelli P, Wain J, Rubino S. 2013. Diversity among human non-typhoidal salmonellae isolates from Zimbabwe. Trans R Soc Trop Med Hyg 107:487–492.

56. Guiney DG, Fang FC, Krause M, Libby S, Buchmeier NA, Fierer J, Fang FC, Krause M, Libby S, Buchmeier NA, Fierer J. 1995. Biology and clinical significance of virulence plasmids in Salmonella serovars. Clin Infect Dis 21(Suppl 2) :S146–S151.

57. Fierer J, Krause M, Tauxe R, Guiney D. 1992. Salmonella typhimurium bacteremia: association with the virulence plasmid. J Infect Dis 166:639–642.

58. Kintz E, Davies MR, Hammarlöf DL, Canals R, Hinton JCD, van der Woude MW. 2015. A BTP1 prophage gene present in invasive non-typhoidal Salmonella determines composition and length of the O-antigen of the lipopolysaccharide. Mol Microbiol 96:263–275.

59. Yang J, Barrila J, Roland KL, Kilbourne J, Ott CM, Forsyth RJ, Nickerson CA. 2015. Characterization of the invasive, multidrug resistant non-typhoidal Salmonella strain D23580 in a murine model of infection. PLoS Negl Trop Dis 9:e0003839. doi:10.1371/journal.pntd.0003839.

60. Parsons BN, Humphrey S, Salisbury AM, Mikoleit J, Hinton JCD, Gordon MA, Wigley P. 2013. Invasive non-typhoidal Salmonella typhimurium ST313 are not host-restricted and have an invasive phenotype in experimentally infected chickens. PLoS Negl Trop Dis 7:e2487. doi:10.1371/journal.pntd.0002487.

61. Okoro CK, Barquist L, Connor TR, Harris SR, Clare S, Stevens MP, Arends MJ, Hale C, Kane L, Pickard DJ, Hill J, Harcourt K, Parkhill J, Dougan G, Kingsley RA. 2015. Signatures of adaptation in human invasive Salmonella Typhimurium ST313 populations from sub-Saharan Africa. PLoS Negl Trop Dis 9:e0003611. doi:10.1371/journal.pntd.0003611.

62. Carden S, Okoro C, Dougan G, Monack D. 2015. Non-typhoidal Salmonella Typhimurium ST313 isolates that cause bacteremia in humans stimulate less inflammasome activation than ST19 isolates associated with gastroenteritis. Pathog Dis 73:ftu023–ftu023.

63. Singletary LA, Karlinsey JE, Libby SJ, Mooney JP, Lokken KL, Tsolis RM, Byndloss MX, Hirao LA, Gaulke CA, Crawford RW, Dandekar S, Kingsley RA, Msefula CL, Heyderman RS, Fang FC. 2016. Loss of multicellular behavior in epidemic African nontyphoidal Salmonella enterica Serovar Typhimurium ST313 strain D23580. MBio 7:e02265. doi:10.1128/mBio.02265-15.

64. Hammarlöf DL, Kröger C, Owen SV, Canals R, Lacharme-Lora L, Wenner N, Schager AE, Wells TJ, Henderson IR, Wigley P, Hokamp K, Feasey NA, Gordon MA, Hinton JCD. 2018. Role of a single noncoding nucleotide in the evolution of an epidemic African clade of Salmonella. Proc Natl Acad Sci USA 115:E2614–E2623. [PubMed]

65. Carden SE, Walker GT, Honeycutt J, Lugo K, Pham T, Jacobson A, Bouley D, Idoyaga J, Tsolis RM, Monack D. 2017. Pseudogenization of the secreted effector gene sseI confers rapid systemic dissemination of S. Typhimurium ST313 within migratory dendritic cells. Cell Host Microbe 21:182–194. [PubMed]

66. Feasey NA, Hadfield J, Keddy KH, Dallman TJ, Jacobs J, Deng X, Wigley P, Barquist L, Langridge GC, Feltwell T, Harris SR, Mather AE, Fookes M, Aslett M, Msefula C, Kariuki S, Maclennan CA, Onsare RS, Weill F-X, Le Hello S, Smith AM, McClelland M, Desai P, Parry CM, Cheesbrough J, French N, Campos J, Chabalgoity JA, Betancor L, Hopkins KL, Nair S, Humphrey TJ, Lunguya O, Cogan TA, Tapia MD, Sow SO, Tennant SM, Bornstein K, Levine MM, Lacharme-Lora L, Everett DB, Kingsley RA, Parkhill J, Heyderman RS, Dougan G, Gordon MA, Thomson NR. 2016. Distinct Salmonella Enteritidis lineages associated with enterocolitis in high-income settings and invasive disease in low-income settings. Nat Genet 48:1211–1217. [PubMed]

67. Holt KE, Thomson NR, Wain J, Langridge GC, Hasan R, Bhutta ZA, Quail MA, Norbertczak H, Walker D, Simmonds M, White B, Bason N, Mungall K, Dougan G, Parkhill J. 2009. Pseudogene accumulation in the evolutionary histories of Salmonella enterica serovars Paratyphi A and Typhi. BMC Genomics 10:36. doi:10.1186/1471-2164-10-36. [PubMed]

68. Thomson NR, Clayton DJ, Windhorst D, Vernikos G, Davidson S, Churcher C, Quail MA, Stevens M, Jones MA, Watson M, Barron A, Layton A, Pickard D, Kingsley RA, Bignell A, Clark L, Harris B, Ormond D, Abdellah Z, Brooks K, Cherevach I, Chillingworth T, Woodward J, Norberczak H, Lord A, Arrowsmith C, Jagels K, Moule S, Mungall K, Sanders M, Whitehead S, Chabalgoity JA, Maskell D, Humphrey T, Roberts M, Barrow PA, Dougan G, Parkhill J. 2008. Comparative genome analysis of Salmonella Enteritidis PT4 and Salmonella Gallinarum 287/91 provides insights into evolutionary and host adaptation pathways. Genome Res 18:1624–1637. [PubMed]

69. Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR, Honoré N, Garnier T, Churcher C, Harris D, Mungall K, Basham D, Brown D, Chillingworth T, Connor R, Davies RM, Devlin K, Duthoy S, Feltwell T, Fraser A, Hamlin N, Holroyd S, Hornsby T, Jagels K, Lacroix C, Maclean J, Moule S, Murphy L, Oliver K, Quail MA, Rajandream MA, Rutherford KM, Rutter S, Seeger K, Simon S, Simmonds M, Skelton J, Squares R, Squares S, Stevens K, Taylor K, Whitehead S, Woodward JR, Barrell BG. 2001. Massive gene decay in the leprosy bacillus. Nature 409:1007–1011. [PubMed]

70. Parkhill J, Wren BW, Thomson NR, Titball RW, Holden MT, Prentice MB, Sebaihia M, James KD, Churcher C, Mungall KL, Baker S, Basham D, Bentley SD, Brooks K, Cerdeño-Tárraga AM, Chillingworth T, Cronin A, Davies RM, Davis P, Dougan G, Feltwell T, Hamlin N, Holroyd S, Jagels K, Karlyshev AV, Leather S, Moule S, Oyston PC, Quail M, Rutherford K, Simmonds M, Skelton J, Stevens K, Whitehead S, Barrell BG. 2001. Genome sequence of Yersinia pestis, the causative agent of plague. Nature 413:523–527. [PubMed]

71. Kariuki S, Revathi G, Gakuya F, Yamo V, Muyodi J, Hart CA. 2002. Lack of clonal relationship between non-typhi Salmonella strain types from humans and those isolated from animals living in close contact. FEMS Immunol Med Microbiol 33:165–171. [PubMed]

72. Kariuki S, Revathi G, Kariuki N, Kiiru J, Mwituria J, Muyodi J, Githinji JW, Kagendo D, Munyalo A, Hart CA. 2006. Invasive multidrug-resistant non-typhoidal Salmonella infections in Africa: zoonotic or anthroponotic transmission? J Med Microbiol 55:585–591. [PubMed]

73. Dione MM, Ikumapayi UN, Saha D, Mohammed NI, Geerts S, Ieven M, Adegbola RA, Antonio M. 2011. Clonal differences between non-typhoidal Salmonella (NTS) recovered from children and animals living in close contact in the Gambia. PLoS Negl Trop Dis 5:e1148. doi:10.1371/journal.pntd.0001148. [PubMed]

74. Ramachandran G, Aheto K, Shirtliff ME, Tennant SM. 2016. Poor biofilm-forming ability and long-term survival of invasive Salmonella Typhimurium ST313. Pathog Dis 74:ftw049. doi:10.1093/femspd/ftw049. [PubMed]

75. Okoro CK, Kingsley RA, Quail MA, Kankwatira AM, Feasey NA, Parkhill J, Dougan G, Gordon MA. 2012. High-resolution single nucleotide polymorphism analysis distinguishes recrudescence and reinfection in recurrent invasive nontyphoidal Salmonella typhimurium disease. Clin Infect Dis 54:955–963. [PubMed]

76. Klemm EJ, Gkrania-Klotsas E, Hadfield J, Forbester JL, Harris SR, Hale C, Heath JN, Wileman T, Clare S, Kane L, Goulding D, Otto TD, Kay S, Doffinger R, Cooke FJ, Carmichael A, Lever AM, Parkhill J, MacLennan CA, Kumararatne D, Dougan G, Kingsley RA. 2016. Emergence of host-adapted Salmonella Enteritidis through rapid evolution in an immunocompromised host. Nat Microbiol 1:15023. doi:10.1038/nmicrobiol.2015.23.

77. Gilchrist JJ, MacLennan CA, Hill AVS. 2015. Genetic susceptibility to invasive Salmonella disease. Nat Rev Immunol 15:452–463.

78. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088.

79. Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit VM, Monack DM. 2010. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med 207:1745–1755.

80. Muotiala A, Mäkelä PH. 1990. The role of IFN-gamma in murine Salmonella typhimurium infection. Microb Pathog 8:135–141.

81. Mastroeni P, Vazquez-Torres A, Fang FC, Xu Y, Khan S, Hormaeche CE, Dougan G. 2000. Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. II. Effects on microbial proliferation and host survival in vivo. J Exp Med 192:237–248.

82. Vidal S, Tremblay ML, Govoni G, Gauthier S, Sebastiani G, Malo D, Skamene E, Olivier M, Jothy S, Gros P. 1995. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J Exp Med 182:655–666.

83. Mastroeni P, Villarreal-Ramos B, Hormaeche CE. 1993. Adoptive transfer of immunity to oral challenge with virulent salmonellae in innately susceptible BALB/c mice requires both immune serum and T cells. Infect Immun 61:3981–3984.

84. Hess J, Ladel C, Miko D, Kaufmann SH. 1996. Salmonella typhimurium aroA-infection in gene-targeted immunodeficient mice: major role of CD4+ TCR-alpha beta cells and IFN-gamma in bacterial clearance independent of intracellular location. J Immunol 156:3321–3326.

85. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE, Godinez I, Sankaran S, Paixao TA, Gordon MA, Kolls JK, Dandekar S, Bäumler AJ. 2008. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 14:421–428.

86. Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, Levin M. 1996. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med 335:1941–1949.

87. Dorman SE, Picard C, Lammas D, Heyne K, van Dissel JT, Baretto R, Rosenzweig SD, Newport M, Levin M, Roesler J, Kumararatne D, Casanova J-L, Holland SM. 2004. Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet 364:2113–2121.

88. Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, AlSum Z, Al-Jumaah S, Al-Hajjar S, Frayha H, Alangari A, Al-Mousa H, Mobaireek KF, Ben-Mustapha I, Adimi P, Feinberg J, de Suremain M, Jannière L, Filipe-Santos O, Mansouri N, Stephan JL, Nallusamy R, Kumararatne DS, Bloorsaz MR, Ben-Ali M, Elloumi-Zghal H, Chemli J, Bouguila J, Bejaoui M, Alaki E, AlFawaz TS, Al Idrissi E, ElGhazali G, Pollard AJ, Murugasu B, Wah Lee B, Halwani R, Al-Zahrani M, Al Shehri MA, Al-Zahrani M, Bin-Hussain I, Mahdaviani SA, Parvaneh N, Abel L, Mansouri D, Barbouche R, Al-Muhsen S, Casanova JL. 2013. Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. Medicine (Baltimore) 92:109–122.

89. de Beaucoudrey L, et al. 2010. Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries. Medicine (Baltimore) 89:381–402.

90. Averbuch D, Chapgier A, Boisson-Dupuis S, Casanova J-L, Engelhard D. 2011. The clinical spectrum of patients with deficiency of signal transducer and activator of transcription-1. Pediatr Infect Dis J 30:352–355.

91. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T, Kaneko H, Kondo N, Tsuge I, Yachie A, Sakiyama Y, Iwata T, Bessho F, Ohishi T, Joh K, Imai K, Kogawa K, Shinohara M, Fujieda M, Wakiguchi H, Pasic S, Abinun M, Ochs HD, Renner ED, Jansson A, Belohradsky BH, Metin A, Shimizu N, Mizutani S, Miyawaki T, Nonoyama S, Karasuyama H. 2006. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25:745–755.

92. Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, Frucht DM, Christel K, von Bernuth H, Jouanguy E, Feinberg J, Durandy A, Senechal B, Chapgier A, Vogt G, de Beaucoudrey L, Fieschi C, Picard C, Garfa M, Chemli J, Bejaoui M, Tsolia MN, Kutukculer N, Plebani A, Notarangelo L, Bodemer C, Geissmann F, Israël A, Véron M, Knackstedt M, Barbouche R, Abel L, Magdorf K, Gendrel D, Agou F, Holland SM, Casanova JL. 2006. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med 203:1745–1759.

93. MacLennan C, Fieschi C, Lammas DA, Picard C, Dorman SE, Sanal O, MacLennan JM, Holland SM, Ottenhoff THM, Casanova J-L, Kumararatne DS. 2004. Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans. J Infect Dis 190:1755–1757.

94. Hanson EP, Monaco-Shawver L, Solt LA, Madge LA, Banerjee PP, May MJ, Orange JS. 2008. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol 122:1169–1177.e16.

95. Picard C, Casanova JL, Puel A. 2011. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clin Microbiol Rev 24:490–497.

96. Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. 2000. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore) 79:170–200.

97. Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, Malech HL, Holland SM, Ochs H, Quie P, Buckley RH, Foster CB, Chanock SJ, Dickler H. 2000. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 79:155–169.

98. Adeyokunnu AA, Hendrickse RG. 1980. Salmonella osteomyelitis in childhood. A report of 63 cases seen in Nigerian children of whom 57 had sickle cell anaemia. Arch Dis Child 55:175–184.

99. Williams TN, Uyoga S, Macharia A, Ndila C, McAuley CF, Opi DH, Mwarumba S, Makani J, Komba A, Ndiritu MN, Sharif SK, Marsh K, Berkley JA, Scott JAG. 2009. Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 374:1364–1370.

100. Pearson HA, Spencer RP, Cornelius EA. 1969. Functional asplenia in sickle-cell anemia. N Engl J Med 281:923–926.

101. Johnston RB Jr, Newman SL, Struth AG. 1973. An abnormality of the alternate pathway of complement activation in sickle-cell disease. N Engl J Med 288:803–808.

102. Cunnington AJ, de Souza JB, Walther M, Riley EM. 2011. Malaria impairs resistance to Salmonella through heme- and heme oxygenase-dependent dysfunctional granulocyte mobilization. Nat Med 18:120–127.

103. Ahmad DS, Esmadi M, Steinmann WC. 2013. Idiopathic CD4 Lymphocytopenia: spectrum of opportunistic infections, malignancies, and autoimmune diseases. Avicenna J Med 3:37–47.

104. Klein C, Lisowska-Grospierre B, LeDeist F, Fischer A, Griscelli C. 1993. Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome. J Pediatr 123:921–928.

105. Hermaszewski RA, Webster AD. 1993. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med 86:31–42.

106. Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, Conley ME, Cunningham-Rundles C, Ochs HD. 2006. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 85:193–202.

107. Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, Resnick I, Fasth A, Baer M, Gomez L, Sanders EA, Tabone MD, Plantaz D, Etzioni A, Monafo V, Abinun M, Hammarstrom L, Abrahamsen T, Jones A, Finn A, Klemola T, DeVries E, Sanal O, Peitsch MC, Notarangelo LD. 1997. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 131:47–54.

108. Ross SC, Densen P. 1984. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore) 63:243–273.

109. Geldmacher C, Schuetz A, Ngwenyama N, Casazza JP, Sanga E, Saathoff E, Boehme C, Geis S, Maboko L, Singh M, Minja F, Meyerhans A, Koup RA, Hoelscher M. 2008. Early depletion of Mycobacterium tuberculosis-specific T helper 1 cell responses after HIV-1 infection. J Infect Dis 198:1590–1598.

110. Dandekar S, George MD, Bäumler AJ. 2010. Th17 cells, HIV and the gut mucosal barrier. Curr Opin HIV AIDS 5:173–178.

111. MacLennan CA, Gilchrist JJ, Gordon MA, Cunningham AF, Cobbold M, Goodall M, Kingsley RA, van Oosterhout JJG, Msefula CL, Mandala WL, Leyton DL, Marshall JL, Gondwe EN, Bobat S, López-Macías C, Doffinger R, Henderson IR, Zijlstra EE, Dougan G, Drayson MT, MacLennan ICM, Molyneux ME. 2010. Dysregulated humoral immunity to nontyphoidal Salmonella in HIV-infected African adults. Science 328:508–512.

112. Schwarzer E, Turrini F, Ulliers D, Giribaldi G, Ginsburg H, Arese P. 1992. Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J Exp Med 176:1033–1041.

113. Nyakoe NK, Taylor RP, Makumi JN, Waitumbi JN. 2009. Complement consumption in children with Plasmodium falciparum malaria. Malar J 8:7. doi:10.1186/1475-2875-8-7.

114. Gondwe EN, Molyneux ME, Goodall M, Graham SM, Mastroeni P, Drayson MT, MacLennan CA. 2010. Importance of antibody and complement for oxidative burst and killing of invasive nontyphoidal Salmonella by blood cells in Africans. Proc Natl Acad Sci USA 107:3070–3075.

115. Lokken KL, Mooney JP, Butler BP, Xavier MN, Chau JY, Schaltenberg N, Begum RH, Müller W, Luckhart S, Tsolis RM. 2014. Malaria parasite infection compromises control of concurrent systemic non-typhoidal Salmonella infection via IL-10-mediated alteration of myeloid cell function. PLoS Pathog 10:e1004049. doi:10.1371/journal.ppat.1004049.

116. Mooney JP, Butler BP, Lokken KL, Xavier MN, Chau JY, Schaltenberg N, Dandekar S, George MD, Santos RL, Luckhart S, Tsolis RM. 2014. The mucosal inflammatory response to non-typhoidal Salmonella in the intestine is blunted by IL-10 during concurrent malaria parasite infection. Mucosal Immunol 7:1302–1311.

117. Kossodo S, Monso C, Juillard P, Velu T, Goldman M, Grau GE. 1997. Interleukin-10 modulates susceptibility in experimental cerebral malaria. Immunology 91:536–540.

118. Cunnington AJ, Njie M, Correa S, Takem EN, Riley EM, Walther M. 2012. Prolonged neutrophil dysfunction after Plasmodium falciparum malaria is related to hemolysis and heme oxygenase-1 induction. J Immunol 189:5336–5346.

119. Nyirenda TS, Nyirenda JT, Tembo DL, Storm J, Dube Q, Msefula CL, Jambo KC, Mwandumba HC, Heyderman RS, Gordon MA, Mandala WL. 2017. Loss of humoral and cellular immunity to invasive nontyphoidal Salmonella during current or convalescent Plasmodium falciparum infection in Malawian children. Clin Vaccine Immunol 24:e00057-17. doi:10.1128/CVI.00057-17. [PubMed]

120. Brewster DR, Manary MJ, Menzies IS, O’Loughlin EV, Henry RL. 1997. Intestinal permeability in kwashiorkor. Arch Dis Child 76:236–241. [PubMed]

121. Rytter MJ, Kolte L, Briend A, Friis H, Christensen VB. 2014. The immune system in children with malnutrition—a systematic review. PLoS One 9:e105017. doi:10.1371/journal.pone.0105017. [PubMed]

122. Schopfer K, Douglas SD. 1976. Neutrophil function in children with kwashiorkor. J Lab Clin Med 88:450–461. [PubMed]

123. Rikimaru T, Taniguchi K, Yartey JE, Kennedy DO, Nkrumah FK. 1998. Humoral and cell-mediated immunity in malnourished children in Ghana. Eur J Clin Nutr 52:344–350. [PubMed]

124. Prendergast AJ. 2015. Malnutrition and vaccination in developing countries. Philos Trans R Soc Lond B Biol Sci 370:20140141. doi:10.1098/rstb.2014.0141. [PubMed]

125. Nanton MR, Way SS, Shlomchik MJ, McSorley SJ. 2012. Cutting edge: B cells are essential for protective immunity against Salmonella independent of antibody secretion. J Immunol 189:5503–5507. [PubMed]

126. Browne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA, Kirk JL, Jutivorakool K, Zaman R, Ding L, Hsu AP, Patel SY, Olivier KN, Lulitanond V, Mootsikapun P, Anunnatsiri S, Angkasekwinai N, Sathapatayavongs B, Hsueh P-R, Shieh C-C, Brown MR, Thongnoppakhun W, Claypool R, Sampaio EP, Thepthai C, Waywa D, Dacombe C, Reizes Y, Zelazny AM, Saleeb P, Rosen LB, Mo A, Iadarola M, Holland SM. 2012. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med 367:725–734. [PubMed]

127. Mastroeni P, Arena A, Costa GB, Liberto MC, Bonina L, Hormaeche CE. 1991. Serum TNF alpha in mouse typhoid and enhancement of a Salmonella infection by anti-TNF alpha antibodies. Microb Pathog 11:33–38.

128. Peña-Sagredo JL, Fariñas MC, Perez-Zafrilla B, Cruz-Valenciano A, Crespo M, Joven-Ibañez B, Riera E, Manero-Ruiz FJ, Chalmeta I, Hernández MV, Rodríguez-Gómez M, Maíz O, López R, Cobo T, Pita J, Carmona L, Gonzalez-Gay MA, BIOBADASER and EMECAR Groups. 2009. Non-typhi Salmonella infection in patients with rheumatic diseases on TNF-alpha antagonist therapy. Clin Exp Rheumatol 27:920–925. [PubMed]

129. MacLennan CA, Gondwe EN, Msefula CL, Kingsley RA, Thomson NR, White SA, Goodall M, Pickard DJ, Graham SM, Dougan G, Hart CA, Molyneux ME, Drayson MT. 2008. The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children. J Clin Invest 118:1553–1562. [PubMed]

130. Nyirenda TS, Gilchrist JJ, Feasey NA, Glennie SJ, Bar-Zeev N, Gordon MA, MacLennan CA, Mandala WL, Heyderman RS. 2014. Sequential acquisition of T cells and antibodies to nontyphoidal Salmonella in Malawian children. J Infect Dis 210:56–64. [PubMed]

131. Gilchrist JJ, Rautanen A, Fairfax BP, Mills TC, Naranbhai V, Trochet H, Pirinen M, Muthumbi E, Mwarumba S, Njuguna P, Mturi N, Msefula CL, Gondwe EN, MacLennan JM, Chapman SJ, Molyneux ME, Knight JC, Spencer CCA, Williams TN, MacLennan CA, Scott JAG, Hill AVS. 2018. Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4. Nat Commun 9:1014. doi:10.1038/s41467-017-02398-z. [PubMed]

132. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O’Shea JJ. 2004. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev 202:139–156. [PubMed]

133. Wang L, Ko ER, Gilchrist JJ, Pittman KJ, Rautanen A, Pirinen M, Thompson JW, Dubois LG, Langley RJ, Jaslow SL, Salinas RE, Rouse DC, Moseley MA, Mwarumba S, Njuguna P, Mturi N, Williams TN, Scott JA, Hill AV, Woods CW, Ginsburg GS, Tsalik EL, Ko DC, Wellcome Trust Case Control Consortium 2, Kenyan Bacteraemia Study Group. 2017. Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis. Sci Adv 3:e1602096. doi:10.1126/sciadv.1602096. [PubMed]

134. Gilchrist JJ, Heath JN, Msefula CL, Gondwe EN, Naranbhai V, Mandala W, MacLennan JM, Molyneux EM, Graham SM, Drayson MT, Molyneux ME, MacLennan CA. 2016. Cytokine profiles during invasive nontyphoidal Salmonella disease predict outcome in African children. Clin Vaccine Immunol 23:601–609. [PubMed]

135. MacLennan CA, Martin LB, Micoli F. 2014. Vaccines against invasive Salmonella disease: current status and future directions. Hum Vaccin Immunother 10:1478–1493. [PubMed]

136. Feasey NA, Archer BN, Heyderman RS, Sooka A, Dennis B, Gordon MA, Keddy KH. 2010. Typhoid fever and invasive nontyphoid salmonellosis, Malawi and South Africa. Emerg Infect Dis 16:1448–1451. [PubMed]

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Abstract:

Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis. Available epidemiological data indicate that iNTS disease is endemic in much of the region. Antimicrobial resistance is common and case fatality rates are high. There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease. However, the clinical presentation of iNTS disease is often with fever alone, so clinical diagnosis is impossible without blood culture confirmation. No vaccine is currently available, making this a priority area for global health research. Over the past ten years, it has emerged that iNTS disease in Africa is caused by distinct pathovars of Salmonella Typhimurium, belonging to sequence type ST313, and Salmonella Enteritidis. These are characterized by genome degradation and appear to be adapting to an invasive lifestyle. Investigation of rare patients with primary immunodeficiencies has suggested a key role for interferon gamma–mediated immunity in host defense against NTS. This concept has been supported by recent population-based host genetic studies in African children. In contrast, immunoepidemiological studies from Africa indicate an important role for antibody for protective immunity, supporting the development of antibody-inducing vaccines against iNTS disease. With candidate O-antigen–based vaccines due to enter clinical trials in the near future, research efforts should focus on understanding the relative contributions of antibody and cell-mediated immunity to protection against iNTS disease in humans.

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Invasive Nontyphoidal Salmonella Disease in Africa

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Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

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Figure 1

Global distribution of invasive nontyphoidal Salmonella disease. High burden of disease is defined as >100 episodes per 100,000 person-years, and medium burden as 10 to 100 per 100,000 person-years. Reproduced from reference 135 : MacLennan CA, Martin LB, Micoli F. 2014. Hum Vaccin Immunother 10:1478–1493, with permission.

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Figure 1

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

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Figure 2

Variation in invasive nontyphoidal Salmonella disease incidence in Africa over time. Variation in iNTS disease incidence in African children at seven sites between 2008 and 2014 ( 9 , 11 , 13 , 14 , 44 , 45 ). Incidence per 100,000 person-years observation in children under 5 years.

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Figure 2

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

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Figure 3

Multidrug resistance and incidence of invasive nontyphoidal Salmonella disease. The relationship between the annual frequency of invasive disease caused by S. Enteritidis and the rate of S. Enteritidis multidrug resistance. Poisson regression, curve plotted in blue, demonstrates significant positive correlation between MDR rates among S. Enteritidis isolates and the incidence of S. Enteritidis disease (P = 1.9 × 10−4). Data extracted from reference 50 .

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Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

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Figure 4

Proposed effects of ST313 phenotypes on the pathogenesis of an invasive NTS infection. Numbered steps in the progression of disseminated infection are as follows: 1, epithelial invasion of luminal bacteria; 2, infection of submucosal tissue phagocytes; 3, proinflammatory cytokine-mediated recruitment of neutrophils to the infected gut; 4, migration of infected phagocytes to the mesenteric lymph nodes; 5, systemic dissemination takes place with intracellular and extracellular bacteremia; 6, establishment of new foci of infection systemically, in particular, in the reticuloendothelial system; 7, periodic recirculation, establishing new infectious foci. Text boxes highlight phenotypes thought to be associated with the ST313 pathovar that may enhance invasiveness. Figure reproduced from reference 77 : Gilchrist JJ, MacLennan CA, Hill AVS. 2015. Nat Rev Immunol 15:452–463, with permission.

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Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

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Figure 5

Cell-mediated immunity to intracellular nontyphoidal Salmonella infections. Following uptake of nontyphoidal Salmonella (NTS) by a host phagocyte, IL-12, and IL-23 (heterodimeric cytokines with one shared and one distinct subunit) are released. In the case of IL-12, signaling occurs via the IL-12 receptor complex on natural killer (NK) cells and CD4+ T cells, resulting in TH1 polarization and IFNγ release. IFNγ signaling at the IFNγ receptor complex on infected phagocytes results in STAT1 homodimerization and nuclear translocation, leading to phagocyte activation and control of the intracellular NTS infection. In the case of IL-23 signaling, signaling via the IL-23 receptor complex on CD4+ T cells results in TH17 polarization, facilitating gut mucosal immunity. Genes for which there is host genetic evidence for acting as a determinant of NTS susceptibility are colored according to whether that evidence is derived from the mouse model, human studies, or both. Reproduced from reference 77 , Nature Reviews Immunology, 15:452–463, by Nature Publishing Group.

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Figure 5

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

Tables

Invasive Nontyphoidal Salmonella Disease in Africa

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

/content/ecosalplus/10.1128/ecosalplus.ESP-0007-2018.T1

Table 1

Incidence estimates for iNTS disease in African children a

Table 1

Incidence estimates for iNTS disease in African children a

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

/content/ecosalplus/10.1128/ecosalplus.ESP-0007-2018.T2

Table 2

Clinical features and outcome of African children with invasive nontyphoidal Salmonella disease a

Table 2

Clinical features and outcome of African children with invasive nontyphoidal Salmonella disease a

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

/content/ecosalplus/10.1128/ecosalplus.ESP-0007-2018.T3

Table 3

Risk factors for invasive nontyphoidal Salmonella disease in African children a

Table 3

Risk factors for invasive nontyphoidal Salmonella disease in African children a

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

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Table 4

Risk factors for invasive nontyphoidal Salmonella disease in high-income settings a

Table 4

Risk factors for invasive nontyphoidal Salmonella disease in high-income settings a

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

/content/ecosalplus/10.1128/ecosalplus.ESP-0007-2018.T5

Table 5

Nontyphoidal Salmonella isolates causing invasive disease in Africa a

Table 5

Nontyphoidal Salmonella isolates causing invasive disease in Africa a

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Salmonella Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

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EcoSal Plus

Domain 8: Pathogenesis

Invasive Nontyphoidal Salmonella Disease in Africa

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References

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Tables

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Supplemental Material

Domain 8:
Pathogenesis