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EcoSal Plus

Domain 8:

Pathogenesis

Invasive Nontyphoidal 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 Typhimurium, belonging to sequence type ST313, and 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 Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018

Article Version

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/content/journal/ecosalplus/10.1128/ecosalplus.ESP-0007-2018
2019-01-18
2019-04-25

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 Typhimurium, belonging to sequence type ST313, and 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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Figure 1

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. 10:1478–1493, with permission.

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018
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Figure 2

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.

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018
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Figure 3

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

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018
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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. 15:452–463, with permission.

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018
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Following uptake of nontyphoidal (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 T1 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 T17 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 , , 15:452–463, by Nature Publishing Group.

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

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Table 1

Incidence estimates for iNTS disease in African children

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018
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Table 2

Clinical features and outcome of African children with invasive nontyphoidal disease

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018
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Table 3

Risk factors for invasive nontyphoidal disease in African children

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018
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Table 4

Risk factors for invasive nontyphoidal disease in high-income settings

Citation: Gilchrist J, MacLennan C. 2019. Invasive Nontyphoidal Disease in Africa, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0007-2018
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Table 5

Nontyphoidal isolates causing invasive disease in Africa

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

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