Invasive Nontyphoidal Salmonella Disease in Africa

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.

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 : MacLennan CA, Martin LB, Micoli F. 2014. Hum Vaccin Immunother 10:1478–1493, with permission.

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.

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 .

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 : Gilchrist JJ, MacLennan CA, Hill AVS. 2015. Nat Rev Immunol 15:452–463, with permission.

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 T_H1 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 T_H17 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 , Nature Reviews Immunology, 15:452–463, by Nature Publishing Group.