Distinct climate influences on the risk of typhoid compared to invasive non-typhoid Salmonella disease in Blantyre, Malawi.

Invasive Salmonella diseases, both typhoid and invasive non-typhoidal Salmonella (iNTS), are seasonal bloodstream infections causing important morbidity and mortality globally in Africa. The reservoirs and transmission of both are not fully understood. We hypothesised that differences in the time-lagged relationships of rainfall or temperature with typhoid and iNTS incidence might infer differences in epidemiology. We assessed the dynamics of invasive Salmonella incidence over a 16-year period of surveillance, quantifying incidence peaks, seasonal variations, and nonlinear effects of rainfall and temperature exposures on the relative risks of typhoid and iNTS, using monthly lags. An increased relative risk of iNTS incidence was short-lasting but immediate after the onset of the rains, whereas that of typhoid was long-lasting but with a two months delayed start, implying a possible difference in transmission. The relative-risk function of temperature for typhoid was bimodal, with higher risk at both lower (with a 1 month lag) and higher (with a ≥4 months lag) temperatures, possibly reflecting the known patterns of short and long cycle typhoid transmission. In contrast, the relative-risk of iNTS was only increased at lower temperatures, suggesting distinct transmission mechanisms. Environmental and sanitation control strategies may be different for iNTS compared to typhoid disease

Global Burden of Invasive Nontyphoidal Salmonella Disease, 2010

Nontyphoidal Salmonella is a major cause of bloodstream infections worldwide, and HIV-infected persons and malaria-infected and malnourished children are at increased risk for the disease. We conducted a systematic literature review to obtain age group–specific, population-based invasive nontyphoidal Salmonella (iNTS) incidence data. Data were categorized by HIV and malaria prevalence and then extrapolated by using 2010 population data. The case-fatality ratio (CFR) was determined by expert opinion consensus. We estimated that 3.4 (range 2.1–6.5) million cases of iNTS disease occur annually (overall incidence 49 cases [range 30–94] per 100,000 population). Africa, where infants, young children, and young adults are most affected, had the highest incidence (227 cases [range 152–341] per 100,000 population) and number of cases (1.9 [range 1.3–2.9] million cases). An iNTS CFR of 20% yielded 681,316 (range 415,164–1,301,520) deaths annually. iNTS disease is a major cause of illness and death globally, particularly in Africa. Improved understanding of the epidemiology of iNTS is needed

What is the Source of Infections Causing Invasive Nontyphoidal <i>Salmonella</i> Disease?

Invasive nontyphoidal Salmonella (iNTS) disease is a clinical condition distinct from Salmonella gastroenteritis. With an overall case-fatality rate of 14.5%, iNTS remains a major cause of morbidity and mortality, particularly in sub-Saharan Africa. However, the sources of infections that lead to cases of iNTS remain unclear. Broadly, there are 2 hypotheses as to the source of infections: (i) transmission from a zoonotic reservoir, similar to other nontyphoidal salmonelloses; or (ii) person-to-person transmission. Here we review several recent studies that have asked, "What is the source of infections causing invasive nontyphoidal Salmonella disease?" Two studies reported isolates in the stool of household members of iNTS cases that were very closely related (Salmonella Enteritidis isolate. Therefore, we recommend that future studies test the hypothesis that iNTS is transmitted between people within the domestic environment. Further studies of food and water pathways are also warranted

Evasion of MAIT cell recognition by the African Salmonella Typhimurium ST313 pathovar that causes invasive disease

Mucosal-associated invariant T (MAIT) cells are innate T lymphocytes activated by bacteria that produce vitamin B2 metabolites. Mouse models of infection have demonstrated a role for MAIT cells in antimicrobial defense. However, proposed protective roles of MAIT cells in human infections remain unproven and clinical conditions associated with selective absence of MAIT cells have not been identified. We report that typhoidal and nontyphoidal Salmonella enterica strains activate MAIT cells. However, S. Typhimurium sequence type 313 (ST313) lineage 2 strains, which are responsible for the burden of multidrug-resistant nontyphoidal invasive disease in Africa, escape MAIT cell recognition through overexpression of ribB. This bacterial gene encodes the 4-dihydroxy-2-butanone-4-phosphate synthase enzyme of the riboflavin biosynthetic pathway. The MAIT cell-specific phenotype did not extend to other innate lymphocytes. We propose that ribB overexpression is an evolved trait that facilitates evasion from immune recognition by MAIT cells and contributes to the invasive pathogenesis of S. Typhimurium ST313 lineage 2

Typhoid Fever and Invasive Nontyphoid Salmonellosis, Malawi and South Africa

To determine the prevalence of invasive nontyphoid salmonellosis and typhoid fever in Malawi and South Africa, we compared case frequency and patient age distribution. Invasive nontyphoid salmonellosis showed a clear bimodal age distribution; the infection developed in women at a younger age than in men. Case frequency for typhoid fever was lower than for salmonellosis

Mathematical Modeling to Assess the Drivers of the Recent Emergence of Typhoid Fever in Blantyre, Malawi

Background. Multiyear epidemics of Salmonella enterica serovar Typhi have been reported from countries across eastern and southern Africa in recent years. In Blantyre, Malawi, a dramatic increase in typhoid fever cases has recently occurred, and may be linked to the emergence of the H58 haplotype. Strains belonging to the H58 haplotype often exhibit multidrug resistance and may have a fitness advantage relative to other Salmonella Typhi strains. Methods. To explore hypotheses for the increased number of typhoid fever cases in Blantyre, we fit a mathematical model to culture-confirmed cases of Salmonella enterica infections at Queen Elizabeth Central Hospital, Blantyre. We explored 4 hypotheses: (1) an increase in the basic reproductive number (R(0)) in response to increasing population density; (2) a decrease in the incidence of cross-immunizing infection with Salmonella Enteritidis; (3) an increase in the duration of infectiousness due to failure to respond to first-line antibiotics; and (4) an increase in the transmission rate following the emergence of the H58 haplotype. Results. Increasing population density or decreasing cross-immunity could not fully explain the observed pattern of typhoid emergence in Blantyre, whereas models allowing for an increase in the duration of infectiousness and/or the transmission rate of typhoid following the emergence of the H58 haplotype provided a good fit to the data. Conclusions. Our results suggest that an increase in the transmissibility of typhoid due to the emergence of drug resistance associated with the H58 haplotype may help to explain recent outbreaks of typhoid in Malawi and similar settings in Africa

High-Resolution Single Nucleotide Polymorphism Analysis Distinguishes Recrudescence and Reinfection in Recurrent Invasive Nontyphoidal Salmonella Typhimurium Disease

Invasive nontyphoidal Salmonella Typhimurium disease is a common and frequently recurrent cause of bacteremia across sub-Saharan Africa. We use high-resolution single nucleotide polymorphism analysis to distinguish between reinfection and recrudescence in disease recurrence within single individuals over time

The Human Transcriptome During Nontyphoid Salmonella and HIV Coinfection Reveals Attenuated NFκB-Mediated Inflammation and Persistent Cell Cycle Disruption

Background. Invasive nontyphoid Salmonella (iNTS) disease is common and severe in adults with human immunodeficiency virus (HIV) infection in Africa. We previously observed that ex vivo macrophages from HIV-infected subjects challenged with Salmonella Typhimurium exhibit dysregulated proinflammatory cytokine responses

The Fitness Landscape of the African \u3cem\u3eSalmonella\u3c/em\u3e Typhimurium ST313 Strain D23580 Reveals Unique Properties of the pBT1 Plasmid

We have used a transposon insertion sequencing (TIS) approach to establish the fitness landscape of the African Salmonella enterica serovar Typhimurium ST313 strain D23580, to complement our previous comparative genomic and functional transcriptomic studies. We used a genome-wide transposon library with insertions every 10 nucleotides to identify genes required for survival and growth in vitro and during infection of murine macrophages. The analysis revealed genomic regions important for fitness under two in vitro growth conditions. Overall, 724 coding genes were required for optimal growth in LB medium, and 851 coding genes were required for growth in SPI-2-inducing minimal medium. These findings were consistent with the essentiality analyses of other S. Typhimurium ST19 and S. Typhi strains. The global mutagenesis approach also identified 60 sRNAs and 413 intergenic regions required for growth in at least one in vitro growth condition. By infecting murine macrophages with the transposon library, we identified 68 genes that were required for intra-macrophage replication but did not impact fitness in vitro. None of these genes were unique to S. Typhimurium D23580, consistent with a high conservation of gene function between S. Typhimurium ST313 and ST19 and suggesting that novel virulence factors are not involved in the interaction of strain D23580 with murine macrophages. We discovered that transposon insertions rarely occurred in many pBT1 plasmid-encoded genes (36), compared with genes carried by the pSLT-BT virulence plasmid and other bacterial plasmids. The key essential protein encoded by pBT1 is a cysteinyl-tRNA synthetase, and our enzymological analysis revealed that the plasmid-encoded CysRSpBT1 had a lower ability to charge tRNA than the chromosomally-encoded CysRSchr enzyme. The presence of aminoacyl-tRNA synthetases in plasmids from a range of Gram-negative and Gram-positive bacteria suggests that plasmid-encoded essential genes are more common than had been appreciated