Cellular and Cytokine Responses to Salmonella enterica Serotype Typhi Proteins in Patients with Typhoid Fever in Bangladesh

Abstract

We assessed interferon-gamma (IFN-γ) responses via enzyme-linked immunosorbent spot (ELISPOT) to a number of S. Typhi antigens in samples from humans with S. Typhi bacteremia and typhoid fever in Bangladesh. Compared with responses in healthy endemic zone controls, there were significantly increased IFN-γ responses at the time of clinical presentation (acute phase) and at convalescence 14–28 days later. The majority (80–90%) of IFN-γ expressing T cells were CD4+. We observed a significant increase in interleukin-17 (IL-17) positive CD4 + T cells at convalescent versus acute stage of infection using an intracellular cytokine staining assay. We also found that stimulated peripheral blood mononuclear cells (PBMCs) produced significantly increased levels of a number of cytokines at the convalescent versus acute phase of infection, including IFN-γ, MIP-1β, sCD40L, TNF-β, IL-13, and IL-9. These results suggest that S. Typhi antigens induce a predominantly Th1 response, but that elevations in other cytokines may be modulatory.

Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a

“…Of importance, PBMC obtained from S. Typhi-infected convalescent patients showed an increase in the production of β-chemokines (i.e., RANTES, MIP-1α, MIP-1β) in response to S. Typhi antigens [51]. Recently, we have shown the induction of Salmonella -cross-reactive MF CD8+ MIP-1β+ cells following immunization with Ty21a, suggesting an important role of MIP-1β in host immunity to Salmonella [30].…”

“…Recently IL-17-producing CD4+ T helper cells (Th-17) cells have been described as a distinct cell lineage that contributes to host defense against various microbes including Salmonella [37, 52]. In addition to Th1 cells, IL-17A and IL-22 producing cells play a critical role in preventing intestinal dissemination of Salmonella in animal models of infections [37]; in humans, production of IL-17 by CD4+ cells were reported among convalescent but not acute stage of typhoid fever patients [51]. We also previously reported that immunization with Ty21a elicited only small increases in IL-17+ CD8+ T cells [30].…”

Live Attenuated Human Salmonella Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity

“…Upon infection of phagocytic and professional antigen presenting cells (i.e. macrophages and dendritic cells) Salmonella antigens are processed and presented for stimulation of CD4 and CD8 T cells, resulting in activation and differentiation of T helper (Th) 1, Th2 and Th17 cells(60–62), as well as T cytotoxic (Tc)(63, 64) and T regulatory (Treg) cells(65), which are believed to be essential for protection against disease (66). Natural infection also results in the induction of Th1 type CD4+ and CD8+ T cells that produce high levels of IFN-γ during acute and convalescent phases of infection(60).…”

“…Natural infection also results in the induction of Th1 type CD4+ and CD8+ T cells that produce high levels of IFN-γ during acute and convalescent phases of infection(60). Peripheral blood cells isolated from typhoid patients and stimulated with bacterial antigens produced higher levels of other cytokines including IFN-γ, MIP-1β, sCD40L, TNF-β, IL-13, and IL-9 during convalescence, which are likely required for an effective immune response that leads to bacterial clearance(62). Recent studies have also shown that natural infection results in the upregulation of the gut-homing integrin α4β7 on T regulatory cells (65), which may play a role in downregulating proinflammatory CD4 and CD8 T cell responses.…”

Genome divergence and increased virulence of outbreak associated Salmonella enterica subspecies enterica serovar Heidelberg

“…Transcription of saf fimbrial genes has been found in blood samples from patients infected with Salmonella ser. Typhi [33] and Salmonella ser. Paratyphi A [34], which is indicative of a role for these genes in the human pathogenesis.…”