Abstract
Typhoid fever, caused by the human-restricted organism Salmonella enterica serovar Typhi (S. Typhi), constitutes a major global health problem. The development of improved attenuated vaccines is pressing, but delayed by the lack of appropriate preclinical models. Herein, we report that high levels of S. Typhi-responsive CD8+ T cells at baseline significantly correlate with an increased risk of disease in humans challenged with a high dose (~104 CFU) wild-type S. Typhi. Typhoid fever development was associated with higher multifunctional S. Typhi-responsive CD8+ T effector memory cells at baseline. Early decreases of these cells in circulation following challenge were observed in both S. Typhi-responsive integrin α4β7− and integrin α4β7+ CD8+ T effector memory (TEM) cells, suggesting their potential to home to both mucosal and extra-intestinal sites. Participants with higher baseline levels of S. Typhi-responsive CD8+ T memory cells had a higher risk of acquiring disease, but among those who acquired disease, those with a higher baseline responses took longer to develop disease. In contrast, protection against disease was associated with low or absent S. Typhi-responsive T cells at baseline and no changes in circulation following challenge. These data highlight the importance of pre-existing S. Typhi-responsive immunity in predicting clinical outcome following infection with wild-type S. Typhi and provide novel insights into the complex mechanisms involved in protective immunity to natural infection in a stringent human model with a high challenge dose. They also contribute important information on the immunological responses to be assessed in the appraisal and selection of new generation typhoid vaccines.
Highlights
Typhoid fever remains a major public health priority worldwide, with an estimated 21.7 million cases and 200,000 deaths per year [1]
Typhimurium “typhoid” mouse model has led to important insights into the role that various innate and adaptive effector mechanisms might play in protection from Salmonella infection, including production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α by CD8+ T cells [3]
We first explored whether CD8+ T cell responses at baseline in healthy participants challenged with wt S
Summary
Typhoid fever remains a major public health priority worldwide, with an estimated 21.7 million cases and 200,000 deaths per year [1]. Typhi) is a humanrestricted facultative intracellular Gram negative organism that causes typhoid fever [2]. A better understanding of the immunological correlates of protection against S. Typhi is required for the development of improved attenuated typhoid vaccines. Current knowledge is limited due to the difficulties associated with performing challenge studies in humans and the lack of an animal model that faithfully recapitulates human disease. Typhimurium “typhoid” mouse model has led to important insights into the role that various innate and adaptive effector mechanisms might play in protection from Salmonella infection, including production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α by CD8+ T cells [3]
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