The Effects of Vaccination and Immunity on Bacterial Infection Dynamics In Vivo

Abstract

Salmonella enterica infections are a significant global health issue, and development of vaccines against these bacteria requires an improved understanding of how vaccination affects the growth and spread of the bacteria within the host. We have combined in vivo tracking of molecularly tagged bacterial subpopulations with mathematical modelling to gain a novel insight into how different classes of vaccines and branches of the immune response protect against secondary Salmonella enterica infections of the mouse. We have found that a live Salmonella vaccine significantly reduced bacteraemia during a secondary challenge and restrained inter-organ spread of the bacteria in the systemic organs. Further, fitting mechanistic models to the data indicated that live vaccine immunisation enhanced both the bacterial killing in the very early stages of the infection and bacteriostatic control over the first day post-challenge. T-cell immunity induced by this vaccine is not necessary for the enhanced bacteriostasis but is required for subsequent bactericidal clearance of Salmonella in the blood and tissues. Conversely, a non-living vaccine while able to enhance initial blood clearance and killing of virulent secondary challenge bacteria, was unable to alter the subsequent bacterial growth rate in the systemic organs, did not prevent the resurgence of extensive bacteraemia and failed to control the spread of the bacteria in the body.

Clonal analysis of Salmonella-specific effector T cells reveals serovar-specific and cross-reactive T cell responses

“…Both B and T cell responses are known to contribute to protection in mouse models of Salmonella infection and vaccination. While B cells can confer the first line of protection against mucosal invasion and systemic dissemination, T cells are needed for the efficient clearance of Salmonella 11 . In particular, CD4 + T cells play a major protective role in mouse models of S. Typhimurium infection 12 , with CD8 + T cells not essential for acquired immunity to this pathogen 13 .…”

Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression

“…The migration is assumed to be constant over time in the model, however, previous research has shown that the number of bacteria in the blood exponentially decreases for iv inoculation. 99 Therefore, the migration we estimate to occur with a constant rate over one day, might have migrated only within the first few hours after inoculation. However, because we are not primarily interested in the migration rates themselves but rather the differences in migration rates between wildtype and knockout mice, this interpretational subtlety does not confound our conclusions.…”

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

“…Live attenuated vaccines saved countless lives and have helped to eradicate or control serious infectious diseases such as smallpox, measles, or polio . The advantages of live vaccines include easier application (eg, orally or nasally), the long‐term protection, and that booster injections are often dispensable . But what makes living microbes much more effective in comparison with their dead counterparts, and how does the immune system discriminate between live and inactivated vaccines?…”