Dissemination of Persistent Intestinal Bacteria via the Mesenteric Lymph Nodes Causes Typhoid Relapse

Abstract

Enteric pathogens can cause relapsing infections in a proportion of treated patients, but greater understanding of this phenomenon is hindered by the lack of appropriate animal models. We report here a robust animal model of relapsing primary typhoid that initiates after apparently successful antibiotic treatment of susceptible mice. Four days of enrofloxacin treatment were sufficient to reduce bacterial loads below detectable levels in all major organs, and mice appeared otherwise healthy. However, any interruption of further antibiotic therapy allowed renewed fecal shedding and renewed bacterial growth in systemic tissues to occur, and mice eventually succumbed to relapsing infection. In vivo imaging of luminescent Salmonella identified the mesenteric lymph nodes (MLNs) as a major reservoir of relapsing infection. A magnetic-bead enrichment strategy isolated MLN-resident CD11b؉ Gr-1 ؊ monocytes associated with low numbers of persistent Salmonella. However, the removal of MLNs increased the severity of typhoid relapse, demonstrating that this organ serves as a protective filter to restrain the dissemination of bacteria during antibiotic therapy. Together, these data describe a robust animal model of typhoid relapse and identify an important intestinal phagocyte subset involved in protection against the systemic spread of enteric infection.

Cross-Differentiation from the CD8 Lineage to CD4 T Cells in the Gut-Associated Microenvironment with a Nonessential Role of Microbiota

“…Mock surgery or surgical removal of MLN were conducted on 13- to 14-day old OT1 + Rag o mice with a procedure similar to previously reported (Griffin et al, 2011). Thymectomy was conducted according to a standard procedure.…”

Protective Host Immune Responses to Salmonella Infection

“…Additional studies point to an important protective role of the MLN during infection since removal of this lymphoid tissue correlates with increased bacterial loads and severe immunopathology in liver of infected mice [24]. It has also been reported that mice lacking MLNs are more susceptible to relapsing typhoid following antibiotic treatment, further suggesting the host response within MLNs functions to inhibit the dissemination of bacteria [50]. …”

Identification of a common immune signature in murine and human systemic Salmonellosis

“…Many features of human Salmonellosis are reproduced in the murine model, including the route of intestinal entry, tissue and cellular tropism of the bacteria, the activation of innate and adaptive immunity, and development of chronic bacterial shedding and relapsing disease (24)(25)(26)(27)(28)(29). However, as mice can only be infected with nontyphoidal strains of Salmonella, it is not clear whether this model is relevant for understanding typhoid or disseminated NTS infection.…”