Yersinia Has a Tropism for B and T Cell Zones of Lymph Nodes That Is Independent of the Type III Secretion System

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Abstract
Pathogenic Yersinia have a pronounced tropism for lymphatic tissues and harbor a virulence plasmid that encodes a type III secretion system, pTTSS, that transports Yops into host cells. Yops are critical virulence factors that prevent phagocytosis by macrophages and neutrophils and Yersinia mutants lacking one or more Yops are defective for survival in lymphatic tissues, liver, and gastrointestinal tract. However, here we demonstrate that Y. pseudotuberculosis (Yptb) mutants lacking the pTTSS survived as well as or better than wild-type (WT) Yptb in the mesenteric lymph nodes (MLN). Infection with pTTSS mutants caused lymphadenitis with little necrosis, whereas infection with WT Yptb provoked lymphadenitis with multiple necrotic suppurative foci. Gentamicin protection assays and microscopic examination of the MLN revealed that pTTSS mutants resided extracellularly adjacent to B and T lymphocytes in the cortex and paracortex. WT Yptb was found extracellularly adjacent to neutrophils and macrophages in necrotic areas and adjacent to B and T lymphocytes in less-inflamed areas. To determine whether lymphocytes protected pTTSS mutants from phagocytic cells, Rag1−/− mice were infected with pTTSS mutants or WT Yptb. pTTSS mutants but not WT, were impaired for survival in MLN of Rag1−/− mice, suggesting that lymphocyte-rich regions constitute a protective niche for pTTSS mutants. Finally, we show that invasin and the chromosomally encoded TTSS were not required for Yptb survival in MLN. In summary, chromosomally encoded factors are sufficient for Yptb replication in the cortex and paracortex of MLN; the pTTSS enables Yersinia to survive within phagocyte-rich areas of lymph nodes, and spread to other tissues. The pathogenic bacteria, Yersinia, synthesize an apparatus called a type III secretion system, which transports bacterial proteins, Yops, from the bacteria into important immune cells, such as macrophages and neutrophils. Normally, macrophages and neutrophils control bacterial infections by ingesting the bacteria; however, the Yops inactivate these immune cells, which in turn, enable Yersinia to replicate extracellularly and cause disease in many types of tissues. Pathogenic Yersinia are frequently found in lymph nodes of infected hosts, and the Yops are important for the bacteria to replicate and cause disease in lymph nodes since Yersinia mutants that lack Yops do not colonize lymph nodes efficiently. Surprisingly, the authors found that Yersinia pseudotuberculosis lacking the type III secretion system colonizes the mesenteric lymph nodes and survives extracellularly next to lymphocytes. However, in mice lacking lymphocytes, the type III secretion mutants did not survive although wild-type Yersinia did. The authors' findings reveal that other bacterial factors are sufficient for mesenteric lymph node (MLN) colonization of Yersinia and that lymphocytes provide a protective niche for Yersinia strains lacking the type III secretion system. Potentially, these avirulent mutant strains, which persist for at least 5 d in the mesenteric lymph nodes, could be used as live attenuated vaccines to protect against Yersinia infections, or as carriers of other antigens.