Differential clearance and host-pathogen interactions of YopE- and YopK- YopL- Yersinia pestis in BALB/c mice

Abstract

This study characterized infections in BALB/c mice by the nonpigmented Yersinia pestis KIM and its derivatives lacking the low-Ca2+-response virulence plasmid pCD1 or failing to express selected yersinial outer membrane proteins (YOPs). The parent Y. pestis showed net growth in the spleen by 2 h and in the liver after 7 h; exponential growth in both the liver and spleen culminated in death of the mice starting on day 4, with total bacterial numbers of less than 108 in the blood, liver, and spleen together. The histopathology progressed from microabscesses to extensive coagulative necrosis unaccompanied by further immigration of inflammatory cells. This, together with the relatively low bacterial numbers, suggests a toxigenic mechanism. YopEor YopK-YopLyersiniae were cleared from the spleen but grew in the liver after an initial lag. Their growth was curbed after 1 to 2 days and entered a plateau that lasted 5 to 6 days; viable numbers then declined rapidly. This suggests that these Yopmutations distinguish, at least kinetically, between host responses in liver and spleen. Both strains caused acute inflammation in liver that evolved into structured lesions surrounded by progressively mononuclear inflammation suggestive of a granulomatous response. Accordingly, YOP E and YOPs K and L are necessary in the early days of the infection for net growth in spleen and prolonged growth in the liver; their absence is reflected morphologically by the emergence of cell-mediated immunity in the liver. The YopEand YopK-YopLmutants bound only slightly increased amounts of C3, suggesting that YOPs E, K, and L are protective through mechanisms other than interfering with the binding of complement.

ROS-inhibitory activity of YopE is required for full virulence of Yersinia in mice

“…YopE contributes to Yersinia spp. colonization of the small intestine, Peyer's patches (PP), mesenteric lymph node (MLN) and spleen of mice (Straley and Cibull, 1989;Black and Bliska, 2000;Logsdon and Mecsas, 2003;Trulzsch et al, 2004). In mice infected intravenously with Yersinia pestis, a YopE-b-lactamase fusion protein is detected in neutrophils, macrophages and dendritic cells of spleens (Marketon et al, 2005), indicating that YopE likely exerts its function directly on these cell types.…”

YopJ of Yersinia pseudotuberculosis is required for the inhibition of macrophage TNF‐α production and downregulation of the MAP kinases p38 and JNK

“…to inhibit the production of TNF-␣ in vivo. First, several studies have shown that wild-type strains of Yersinia, but not plasmid-defective mutants, suppress granuloma formation in animal lymphoid tissues (Lian et al, 1987;Straley and Cibull, 1989;Simonet et al, 1990). Secondly, there is evidence based on immunohistochemical analysis that wildtype Y. enterocolitica can inhibit TNF-␣ production in murine Peyer's patches (Beuscher et al, 1995).…”

YopK of Yersinia pseudotuberculosis controls translocation of Yop effectors across the eukaryotic cell membrane

“…YopK (YopQ) is a 21 kDa secreted protein that is required for virulence in the pathogenic Yersinia species (Straley and Bowmer, 1986;Mulder et al, 1989;Straley and Cibull, 1989;Holmströ m et al, 1995). Although a yopK mutant of Y. pseudotuberculosis was found to be avirulent, it was still able to induce cytotoxicity in HeLa cells and to inhibit phagocytosis by the mouse-macrophage cell line J774 .…”