Helicobacter pylori causes clinical disease primarily in those individuals infected with a strain that carries the cytotoxin associated gene pathogenicity island (cagPAI). The cagPAI encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into epithelial cells and is required for induction of the pro-inflammatory cytokine, interleukin-8 (IL-8). CagY is an essential component of the H. pylori T4SS that has an unusual sequence structure, in which an extraordinary number of direct DNA repeats is predicted to cause rearrangements that invariably yield in-frame insertions or deletions. Here we demonstrate in murine and non-human primate models that immune-driven host selection of rearrangements in CagY is sufficient to cause gain or loss of function in the H. pylori T4SS. We propose that CagY functions as a sort of molecular switch or perhaps a rheostat that alters the function of the T4SS and “tunes” the host inflammatory response so as to maximize persistent infection.

The Helicobacter pylori babA gene encodes an outer membrane protein that mediates binding to fucosylated ABH antigens of the ABO blood group. We recently demonstrated that BabA expression is lost during experimental infection of rhesus macaques with H. pylori J166. We sought to test the generality of this observation by comparison of different H. pylori strains and different animal hosts. Challenge of macaques with H. pylori J99 yielded output strains that lost BabA expression, either by selection and then expansion of a subpopulation of J99 that had a single-base-pair mutation that encoded a stop codon or by gene conversion of babA with a duplicate copy of babB, a paralog of unknown function. Challenge of mice with H. pylori J166, which unlike J99, has 5 CT repeats in babA, resulted in loss of BabA expression due to phase variation. In the gerbil, Leb binding was lost by replacement of the babA gene that encoded Leb binding with a nonbinding allele that differed at six amino acid residues. Complementation experiments confirmed that change in these six amino acids of BabA was sufficient to eliminate binding to Leb and to gastric tissue. These results demonstrate that BabA expression in vivo is highly dynamic, and the findings implicate specific amino acid residues as critical for binding to fucosylated ABH antigens. We hypothesize that modification of BabA expression during H. pylori infection is a mechanism to adapt to changing conditions of inflammation and glycan expression at the epithelial surface.

Intrauterine infection is a major detriment for maternal-child health and occurs despite local mechanisms that protect the maternal-fetal interface from a wide variety of pathogens. The bacterial pathogen Listeria monocytogenes causes spontaneous abortion, stillbirth, and preterm labor in humans and serves as a model for placental pathogenesis. Given the unique immunological environment of the maternal-fetal interface, we hypothesized that virulence determinants with placental tropism are required for infection of this tissue. We performed a genomic screen in pregnant guinea pigs that led to the identification of 201 listerial genes important for infection of the placenta but not maternal liver. Among these genes was lmrg1778 (lmo2470), here named inlP, predicted to encode a secreted protein that belongs to the internalin family. InlP is conserved in virulent L. monocytogenes strains but absent in Listeria species that are nonpathogenic for humans. The intracellular life cycle of L. monocytogenes deficient in inlP (⌬inlP) was not impaired. In guinea pigs and mice, InlP increased the placental bacterial burden by a factor of 3 log 10 while having only a minor role in other maternal organs. Furthermore, the ⌬inlP strain was attenuated in intracellular growth in primary human placental organ cultures and trophoblasts. InlP is a novel virulence factor for listeriosis with a strong tropism for the placenta. This virulence factor represents a tool for the development of new modalities to prevent and treat infection-related pregnancy complications.T he immunological environment of the maternal-fetal interface is unique because protection of the fetus from pathogens has to be balanced with tolerance of the fetus by the maternal immune system (1, 2). How this is accomplished is one of the major enigmas of mammalian reproduction. Contrary to the long-standing hypothesis that the pregnant mother is immunocompromised (3), recent evidence suggests that the maternal immune system is intricately regulated during pregnancy, and the placenta is well guarded against infection (4-6). A few predominantly intracellular microbes are able to infect the placenta and cause pregnancy complications such as preterm labor, fetal damage, and death (5, 7). Given the unique immunological environment of the maternal-fetal interface and the inability of many pathogens to colonize the placenta, we hypothesized that specific virulence determinants are required for microbes to survive and replicate in this tissue.Listeria monocytogenes is a facultative intracellular bacterial pathogen that causes spontaneous abortion, preterm labor, and stillbirth in humans and other mammals (8, 9). There are ϳ1,600 human cases in the United States per year, and about one-third of these cases are pregnancy associated (10). L. monocytogenes is also extremely amenable to experimental analysis and therefore has been exploited over the past 5 decades to understand host-pathogen interactions of intracellular microbes (11, 12). L. monocytogenes can infect a wide variety ...

The increased occurrence of enrofloxacin-resistant E. coli from urine samples from dogs at the VMTH was not likely attributable to a single enrofloxacin-resistant clone but may be attributed to a collective increase in enrofloxacin resistance among uropathogenic E. coli in dogs in general.