Interleukin-8 Receptor 2 (IL-8R2)-Deficient Mice Are More Resistant to Pulmonary Coccidioidomycosis than Control Mice.

The pathology of human coccidioidomycosis is granulomatous inflammation with many neutrophils surrounding ruptured spherules, but the chemotactic pathways that draw neutrophils into the infected tissues are not known. We previously showed that formalin-killed spherules (FKS) stimulate mouse macrophages to secret macrophage inflammatory protein 2 (MIP-2), which suggested that CXC ELR+ chemokines might be involved in neutrophil recruitment To test that hypothesis, we intranasally infected interleukin-8R2 (IL-8R2) ()-deficient mice on a BALB/c background with RS. IL-8R2-deficient mice had fewer neutrophils in infected lungs than controls, but unexpectedly the IL-8R2-deficient mice had fewer organisms in their lungs than the control mice.

APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Pneumonia.

Coccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, and , that are endemic in the southwestern United States and other areas in the Western Hemisphere. Chronic cavitary pulmonary infections and extrapulmonary sites of infection are very difficult to treat and often require lifelong azole therapy. APX001A is the first in a new class of broad-spectrum antifungal agents that inhibit Gwt1, an enzyme which is required for cell wall localization of glycosylphosphatidylinositol (GPI)-anchored mannoproteins in fungi.

Myeloid Differentiation Factor 88 and Interleukin-1R1 Signaling Contribute to Resistance to Coccidioides immitis.

Rodents are a natural host for the dimorphic pathogenic fungi and , and mice are a good model for human infection. Humans and rodents both express Dectin-1 and Toll-like receptor 2 (TLR2) on myeloid cells, and those receptors collaborate to maximize the cytokine/chemokine responses to spherules (the tissue form of the fungi) and to formalin-killed spherules (FKS). We showed that Dectin-1 is necessary for resistance to pulmonary coccidioidomycosis, but the importance of TLR2 is uncertain.

Salmonella-induced Diarrhea Occurs in the Absence of IL-8 Receptor (CXCR2)-Dependent Neutrophilic Inflammation.

Background: Gastroenteritis is the most common manifestation of nontyphoidal Salmonella enterica infections, but little is known about the pathogenesis of diarrhea in this infection

Methods: To determine whether polymorphonuclear neutrophils (PMNs) are required for diarrhea for Salmonella colitis, we infected kanamycin-pretreated interleukin 8R (IL-8R) mutant mice and controls, both with nonmutant Slc11a1 (Nramp1, ItyR). We compared the 2 mouse strains for increases in fecal water content (diarrhea) 3 days after infection, changes in expression of ion transporters in colonic epithelial cells, proliferation of epithelial cells, and severity of infection as measured by colony-forming units (CFUs).

Results: The IL-8R knockout mice had fewer PMNs in the colon but the other variables we measured were unaffected except for an increase in CFUs in the colon.

Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis.

Background & Aims: Salmonella enterica serovar Typhimurium is an enteropathogen that causes self-limiting diarrhea in healthy individuals, but poses a significant health threat to vulnerable populations. Our understanding of the pathogenesis of Salmonella-induced diarrhea has been hampered by the lack of a suitable mouse model. After a dose of oral kanamycin, Salmonella-infected congenic BALB/c.

Diarrhea and colitis in mice require the Salmonella pathogenicity island 2-encoded secretion function but not SifA or Spv effectors.

We investigated the roles of Salmonella pathogenicity island 2 (SPI-2) and two SPI-2 effectors in Salmonella colitis and diarrhea in genetically resistant BALB/c.D2(Slc11a1) congenic mice with the wild-type Nramp1 locus. Wild-type Salmonella enterica serovar Typhimurium 14028s caused a pan-colitis, and the infected mice developed frank diarrhea with a doubling of the fecal water content.

A model of Salmonella colitis with features of diarrhea in SLC11A1 wild-type mice.

Background: Mice do not get diarrhea when orally infected with S. enterica, but pre-treatment with oral aminoglycosides makes them susceptible to Salmonella colitis. However, genetically susceptible ItyS mice (Nramp1(G169D) allele) die from systemic infection before they develop diarrhea, so a new model is needed to study the pathogenesis of diarrhea.

Identification of Salmonella SPI-2 secretion system components required for SpvB-mediated cytotoxicity in macrophages and virulence in mice.

The Salmonella SpvB protein possesses ADP-ribosyl transferase activity. SpvB, acting as an intracellular toxin, covalently modifies monomeric actin, leading to loss of F-actin filaments in Salmonella-infected human macrophages. Using defined Salmonella mutants, different functional components of the SPI-2 type three secretion system (TTSS), ssaV, spiC, sseB, sseC, and sseD, were found to be required for SpvB-mediated actin depolymerization in human macrophages.

Vaccination with irradiated Listeria induces protective T cell immunity.

We evaluated gamma-irradiated Listeria monocytogenes as a killed bacterial vaccine, testing the hypothesis that irradiation preserves antigenic and adjuvant structures destroyed by traditional heat or chemical inactivation. Irradiated Listeria monocytogenes (LM), unlike heat-killed LM, efficiently activated dendritic cells via Toll-like receptors and induced protective T cell responses in mice. Like live LM, irradiated LM induced Toll-like-receptor-independent T cell priming.