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ABSTRACTWe investigated the roles of Salmonellapathogenicity island 2 (SPI-2) and two SPI-2 effectors in Salmonellacolitis and diarrhea in genetically resistant BALB/c.D2Slc11a1congenic mice with the wild-type Nramp1 locus. Wild-type Salmonella entericaserovar Typhimurium 14028s caused a pan-colitis, and the infected mice developed frank diarrhea with a doubling of the fecal water content. An ssaVmutant caused only a 26% increase in fecal water content, without producing the pathological changes of colitis, and it did not cause weight loss over a 1-week period of observation. However, two SPI-2 effector mutants, the spvBand sifAmutants, and a double spvB sifAmutant caused diarrhea and colitis, even though the sifAmutant was sensitive to killing by bone marrow-derived macrophages from BALB/c.D2 mice and was severely impaired in extraintestinal growth but not in growth in the cecum. These results demonstrate that systemic S. entericainfection and diarrhea/colitis are distinct pathogenic processes and that only the former requires spvBand sifA.

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 in vivo. To test that hypothesis, we intranasally infected interleukin-8R2 (IL-8R2) (Cxcr2)-deficient mice on a BALB/c background with Coccidioides immitisRS.

Coccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, Coccidioides immitisand C. posadasii, 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.

ABSTRACTRodents are a natural host for the dimorphic pathogenic fungi Coccidioides immitisand Coccidioides posadasii, 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 in vivois uncertain. Myeloid differentiation factor 88 (MyD88) is the adapter protein for TLR2 and -4, interleukin-1R1 (IL-1R1), and IL-18R1. MyD88/TRIF−/−and MyD88−/−mice were equally susceptible to C. immitisinfection, in contrast to C57BL/6 (B6) controls. Of the four surface receptors, only IL-1R1 was required for resistance to C. immitis, partially explaining the susceptibility of MyD88−/−mice. We also found that FKS stimulated production of IL-1Ra by bone marrow-derived dendritic cells (BMDCs), independent of MyD88 and Dectin-1. There also was a very high concentration of IL-1Ra in the lungs of infected B6 mice, supporting the potential importance of this regulatory IL-1 family protein in the largely ineffective response of B6 mice to coccidioidomycosis. These results suggest that IL-1R1 signaling is important for defense against C. immitisinfection.