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PIR-B-Deficient Mice Are Susceptible to Salmonella Infection¹

Ikuko Torii^2,*, Satoshi Oka^2,*, Muneki Hotomi, William H. Benjamin, Jr^*, Toshiyuki Takai, John F. Kearney, David E. Briles and Hiromi Kubagawa^3,*

^* Department of Pathology and Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294-3300, and Department of Experimental Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan

Paired Ig-like receptors of activating (PIR-A) and inhibitory (PIR-B) isoforms are expressed by many hematopoietic cells, including B lymphocytes and myeloid cells. To determine the functional roles of PIR-A and PIR-B in primary bacterial infection, PIR-B-deficient (PIR-B^–/–) and wild-type (WT) control mice were injected i.v. with an attenuated strain of Salmonella enterica Typhimurium (WB335). PIR-B^–/– mice were found to be more susceptible to Salmonella infection than WT mice, as evidenced by high mortality rate, high bacterial loads in the liver and spleen, and a failure to clear bacteria from the circulation. Although blood levels of major cytokines and Salmonella-specific Abs were mostly comparable in the two groups of mice, distinct patterns of inflammatory lesions were found in their livers at 7–14 days postinfection: diffuse spreading along the sinusoids in PIR-B^–/– mice vs nodular restricted localization in WT mice. PIR-B^–/– mice have more inflammatory cells in the liver but fewer B cells and CD8⁺ T cells in the spleen than WT mice at 14 days postinfection. PIR-B^–/– bone marrow-derived macrophages (BMM) failed to control intracellular replication of Salmonella in vitro, in part due to inefficient phagosomal oxidant production, when compared with WT BMM. PIR-B^–/– BMM also produced more nitrite and TNF- upon exposure to Salmonella than WT BMM did. These findings suggest that the disruption of PIR-A and PIR-B balance affects their regulatory roles in host defense to bacterial infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was in part supported by National Institutes of Health grants AI14782 (J.F.K.), AI21548 (D.E.B.), AI42127 (H.K.). I.T. was an overseas Research Scholar of the Ministry of Education, Culture, Sports, Science and Technology in Japan.

I.T. and M.H. initiated this study and developed the in vivo results (Figs. 1 and 2). Serological (Fig. 3) and histological analyses (Fig. 4) were performed by S.O. and I.T. and by I.T and H.K., respectively. S.O. performed the flow cytometric analysis (Fig. 5), the ex vivo studies (Fig. 6) and the statistical evaluation. T.T provided PIR-B^–/– mice. J.F.K. conducted the immunohistochemical analysis. W.H.B., D.E.B., and H.K. designed the research and H.K. wrote the paper.

² I.T. and S.O. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Hiromi Kubagawa, Department of Pathology, University of Alabama at Birmingham, SHEL Room 506, 1825 University Boulevard, Birmingham, AL 35294-2182. E-mail address: hiromikubagawa{at}uab.edu

⁴ Abbreviations used in this paper: PIR-A, paired Ig-like receptors of activating isoform; PIR-B, paired Ig-like receptor of inhibitory isoform; BMM, bone marrow-derived macrophages; BMPMN, bone marrow polymorphonuclear leukocytes; DC, dendritic cells; GVH, graft-versus host; WT, wild type; ITSM, immunoreceptor tyrosine-based switch motif; LILR, leukocyte Ig-like receptors; LSEC, liver sinusoidal endothelial cell; MFI, mean fluorescence intensity; MNC, mononuclear cells; M-CSF, macrophage CSF; MOI, multiplicity of infection; SCV, Salmonella-containing vacuoles; SHP, Src homology region 2 domain-containing phosphatase.

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