Phenotypic, Morphological, and Functional Heterogeneity of Splenic Immature Myeloid Cells in the Host Response to Tularemia

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Recent studies have linked accumulation of the Gr-1<jats:sup>+</jats:sup>CD11b<jats:sup>+</jats:sup>cell phenotype with functional immunosuppression in diverse pathological conditions, including bacterial and parasitic infections and cancer. Gr-1<jats:sup>+</jats:sup>CD11b<jats:sup>+</jats:sup>cells were the largest population of cells present in the spleens of mice infected with sublethal doses of the<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Francisella tularensis</jats:named-content>live vaccine strain (LVS). In contrast, the number of T cells present in the spleens of these mice did not increase during early infection. There was a significant delay in the kinetics of accumulation of Gr-1<jats:sup>+</jats:sup>CD11b<jats:sup>+</jats:sup>cells in the spleens of B-cell-deficient mice, indicating that B cells play a role in recruitment and maintenance of this population in the spleens of mice infected with<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">F. tularensis</jats:named-content>. The splenic Gr-1<jats:sup>+</jats:sup>CD11b<jats:sup>+</jats:sup>cells in tularemia were a heterogeneous population that could be further subdivided into monocytic (mononuclear) and granulocytic (polymorphonuclear) cells using the Ly6C and Ly6G markers and differentiated into antigen-presenting cells following<jats:italic>ex vivo</jats:italic>culture. Monocytic, CD11b<jats:sup>+</jats:sup>Ly6C<jats:sup>hi</jats:sup>Ly6G<jats:sup>−</jats:sup>cells but not granulocytic, CD11b<jats:sup>+</jats:sup>Ly6C<jats:sup>int</jats:sup>Ly6G<jats:sup>+</jats:sup>cells purified from the spleens of mice infected with<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">F. tularensis</jats:named-content>suppressed polyclonal T-cell proliferation via a nitric oxide-dependent pathway. Although the monocytic, CD11b<jats:sup>+</jats:sup>Ly6C<jats:sup>hi</jats:sup>Ly6G<jats:sup>−</jats:sup>cells were able to suppress the proliferation of T cells, the large presence of Gr-1<jats:sup>+</jats:sup>CD11b<jats:sup>+</jats:sup>cells in mice that survived<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">F. tularensis</jats:named-content>infection also suggests a potential role for these cells in the protective host response to tularemia.</jats:p>

Host-based lipid inflammation drives pathogenesis in Francisella infection

“…S3A). By 48 h.p.i., lipid A was also detected in the central area of white pulp nodules corresponding to a previous observation(36) that necrotic regions of the splenic white pulp contain replicating organisms late in infection. Bacterial burden counts in F. novicida-infected spleens showed 10 8 cfu/ spleen at 36 h.p.i., concurrent with detection of F. novicida lipid A (SI Appendix,Fig.…”

Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases

“…Since then, their regulatory role in additional hematopoietic cell types, including platelets and mast cells, has been described (22,23). As a wide range of leukocytes, including bone marrow-derived phagocytes and granulocytes, play a critical role during the initial primary immune response to F. tularensis (9,12,37), this study suggests the Sts proteins regulate immunological responses in a broader population of cells than previously appreciated. The enhanced restriction of F. tularensis in Sts Ϫ/Ϫ bone marrow-derived monocytes relative to wild-type bone marrow-derived monocytes following ex vivo infection supports this hypothesis.…”

CD11b+Ly6ChiLy6G−Immature Myeloid Cells Recruited in Response to Salmonella enterica Serovar Typhimurium Infection Exhibit Protective and Immunosuppressive Properties

“…ϩ Gr-1 ϩ cells with functional immunosuppression in the host response to infection (29,30,(32)(33)(34)(35)(36), and some have implicated NO production by these cells in the suppression of T cell function. Thus, a role for NO-producing immature myeloid cells in mediating immunosuppression may be a common feature of many types of infections, particularly persistent or chronic infections.…”