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Roles for phagocytic cells and complement in controlling relapsing fever infection.

ABSTRACT: Relapsing fever spirochetes, such as Borrelia hermsii, proliferate to high levels in their hosts' bloodstream until production of IgM against borrelial surface proteins promotes bacterial clearance. The mechanisms by which B. hermsii survives in host blood, as well as the immune mediators that control this infection, remain largely unknown. It has been hypothesized that B. hermsii is naturally resistant to killing by the alternative pathway of complement activation as a result of its ability to bind factor H, a host complement regulator. However, we found that Cfh(-/-) mice were infected to levels identical to those seen in wild-type mice. Moreover, only a small minority of B. hermsii in the blood of wild-type mice had detectable levels of factor H adhered to their outer surfaces. In vitro, complement was found to play a statistically significant role in antibody-mediated inactivation of B. hermsii, although in vivo studies indicated that complement is not essential for host control of B. hermsii. Depletion of mphi and DC from mice had significant impacts on B. hermsii infection, and depleted mice were unable to control bloodstream infections, leading to death. Infection studies using muMT indicated a significant antibody-independent role for mphi and/or DC in host control of relapsing fever infection. Together, these findings indicate mphi and/or DC play a critical role in the production of B. hermsii-specific IgM and for antibody-independent control of spirochete levels.

SUBMITTER: Woodman ME

PROVIDER: S-EPMC6608040 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Roles for phagocytic cells and complement in controlling relapsing fever infection.

Woodman Michael E ME Cooley Anne E AE Avdiushko Rita R Bowman Amy A Botto Marina M Wooten R Mark RM van Rooijen Nico N Cohen Donald A DA Stevenson Brian B

Journal of leukocyte biology 20090520 3

Relapsing fever spirochetes, such as Borrelia hermsii, proliferate to high levels in their hosts' bloodstream until production of IgM against borrelial surface proteins promotes bacterial clearance. The mechanisms by which B. hermsii survives in host blood, as well as the immune mediators that control this infection, remain largely unknown. It has been hypothesized that B. hermsii is naturally resistant to killing by the alternative pathway of complement activation as a result of its ability to ...[more]

PMID: 19458267

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Project description:Microglia play important roles in shaping the developing CNS, and at early stages they have been proposed to regulate progenitor proliferation, differentiation, and neuronal survival. However, these studies reveal contradictory outcomes, highlighting the complexity of these cell-cell interactions. Here, we investigate microglia function during embryonic mouse retina development, where only microglia, progenitors, and neurons are present. In both sexes, we determine that microglia primarily interact with retinal neurons and find that depletion of microglia via conditional KO of the Csf1 receptor results in increased density of retinal ganglion cells (RGCs). Pharmacological inhibition of microglia also results in an increase in RGCs, with no effect on retinal progenitor proliferation, RGC genesis, or apoptosis. We show that microglia in the embryonic retina are enriched for phagocytic markers and observe engulfment of nonapoptotic Brn3-labeled RGCs. We investigate the molecular pathways that can mediate cell engulfment by microglia and find selective downregulation of complement pathway components with microglia inhibition, and further show that C1q protein marks a subset of RGCs in the embryonic retina. KO of complement receptor 3 (CR3; Itgam), which is only expressed by microglia, results in increased RGC density, similar to what we observed after depletion or inhibition of microglia. Thus, our data suggest that microglia regulate neuron elimination in the embryonic mouse retina by complement-mediated phagocytosis of non-apoptotic newborn RGCs.SIGNIFICANCE STATEMENT Microglia are emerging as active and important participants in regulating neuron number in development, during adult neurogenesis, and following stem cell therapies. However, their role in these contexts and the mechanisms involved are not fully defined. Using a well-characterized in vivo system, we provide evidence that microglia regulate neuronal elimination by complement-mediated engulfment of nonapoptotic neurons. This work provides a significant advancement of the field by defining in vivo molecular mechanisms for microglia-mediated cell elimination. Our data add to a growing body of evidence that microglia are essential for proper nervous system development. In addition, we elucidate microglia function in the developing retina, which may shed light on microglia involvement in the context of retinal injury and disease.

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Roles for phagocytic cells and complement in controlling relapsing fever infection.

Publications

Roles for phagocytic cells and complement in controlling relapsing fever infection.

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