Abstract
Bacterial infection of the lungs triggers a swift innate immune response that involves the production of cytokines and chemokines that promote recruitment of immune cells from the bone marrow (BM) into the infected tissue and limit the ability of the pathogen to replicate. Recent in vivo studies of pneumonic plague in animal models indicate that the pulmonary pro-inflammatory response to airway infection with Yersinia pestis is substantially delayed in comparison to other pathogens. Consequently, uncontrolled proliferation of the pathogen in the lungs is observed, followed by dissemination to internal organs and death. While the lack of an adequate early immune response in the lung is well described, the response of BM-derived cells is poorly understood. In this study, we show that intranasal (i.n.) infection of mice with a fully virulent Y. pestis strain is sensed early by the BM compartment, resulting in a reduction in CXCR4 levels on BM neutrophils and their subsequent release into the blood 12 hours (h) post infection. In addition, increased levels of BM-derived hematopoietic stem and progenitor cells (HSPC) were detected in the blood early after infection. Mobilization of both immature and mature cells was accompanied by the reduction of BM SDF-1 (CXCL-12) levels and the reciprocal elevation of SDF-1 in the blood 24 h post infection. RT-PCR analysis of RNA collected from total BM cells revealed an early induction of myeloid-associated genes, suggesting a prompt commitment to myeloid lineage differentiation. These findings indicate that lung infection by Y. pestis is sensed by BM cells early after infection, although bacterial colonization of the BM occurs at late disease stages, and point on a potential cross-talk between the lung and the BM at early stages of pneumonic plague.
Highlights
The respiratory system is continuously exposed to a variety of invading microorganisms
RT-PCR analysis of RNA collected from total bone marrow (BM) cells revealed an early induction of myeloid-associated genes, suggesting a prompt commitment to myeloid lineage differentiation. These findings indicate that lung infection by Y. pestis is sensed by BM cells early after infection, bacterial colonization of the BM occurs at late disease stages, and point on a potential cross-talk between the lung and the BM at early stages of pneumonic plague
As the major site of hematopoiesis, the BM has an important role in the early innate immune response and supplies a range of immune cells, neutrophils in particular, that are recruited quickly to inflamed tissues, limiting the expansion and dissemination of the pathogen
Summary
The respiratory system is continuously exposed to a variety of invading microorganisms. To limit the ability of pathogens to replicate in the lung, a swift innate immune response is induced following pulmonary infection. This response involves the production of cytokines and chemokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, IL-8, and interferons (IFNs), and the vigorous recruitment of immune cells from the bone marrow (BM) into the infected tissue (Lukacs et al, 1999; Nathan, 2002). Neutrophils as well as other hematopoietic cells may be rapidly mobilized from the BM, resulting in a dramatic rise in circulating cell numbers within hours after infection (Rogers and Unanue, 1993; Mantovani et al, 2011; Sadik et al, 2011). Early sensing of infection and rapid trafficking of neutrophils from the BM to sites of inflammation represent critical steps in the ability of the host to effectively clear the infection
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