Research Article: Type I IFNs drive hematopoietic stem and progenitor cell collapse via impaired proliferation and increased RIPK1-dependent cell death during shock-like ehrlichial infection

Date Published: August 6, 2018

Publisher: Public Library of Science

Author(s): Julianne N. P. Smith, Yubin Zhang, Jing Jing Li, Amanda McCabe, Hui Jin Jo, Jackson Maloney, Katherine C. MacNamara, Matthew D Welch.

http://doi.org/10.1371/journal.ppat.1007234

Abstract

Type I interferons (IFNα/β) regulate diverse aspects of host defense, but their impact on hematopoietic stem and progenitor cells (HSC/HSPCs) during infection remains unclear. Hematologic impairment can occur in severe infections, thus we sought to investigate the impact of type I IFNs on hematopoiesis in a tick-borne infection with a virulent ehrlichial pathogen that causes shock-like disease. During infection, IFNα/β induced severe bone marrow (BM) loss, blunted infection-induced emergency myelopoiesis, and reduced phenotypic HSPCs and HSCs. In the absence of type I IFN signaling, BM and splenic hematopoiesis were increased, and HSCs derived from Ifnar1-deficient mice were functionally superior in competitive BM transplants. Type I IFNs impaired hematopoiesis during infection by both limiting HSC/HSPC proliferation and increasing HSPC death. Using mixed BM chimeras we determined that type I IFNs restricted proliferation indirectly, whereas HSPC death occurred via direct IFNαR -mediated signaling. IFNαR-dependent signals resulted in reduced caspase 8 expression and activity, and reduced cleavage of RIPK1 and RIPK3, relative to Ifnar1-deficient mice. RIPK1 antagonism with Necrostatin-1s rescued HSPC and HSC numbers during infection. Early antibiotic treatment is required for mouse survival, however antibiotic-treated survivors had severely reduced HSPCs and HSCs. Combination therapy with antibiotics and Necrostatin-1s improved HSPC and HSC numbers in surviving mice, compared to antibiotic treatment alone. We reveal two mechanisms whereby type I IFNs drive hematopoietic collapse during severe infection: direct sensitization of HSPCs to undergo cell death and enhanced HSC quiescence. Our studies reveal a strategy to ameliorate the type I IFN-dependent loss of HSCs and HSPCs during infection, which may be relevant to other infections wherein type I IFNs cause hematopoietic dysfunction.

Partial Text

Acute infection induces demand-adapted hematopoiesis, characterized by increased hematopoietic stem cell and progenitor cell (HSC and HSPC) proliferation, to support production and mobilization of immune cells or platelets [1–5]. Infection induced ‘emergency myelopoieisis’ results in increased production of effector myeloid cells that promote bacterial clearance [3, 6]. However, excessive proliferation of HSCs and HSPCs can lead to functional impairment and induce hematopoietic suppression [7–10],[11], though the precise mechanisms driving HSC/HSPC impairment have only recently been investigated [3, 12–15]. The Ehrlichiae are emerging tick-borne pathogens that cause an acute, febrile disease called human monocytic ehrlichiosis (HME) [16]. Ehrlichia are obligate, intracellular alpha-proteobacteria of the Anaplasmataceae family, and contain gram-negative cell wall structures but lack the genes that encode lipopolysaccharide and peptidoglycan [17, 18]. HME disease severity can vary greatly, and in some cases life-threatening complications include multi-organ failure similar to septic shock syndrome [19]. Ixodes ovatus ehrlichia (IOE) is a highly virulent strain that causes shock-like illness in mice [20, 21], and is therefore an ideal model to study fatal HME [22]. Vector borne diseases are increasing, and current vaccines are lacking [23], therefore, acute and chronic sequelae induced by tick-borne infections are clinically significant and represent a growing health care concern. HSCs are essential for lifelong hematopoiesis and supply all cells necessary for hemostasis, immunity, and oxygenation, thus delineating the mechanisms that impact HSC function during acute infection is important for our full understanding of infection-induced pathology.

Demand-adapted hematopoiesis is a dynamic process sculpted by cytokines, and can vary depending upon the duration and magnitude of stimulation and the presence of secondary stimuli [1, 4, 58]. IOE infection causes lethal, shock-like disease accompanied by cytopenias and immune dysfunction, similar to what is observed in patients with Rocky Mountain spotted fever and severe hemorrhagic viral infections. IOE is unusual for the ehrlichia because it infects endothelial cells [59], and it elicits shock-like infection driven by TNFα and type I IFNs [20, 28, 29]. We previously found that blocking type I IFN signaling in both the hematopoietic and non-hematopoietic system is necessary for protection against lethal infection [29], and herein we demonstrate a profound impact of type I IFNs on hematopoiesis and HSC and HSPC function. Hematopoiesis produces mature immune cells that can impact immunity and host defense [3, 60], thus the impact of infection and type I IFNs on HSPCs is directly relevant to recovery and survival in patients.

 

Source:

http://doi.org/10.1371/journal.ppat.1007234