Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance

Abstract

Acinetobacter baumannii is a nosocomial pathogen with a high prevalence of multiple-drug-resistant strains, causing pneumonia and sepsis. The current studies further develop a systemic mouse model of this infection and characterize selected innate immune responses to the organism. Five clinical isolates, with various degrees of antibiotic resistance, were assessed for virulence in two mouse strains, and between male and female mice, using intraperitoneal infection. A nearly 1,000-fold difference in virulence was found between bacterial strains, but no significant differences between sexes or mouse strains were observed. It was found that microbes disseminated rapidly from the peritoneal cavity to the lung and spleen, where they replicated. A persistent septic state was observed. The infection progressed rapidly, with mortality between 36 and 48 h. Depletion of neutrophils with antibody to Ly-6G decreased mean time to death and increased mortality. Interleukin-17 (IL-17) promotes the response of neutrophils by inducing production of the chemokine keratinocyte-derived chemoattractant (KC/CXCL1), the mouse homolog of human IL-8. Acinetobacter infection resulted in biphasic increases in both IL-17 and KC/CXCL1. Depletion of neither IL-17 nor KC/CXCL1, using specific antibodies, resulted in a difference in bacterial burdens in organs of infected mice at 10 h postinfection. Comparison of bacterial burdens between IL-17a؊/؊ and wild-type mice confirmed that the absence of this cytokine did not sensitize mice to Acinetobacter infection. These studies definitely demonstrate the importance of neutrophils in resistance to systemic Acinetobacter infection. However, neither IL-17 nor KC/CXCL1 alone is required for effective host defense to systemic infection with this organism.

Recent Advances in the Immunopathogenesis of Acinetobacter baumannii Infection

“…This is consistent with evidence that NOS2 may be predominantly restricted to the control of intracellular pathogens (72). Other factors suspected to play a role such as sex, IL-17A and the chemokine KC (CXCL1) were also ruled out (25). Still unresolved is the role of the lung macrophages and epithelial cells in the initial recognition of the pathogen and subsequent recruitment of neutrophils.…”

“…Knowledge of virulence factors can help both identify potentially dangerous pathogens before they strike and help develop new methods of control or treatments. Unfortunately, to date, aside from antibiotic-resistance genes, few virulence factors have been identified in A. baumannii (Table 1), despite wide variation in the ability of different laboratory strains and clinical isolates to cause disease in experimental models (25,26). In addition, although a number of host factors have been examined for their potential involvement in the control of A. baumannii, only a few have been shown to play a role in resistance to infection ( (28).…”

Severe Acinetobacter baumannii Sepsis Is Associated with Elevation of Pentraxin 3

“…Consequently, mortality rates range from 30 to 75% depending on the route of infection (8). Although specific virulence factors (lipopolysaccharide [LPS] and membrane glycosylation) and a robust cellular innate immune response (neutrophil infiltration) contribute to disease severity and clearance during A. baumannii sepsis, respectively, very little is known about differences in virulence or mortality between strains and the overall protective host immune response necessary for protection against A. baumannii infection (9)(10)(11)(12)(13)(14)(15).…”

Identification of Ata, a Multifunctional Trimeric Autotransporter of Acinetobacter baumannii

“…Ata promotes the survival of A. baumannii in vivo. We investigated the contribution of Ata to the virulence of A. baumannii in vivo by comparing the survival of wild-type A. baumannii ATCC 17978, ⌬ata, ⌬ata-pLVB-Ata (ata complemented in trans and expressed from its own promoter), and ⌬ata-pBAD18kan-Ori (complemented with the empty plasmid) strains in a lethal model of systemic infection based on that recently described by Breslow et al (4).…”

“…baumannii virulence studies. The role of Ata in A. baumannii virulence was investigated in a recently developed lethal model of systemic infection (4). In this model, wild-type A. baumannii ATCC 17978, ⌬ata, ⌬ata-pLVB-Ata, or ⌬ata-pBAD18kan-Ori were grown to an OD 650 of 0.025, washed once with PBS, and used to infect groups of immunocompetent mice (C57BL/6; female; n ϭ 8; 3 to 5 weeks of age) intraperitoneally (i.p.)…”