TABLE 2.

Summary of host defense elements determining outcomes of Acinetobacter infection

Model type and host defense factor(s) or process(es)	Model	Outcome(s)	Reference
In vitro models
Cytokines and pattern recognition receptors	LPS from A. baumannii clinical isolates exposed to human macrophages	High levels of IL-8 and TNF produced but only if TLR4 is functional, not through TLR2—however, whole killed A. baumannii induces cytokines via both TLR4 and TLR2	123
Cytokines	LPS from A. baumannii clinical isolates exposed to mouse splenocytes	High levels of TNF released, mitogen stimulation occurred	122
In vivo–nonlethal models
Neutrophils	Intranasal infection with A. baumannii ATCC 17961 in C57BL/6 or BALB/c mice with or without neutrophil depletion	Depletion of neutrophils substantially increased bacterial burden in the short term and enabled extrapulmonary dissemination, but inflammation remained mild, and the infection was cleared within several days with no deaths in any group	117
Neutrophils and macrophages	Intranasal infection with A. baumannii ATCC 17978 in Fus1 knockout or wild-type mice	The knockout mice displayed enhanced NF-κB activation, higher IL-17A production, lower IL-10 production, more rapid neutrophil and macrophage chemotaxis to the lung, and lower bacterial burden	121
Macrophages	Intranasal infection with A. baumannii ATCC 17961 of C57BL/6 mice treated with liposomal clodronate to deplete macrophages or with placebo	In healthy mice, macrophages are the predominant cells present in the lung through the first 4 h and rapidly take up bacteria. Depletion of macrophages results in substantial increase in bacterial density, but not mortality, as inflammatory cytokine levels are lower (despite higher bacterial density) in depleted mice.	120
Zinc and manganese sequestration	Mice with calprotectin disrupted or wild-type mice infected intranasally with ATCC 17978	Mice with calprotectin disrupted had higher bacterial burden in the lung	317
Pattern recognition receptors and host defense	Intranasal infection with a clinical isolate of A. baumannii RUH 2037 in C57BL/6 mice or congenic CD14, TLR4, or TLR2 knockouts	CD14 and TLR4 knockout mice had higher bacterial density at 4 h and had lower neutrophil influx. At 24 h only, the TLR4 knockout mice had higher bacterial density, but they had cytokine levels similar to those of wild-type mice, and they did not die of infection. TLR2 knockout mice had earlier cellular influx, but their cytokine levels and bacterial density were similar to those of the wild-type mice.	124
Pattern recognition receptors and host defense	Intranasal infection with A. baumannii ATCC 17978 in C57BL/6 mice or isogenic TLR9 knockout mice	TLR9 knockout mice had higher bacterial burden, attenuated cytokine production, and more severe lung pathology, with no mouse deaths	129
In vivo–lethal models
Iron sequestration	Treatment with transferrin or placebo in C3H/FeJ mice lethally infected intravenously with hypervirulent A. baumannii HUMC1	Mice treated with transferrin had lower blood and tissue bacterial burden and marked improvement in survival	72
Neutrophils	Intraperitoneal infection with clinical isolates of A. baumannii in C57BL/6 and C3HeB/Fe mice	Antibody depletion of neutrophils but not abrogation of IL-17A or KC (keratinocyte-derived chemokine) increased lethality and bacterial burden of infection	118
Neutrophils	Intranasal infection with A. baumannii ATCC 17961 in A/J or C57BL/6 mice	A/J mice experienced delayed neutrophil influx into the lungs, resulting in early rapid microbial replication, and later severe inflammation and death, whereas C57BL/6 mice cleared the infection	54
Superoxide production	Intranasal infection of C57BL/6 mice or congenic gp91phox−/− mice or nitric oxide synthase-deficient mice with A. baumannii ATCC 17961	Gp91phox−/− mice had normal neutrophil and macrophage recruitment to the lung by 4 h, but 1,000-fold-higher bacterial density, which resulted in marked increase in inflammatory cell influx into the lung by 24 h and death by 48 h. The nitric oxide-deficient mice had relatively normal phenotype and did not die.	119
Avoidance of innate effector uptake	C3HeB/Fe mice were infected i.v. via the tail vein with >40 clinical isolates of A. baumannii, and then the experiments were repeated with selected strains depleted of combinations of complement, neutrophils, or macrophages in a fatal model of infection	Clinical strains clustered into one of 3 groups: hypervirulent (HUMC1 and LAC-4), virulent (almost all others, including 5075), and avirulent (ATCC 17978 and R2). The differences in virulence (and hence fate of the animal) were definable within 1 h postinfection depending on ability to persist in the blood. Depletion of any of the three components increased bacterial density of the avirulent strain but nonlethally. Double depletion increased bacterial density further but nonlethally, and triple depletion converted the avirulent strain into a hypervirulent strain inducing rapid lethality, while depletion of any individual component had marginal impact on the hypervirulent strain.	70
LPS-TLR4 governance of outcome	C3HeB/FeJ and C3H/HeJ (TLR4 mutant) mice treated with LpxC inhibitor (blocks LPS production) and C57BL/6 or congenic TLR4 knockout mice, infected i.v. via the tail vein with hypervirulent A. baumannii HUMC1 or avirulent ATCC 17978	TLR4 mutant and knockout mice had dramatically lower inflammatory cytokine levels, sepsis biomarkers, and 100% survival compared to 100% fatality in the wild-type mice, despite having similar bacterial densities (dissociation of bacterial density from outcome). LpxC inhibition also blocked cytokine levels and protected mice from lethal infection and modestly lowered CFU likely by enhancing macrophage uptake of the bacteria.	69
Morphine	C57BL/6 and C3HeB/Fe mice with intraperitoneal infection of A. baumannii clinical isolates, treated with morphine or not treated with morphine (control)	Morphine treatment resulted in fatal subcutaneous infection, whereas no control mice died and naltrexone (opiate antagonist) reversed the effect. Morphine did not affect bacterial growth in vitro but increased bacterial density and inflammatory cytokine output in vivo and suppressed phagocyte recruitment to the site of infection.	130