Monoclonal Antibody Requires Immunomodulation for Efficacy Against Acinetobacter baumannii Infection. (24th May 2021)

• Record Type: Journal Article
• Authors: Nielsen, Travis B; Yan, Jun; Luna, Brian M; Talyansky, Yuli; Slarve, Matthew; Bonomo, Robert A; Spellberg, Brad
• Is Part Of: Journal of infectious diseases. Volume 224:Number 12(2021)
• Page Start: 2133
• Page End: 2147
• Publication Date: 2021-05-24
• Subjects: monoclonal antibody -- gram-negative bacterial infection -- Acinetobacter -- cytokines -- passive immunity -- innate immunity; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiab265
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract: Monoclonal antibodies (mAbs) are gaining significant momentum as novel therapeutics for infections caused by antibiotic-resistant bacteria. We evaluated the mechanism by which antibacterial mAb therapy protects against Acinetobacter baumannii infections. Anticapsular mAb enhanced macrophage opsonophagocytosis and rescued mice from lethal infections by harnessing complement, macrophages, and neutrophils; however, the degree of bacterial burden did not correlate with survival. Furthermore, mAb therapy reduced proinflammatory (interleukin-1β [IL-1β], IL-6, tumor necrosis factor-α [TNF-α]) and anti-inflammatory (IL-10) cytokines, which correlated inversely with survival. Although disrupting IL-10 abrogated the survival advantage conferred by the mAb, IL-10–knockout mice treated with mAb could still survive if TNF-α production was suppressed directly (via anti–TNF-α neutralizing antibody) or indirectly (via macrophage depletion). Thus, even for a mAb that enhances microbial clearance via opsonophagocytosis, clinical efficacy required modulation of pro- and anti-inflammatory cytokines. These findings may inform future mAb development targeting bacteria that trigger the sepsis cascade. Abstract : It has long been presumed that passive immunization clears bacterial infections by reducing bacterial burden through opsonophagocytosis. Here, we show that phagocyte cytokine modulation is the key mechanism by which an antibacterial monoclonal antibody resolves infections caused by Acinetobacter baumannii .