Monoclonal Antibody Requires Immunomodulation for Efficacy Against Acinetobacter baumannii Infection

Abstract

Monoclonal antibodies (MAbs) are gaining significant momentum as novel therapeutics for infections caused by antibiotic-resistant bacteria. We evaluated the mechanism by which anti-bacterial MAb therapy protects against Acinetobacter baumannii infections. Anti-capsular MAb enhanced macrophage opsonophagocytosis and rescued mice from lethal infections by harnessing complement, macrophages, and neutrophils, yet the degree of bacterial burden did not correlate with survival. Furthermore, MAb therapy reduced pro-inflammatory (IL-1β, IL-6, TNFα) 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 TNFα production was suppressed directly (via anti-TNFα 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.

Insights into Acinetobacter baumannii protective immunity

“…monoclonal antibody showed that the antibody's efficacy was linked to complement activation, and administration of the mAb led to increased serum levels of C3a consistent with synergistic activation of the classical pathway. This conclusion was further supported by reduced efficacy of the mAb in C3 knockout mice, indicating complement C3 acts in tandem with the humoral immune response to clear A. baumannii (46). Collectively, these data suggest that complement is not essential for antibody-mediated immunity but improves the host's capability to clear A. baumannii via opsonization and phagocytosis.…”

Biomimetic Neutrophil Nanotoxoids Elicit Potent Immunity against Acinetobacter baumannii in Multiple Models of Infection

“…baumannii, dose-dependent bactericidal activity was observed (Figure S3). In contrast, such activity was not observed when using naïve serum or heat-inactivated serum, indicating that the effect could likely be attributed to complement activation. , Immunity against A. baumannii could also be established by intranasally administering Neu-NT (Figure c); the lower serum antibody titers compared with subcutaneous administration was likely due to the various mucosal barriers hindering delivery .…”

“…In contrast, such activity was not observed when using nai ̈ve serum or heat-inactivated serum, indicating that the effect could likely be attributed to complement activation. 34,35 Immunity against A. baumannii could also be established by intranasally administering Neu-NT (Figure 2c); the lower serum antibody titers compared with subcutaneous administration was likely due to the various mucosal barriers hindering delivery. 36 After confirming successful antibody titer generation, we sought to characterize the innate immune response elicited by Neu-NT in greater detail.…”

Review on Characteristics and Immune Response against the Proteobacterian Acinetobacter baumannii Bouvet & Grimont, 1986

“…Particularly, numerous isolates from patients with A. baumannii infections definite surface capsular polysaccharides and contain a preserved gene group, called the K locus, which may regulate invention of capsular polysaccharides (Murray et al, 2020). An accidental transposon screening to recognize genes important for development in an incendiary exudative liquid principal to the proof of identity of the ptk and epsA genes, which are foretold to be required for capsule polymerization and assemblage (Nielsen et al, 2021).…”

“…Three important classes of enzyme, such as phospholipase C (PLC), phospholipase A (PLA) and phospholipase D (PLD) have been definite established on the cleavage location. PLA hydrolyzes fatty acids from the glycerol (Nielsen et al, 2021), while PLC chops the phosphorylated head collection from the phospholipid. PLD is a transphosphatidylase that only cleaves off the head cluster.…”