Insights into Acinetobacter baumannii protective immunity

Abstract

Acinetobacter baumannii is a nosocomic opportunistic Gram-negative bacteria known for its extensive drug-resistant phenotype. A. baumannii hospital-acquired infections are major contributors to increased costs and mortality observed during the COVID-19 pandemic. With few effective antimicrobials available for treatment of this pathogen, immune-based therapy becomes an attractive strategy to combat multi-drug resistant Acinetobacter infection. Immunotherapeutics is a field of growing interest with advances in vaccines and monoclonal antibodies providing insight into the protective immune response required to successfully combat this pathogen. This review focuses on current knowledge describing the adaptive immune response to A. baumannii, the importance of antibody-mediated protection, developments in cell-mediated protection, and their respective therapeutic application going forward. With A. baumannii's increasing resistance to most current antimicrobials, elucidating an effective host adaptive immune response is paramount in the guidance of future immunotherapeutic development.

Keywords: Acinetobacter baumannii; adaptive immunity; antibody-mediated protection; cell-mediated protection; immunotherapeutic; vaccine.

Figure 1

Overview of antibody-mediated protection against A. baumannii. Virulent strains appear to be resistant to direct bactericidal activity via membrane attack complex formation. A. baumannii-specific antibodies, however, still mark the pathogen for C3b deposition on its surface by activation of the classical complement pathway. C3a is released to increase phagocyte recruitment to the site of infection. In the absence of complement, antibodies continue to identify the bacterium for increased phagocytosis through antibody-Fc receptor interactions. Additionally, antibodies generated toward virulence factors required for pathogenesis, such as siderophores, can attenuate A. baumannii’s virulence.

Figure 2

Vaccine induced antibody generation. Schematic illustration of antibody generation from inactivated and live attenuated whole cell, outer membrane vesicle, and protein subunit vaccines towards A. baumannii. The proportion of IgG1 to IgG2c antibody production is utilized as a surrogate indicator of Th1 or Th2 mediated immunity.

Figure 3

Vaccine induced protective immunity. (A) In the absence of protective immunity, hypervirulent A. baumannii rapidly proliferates in the host leading to excess shedding of lipopolysaccharide (LPS) and rampant TLR4 activation. The abundance of pro-inflammatory cytokine secretion results in a cytokine storm and ultimately septic shock. (B) In the presence of protective immunity, antibodies mark the pathogen for phagocytic uptake by innate effector cells. A rapid reduction in bacterial burden maintains a balanced immune response.